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Application of organic carbamates in drug design. Part 1: Anticancer agents - Recent reports
Abstract
Organic carbamates can be used as anticancer, antimicrobial and antimalarial agents, as well as in CNS/CVS disorders and many other areas, either in the form of drugs per se or as prodrugs. As anticancer agents, carbamate chemistry has mainly been used to develop prodrugs. Different mechanism-based approaches have been developed for preparing cytotoxic site-directed drugs of natural as well as synthetic origin. In the preparation of prodrugs, the free phenolic group, generally responsible for causing cytotoxicity in anticancer drugs, is masked in the form of a carbamate ester. The molecule is designed so that the release of the active drug takes place only at the tumor site. Thus, normal cells escape exposure to toxicity causing side effects. Various approaches have been adopted wherein the molecular transformation caused by biochemicals/enzymes at the tumor site releases the active drug: The present review is limited to the use of carbamates as anticancer agents and covers only reports from 1990 onwards. Both natural and synthetic products having a carbamate residue and their potential anticancer activity are discussed, as well as the chemistry behind the mechanism of release of the active component from the prodrugs.
... Two carbamate drugs, mitomycin C and docetaxel, have so far been approved for the treatment of various types of tumours ( Figure 1). Both can be used alone or in combination to other antitumor drugs (48)(49)(50). Their antitumor activity stems from their ability to selectively inhibit the synthesis of DNA in a tumour cell or to inhibit the tubulin polymerisation, both resulting in the arrest of mitotic phase of cell division (48). Mitomycin C is a miscellaneous antibiotic that selectively inhibits DNA synthesis in a tumour cell and is indicated for chemotherapy of gastrointestinal, anal, and breast cancers (49). ...
... Both can be used alone or in combination to other antitumor drugs (48)(49)(50). Their antitumor activity stems from their ability to selectively inhibit the synthesis of DNA in a tumour cell or to inhibit the tubulin polymerisation, both resulting in the arrest of mitotic phase of cell division (48). Mitomycin C is a miscellaneous antibiotic that selectively inhibits DNA synthesis in a tumour cell and is indicated for chemotherapy of gastrointestinal, anal, and breast cancers (49). ...
Due to their very good chemical and proteolytic stability, ability to penetrate cell membranes, and resemblance to a peptide bond, carbamate derivatives have received much attention in recent years and got an important role in modern drug discovery and medicinal chemistry. Today, carbamates make structural and/or functional part of many drugs and prodrugs approved and marketed for the treatment of various diseases such as cancer, epilepsy, hepatitis C, HIV infection, and Alzheimer’s disease. In drugs they can play a role in drug-target interaction or improve the biological activity of parent molecules. In prodrugs they are mainly used to delay first-pass metabolism and enhance the bioavailability and effectiveness of compounds. This brief review takes a look at the properties and use of carbamates in various fields of medicine and provides quick insights into the mechanisms of action for some of them.
... Carbamates are used as a peptide bond surrogate in medicinal chemistry because of its chemical stability and capability to permeate cell membrane. Substitution of -O and -N termini of carbamates offer many opportunities for the modulation of biological properties and pharmacokinetic properties due to its participation in hydrogen bonding through carboxyl group and the back bone NH. [14] Carbamates and their derivatives are widely used as agrochemicals, [12] prodrugs, [15,16] as an intermediates in organic synthesis, [17][18][19][20] in peptide syntheses. [21,22] Some of the examples of the sulfonamide and carbamate drugs possessing various activities are shown in Figure 1. ...
... In overall, the results regarding the biological aspects concerning to the synthesized compounds revealed that the title compounds would stand as the promising antioxidant and antimicrobial drugs in future when compared to the native sulfonamide/carbamate derivatives. [15,16] ...
A series of new bis sulfonamide/carbamate derivatives of bis‐(4‐aminophenyl)methane 3(a–d)/5(a–f) were synthesized from bis‐(4‐aminophenyl)methane (1) using various pharmacologically active sulfonyl chlorides 2(a–d) and carbonochloridates 4(a–f) in high yields. The structures of all the newly synthesized compounds were characterized by the Infrared spectroscopy, NMR (1H and 13C), mass, and elemental analyses. Further, all the synthesized compounds were tested for the antioxidant activity by using 2, 2‐diphenyl‐1‐picrylhydrazyl, NO, and H2O2 scavenging methods and antimicrobial activity. Most of the compounds exhibited good antioxidant and antimicrobial activities.
... The plausible mechanism of zinc chloride-mediated carbamate formation is depicted in Figure 2. Initially, the zinc chloride coordinates with 2 moles of carbamoyl chloride to form a complex (1), followed by the participation of a lone pair of nitrogen to produce an in situ isocyanate intermediate (2) and as a byproduct that released 2 mol of Cl − and ZnCl 2 which is further used in the cycle. Furthermore, the intermolecular nucleophilic addition of alcohol to the reactive isocyanate (2) intermediate resulted in the formation of the unstable intermediate (3). Finally, Cl − abstracts the proton from the obtained intermediate (3) to generate the carbamate motif (4) and liberate HCl as a by-product. ...
Herein, we report a synthetic protocol for the synthesis of carbamates by employing zinc chloride as a catalyst from carbamoyl chlorides and aromatic/aliphatic alcohols. The developed protocol successfully utilizes the gram-scale synthesis of the FDA-approved rivastigmine drug and its derivative. The utility of zinc chloride over other catalysts such as zinc dust and zinc acetate exhibits a 49-87% yield of carbamates.
... Organic carbamates are structural motifs of many approved pharmaceutical drugs [22,23], such as Encorafenib (approved in 2018), Cobicistat (approved in 2013), Irinotecan (approved in 1994), etc (Fig. 2). Structurally, partly owing to the amide-ester hybrid nature, the carbamate functional group displays good chemical and proteolytic stabilities [24]. ...
A novel series of silibinin and 2,3-dehydrosilybin derivatives bearing carbamate groups were designed, synthesized and their in vitro anticancer activities were screened against human cancer cell lines including MCF-7, NCI-H1299, HepG2 and HT29 by CCK-8 assay. The results showed that most of the compounds significantly suppressed the proliferation of tested cancer cells. Among them, compounds 2h, 3h and 3f demonstrated markedly higher antiproliferative activity on MCF-7 cells with IC50 values of 2.08, 5.54 and 6.84 µM, respectively. Compounds 3e, 3g and 2g displayed better cytotoxic activity against NCI-H1299 cells with IC50 values of 8.07, 8.45 and 9.09 µM, respectively. Compounds 3g, 3c and 3h exhibited a promising inhibitory effect against HepG2 cells with IC50 values of 8.88, 9.47 and 9.99 µM, respectively. Compounds 3e, 2e and 3c revealed effective biological potency on HT29 cells with IC50 values of 6.27, 9.13 and 9.32 µM, respectively. In addition, the outcomes of the docking studies between compounds 2f, 2h, 3e, 3g and Hsp90 receptor (PDB ID: 4AWO) suggest the possible mechanism of inhibition against MCF-7 cell lines.
Graphical abstract
... In recent years, several workers from the different part of the world have incorporated carbamates in between the active pharmacophores of structurally diverse natural products and realized that carbamates play a crucial role in increasing the biological activity of these molecules. We have found that several carbamates derivatives of natural products have emerged as potent anticancer drugs and prodrugs [6,7] . Carbamate bearing potent molecules will be discussed in this article. ...
Organic carbamates are the stable class of compounds derived from the unstable carbamic acid having O-CO-NH- linkage
[1,2] with unique applications in the field of pharmaceuticals, agrochemicals (pesticides, herbicides, insecticides, fungicides etc.),
intermediates in organic synthesis, in the forms of drugs and prodrugs, for the protection of amino groups in peptide chemistry,
as a useful synthons, as linkers in combinatorial chemistry and also have interesting medicinal and biological properties [3]. In
recent years, several reports have indicated that carbamate linkage present in between the active pharmacophores of various
structurally diverse molecules increases manifold biological activities of semisynthetic/synthetic natural/synthetic moleculesand
proved to be a boon against various disease such as anti-cancer, anti-bacterial, anti-fungal, anti-malarial, anti-viral, anti-HIV, anti�estrogenic, anti-progestational, anti-osteoporosis, antinflammatory, anti-filarial, anti-tubercular, anti-diabetic, anti-obesity, anti�convulsant, anti-helminthes, Alzheimer disease, CNS and CVS active etc.
... In recent years, several reports have indicated that by incorporating dithiocarbamate linkage in between the active pharmacophores of various structurally diverse molecules increases manifold biological activities of semisynthetic/ synthetic natural/synthetic molecules and proved to be a boon against various disease such as anti-cancer, anti-bacterial, antifungal, anti-malarial, anti-viral, anti-HIV, anti-estrogenic, anti-progestational, anti-osteoporosis, antinflammatory, anti-filarial, anti-tubercular, anti-diabetic, anti-obesity, anti-convulsant, anti-helminthes, anti-alzheimer, CNS and CVS active etc. [4,5] . Keeping in view the importance of dithiocarbamates, our group has been working since more than a decade upon the synthesis and evaluations of these compounds [6][7][8] . ...
Organic dithiocarbamates are the stable class of compounds derived from the unstable dithiocarbamic acid (NH2CSSH)
having S-CS-NH- linkage [1,2], which holds unique applications in the field of pharmaceuticals, agrochemicals(pesticides, herbicides,
insecticides, fungicides, etc.), intermediates in organic synthesis, in the forms of drugs and prodrugs, for the protection of amino
groups in peptide chemistry, as a useful synthons, as linkers in combinatorial chemistry and also have interesting medicinal and
biological properties [3].
... It should also be recalled that carbamates and urea are not only possible intermediates in the production of isocyanate, but are important chemicals themselves. Carbamates are final products and synthetic intermediates for the pharmaceutical [17,18] and agrochemical industries [19] and ureas have a variety of applica- tion [20], from traditional ones such as fertilizers [21] and pesti- cides [22] to more recent and sophisticated ones such as receptors for anion recognition [23], biosensors [24] and pharma- ceutically active agents [25,26]. Thus, the interest in the synthesis of carbamates and ureas goes well beyond their use as intermedi- ates for isocyanate production. ...
The palladium/iodide couple is the most investigated catalytic system for the oxidative carbonylation of amines to give ureas or carbamates. In reinvestigating it, we found that the most prominent role of iodide is to etch the stainless steel of the autoclave employed in most of previous works, releasing in solution small amounts of iron salts. The latter are much better promoters than iodide itself. Iron and iodide have a complex interplay and, depending on relative ratios, can even deactivate each other. The presence of a halide is beneficial, but chloride is better than iodide in this respect. The ideal Fe/Pd ratio is around 10, but even an equimolar amount of iron with respect to palladium (0.02 mol% with respect to aniline, corresponding to 12 ppm Fe with respect to the whole solution) is sufficient to boost the activity of the catalytic system. Such small amount may also come from Fe(CO) 5 impurities present in the CO gas when stored in steel tanks. The role of the solvent has also been investigated. It was found that the reason for the better selectivity in some cases is at least in part due to a hydrolysis of the solvent itself, which removes the coproduced water.
... These are widely used in agrochemicals [32], pharmaceuticals and as an intermediate [33][34][35][36] in organic synthesis. Organic carbamates have been employed as pharmaceutical drugs and prodrugs [37,38]. The synthesized molecules were screened for evaluation of biological activities such as antimicrobial, antioxidant and molecular docking studies with aromatase enzyme. ...
A series of new urea/thiourea derivatives 3a–j were synthesized by simple addition reaction of functionalized phenyl isocyanates/isothiocyanates 2a–j with N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (imatinib intermediate) (1) in the presence of 1,4-dimethyl piperazine (DMPZ) as a base, and another series of new sulfonamide/carbamate derivatives 5a–k were synthesized by reacting 1 with various substituted aromatic sulfonyl chlorides 4a–f and aromatic/aliphatic chloroformates 4g–k in the presence of DMPZ as a base. The title compounds 3a–j and 5a–k were characterized by IR, ¹H, ¹³C NMR and mass spectral data. Antimicrobial, antioxidant and in silico molecular docking studies were made against aromatase.
Graphical abstract
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... The carbamate group is a key structural motif in many approved drugs and prodrugs 20 . There is increasing use of carbamates in medicinal chemistry, and many derivatives are specifically designed to make drug target interactions through their carbamate moiety 21,22 . The carbamates emerging role in medicinal chemistry is also due to its chemical stability and its capability to increase permeability across cellular membranes. ...
p class="MsoNormal" style="margin-bottom: .0001pt; text-align: justify; line-height: normal; tab-stops: 0cm;"> In this study the novel hybrids sulfonamide carbamates were synthesized by treatment of N -substituted 4-isothiocyanatophenyl sulfonamides with ethyl carbamate in dry 1 4-dioxane at reflux temperature in the presence of triethylamine. Also treatment of Phenylacetylisothiocyanate with sulfanilamide in refluxing acetonitrile afforded the corresponding hybrid sulfonamide acylthiourea derivatives. The anti-microbial activities of the synthesized compounds were evaluated. Ethyl ({4-[(5-methyl-1 2-oxazol-3-yl)sulfamoyl)-phenyl]carbamothioyl)-carbamate and 2-Phenyl-N-((4-(N-thiazol-2-yl)sulfamoyl)-phenyl)carbamothioyl)acetamide exhibited the best activity against tested bacteria. Molecular docking studies for the final compounds were performed using the Open Eye docking suite. Moreover Ligand efficiency (LE) and lipophilic ligand efficiency (LLE) parameters for Ethyl({4-[(5-methyl-1 2-oxazol-3-yl)sulfamoyl)phenyl]carbamothioyl)-carbamate and 2-Phenyl-N-((4-(N-thiazol-2-yl)sulfamoyl)phenyl)-carbamothioyl)acetamide were evaluated. Quantum chemical calculations based on density functional theory (DFT) have been performed.
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... Organic carbamates have been presenting extensive utility in many areas of organic synthesis as pharmaceuticals intermediates, for the protection of amino groups in peptide chemistry and linkers in combinatorial chemistry (Yu and Huiyuan 2002;Ray and Chaturvedi 2004;Ray et al. 2005). In addition, carbamates may be converted to isocyanates, which are starting materials for polyurethanes production (Rios et al. 2013). ...
Effects of structure and reactivity of renewable origin alcohols in the conversion and selectivity of the SnCl2-catalyzed reactions in the presence and absence of urea were assessed. Convenient simple and suitable method for the synthesis of carbamates from renewable origin alcohols and urea in one-step are provided. We have assessed the activity of SnCl2 catalyst, a commercially affordable Lewis acid, in reactions of urea alcoholysis with different natural origin alcohols (geranyl, neryl, bornyl, cinnamyl, α-terpinyl and benzyl alcohols), aiming to synthesize carbamates, which are biologically active compounds, building blocks in organic synthesis and raw material to synthesize polyurethanes. The low cost of urea, the water tolerant catalyst and phosgene free reaction are positive aspects of this carbamates synthesis process. The different reaction pathways were assessed. A mechanism was proposed based on FT-IR experiments and experimental data.
... N-acyl carbamates are typical examples of such compounds that undergo a rapid development as pesticides [5,6] and pharmaceuticals [7] due to their biological activity [8]. Several carbamates have been synthesized as anticancer agents recognizing their inhibiting effects for some carbamates on endothelial cell proliferation in vitro and tumor induced angiogenesis in vivo as well as tumor growth in mice [9]. ...
A carbamate compound having tricarbonyl groups, methyl-2-(4-methoxybenzoyl)-3-(4-methoxyphenyl)-3-oxopropanoylcarbamate (BPOC) was investigated from theoretical and vibrational spectroscopic point of view employing quantum chemical methods. Hybrid Density Functionals (B3LYP, X3LYP and B3PW91) with 6-311 G(d,p) basis set were used for the calculations. Rotational barrier and conformational analyses were performed to find the most stable conformers of keto and enol forms of the molecule. Three transition states for keto-enol tautomerism in gas phase were determined. The results of the calculations show that enol-1 form of BPOC is more stable than keto and enol-2 forms. Hydrogen bonding investigation including Natural bond orbital analysis (NBO) for all the tautomeric structures was employed to compare intra-molecular interactions. The energies of HOMO and LUMO molecular orbitals for all tautomeric forms of BPOC were predicted. Normal Coordinate Analysis (NCA) was carried out for the enol-1 to assign vibrational bands of IR and Raman spectra. The scaling factors were calculated as 0.9721, 0.9697 and 0.9685 for B3LYP, X3LYP and B3PW91 methods, respectively. The correlation graphs of experimental versus calculated vibrational wavenumbers were plotted and X3LYP method gave better frequency agreement than the others.
... Carbamates are important final products and synthetic intermediates for the pharmaceutical [7,8] and agrochemical industries [9]. In addition they can be thermally [10e13] or catalytically [12] cracked to give isocyanates (Eq. ...
We previously reported an enhancement in the catalytic activity of a palladium-phenanthroline system towards the carbonylation of nitroarenes to N-methyl arylcarbamates when non-symmetric phenanthrolines were used as ligands. In particular, best results were obtained when an electron donating group was present on just one of the pyridinic rings of the ligand. Here we report the effect of stronger donor groups on the catalytic activity and on the selectivity of the system, even in the presence of different phosphorus acids used as promoters. High catalytic activities were reached but the high basicity of the ligands can negatively affect the product selectivity. The presence of steric hindrance near one or both the nitrogen donor atoms was shown to be detrimental for the activity of the system both with phenanthroline ligands and a quinoline–guanidine hybrid ligand.
... Carbamates have been utilized in anticancer, 67 antimicrobial, 68 and antimalarial 69 agents and to aid in the treatment of central nervous system and cardiovascular system disorders. 70 However, carbamatecontaining insecticides have also been linked to numerous health hazards. 71 Carbamate insecticides reversibly inhibit acetylcholinesterase by carbamylation. ...
The inhibition of plasminogen activator inhibitor-1 (PAI-1) is anticipated to increase our understanding of various human ailments with which high levels of PAI-1 have been associated, including diabetes, stroke, and atherosclerosis. Previous accounts have reported the synthesis of inhibitors that bind to PAI-1 with a low affinity, inhibit the serpin plasma protein antithrombin III, and/or fail to inhibit PAI-1 when vitronectin, a cofactor of PAI-1 is present. The synthesis of small-molecule inhibitors of PAI-1 that improve upon these properties has been the main goal of this research. Research efforts focused on examining changes in inhibitor potency based on the manipulation of the inhibitors’ architecture, with particular attention paid to the number and positioning of multiple polyphenolic groups. The refinement of these synthesized moieties into selective and highly active species has been achieved.
We describe the facile hydrothermal synthesis of a sponge-like 2D layered triazine based covalent organic framework (COF) structure. The substance comprises of 18.49 nm nanoparticles and well-organized mesopores across its 2D layers. This highly ordered π-conjugated metal-free COF structure possesses 1.86 eV band gap energy and performs as a potential
photocatalyst to form formic acid as well as methanol via CO2 (1 atm) reduction under visible light irradiation. The effect of different parameters like solvent type, sacrificial electron donor, time, light intensity, etc. was studied for the production of formic acid as well as methanol. Sunlight irradiation also showed a promising production rate for formic acid and methanol. The synthesized COF material is available to reuse for manifold reaction cycles
with its catalytic efficiency without affecting its structural and morphological
features.
Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are the primary catabolic enzymes for endocannabinoids, anandamide (AEA), and 2-arachidonoyl glycerol. Numerous studies have shown that FAAH and MAGL play an important role in modulating various central nervous system activities; hence, the development of small molecule FAAH/MAGL inhibitors is an active area of research. Several small molecules possessing the carbamate scaffold are documented as potential FAAH/MAGL inhibitors. Here, we designed and synthesized a series of open chain and cyclic carbamates and evaluated their dual FAAH-MAGL inhibition properties. Phenyl [4-(piperidin-1-ylmethyl)phenyl]carbamate (2e) emerged as the most potent MAGL inhibitor (IC50 = 19 nM), benzyl (1H-benzo[d]imidazol-2-yl)carbamate (3h) was the most potent FAAH inhibitor (IC50 = 55 nM), and phenyl (6-fluorobenzo[d]thiazol-2-yl)carbamate (2i) egressed as a nonselective dual FAAH-MAGL inhibitor (FAAH: 82 nM, MAGL: 72 nM). The enzyme kinetics experiments revealed that the compounds inhibit FAAH/MAGL in a covalent-reversible manner, with a mixed binding mode of action. Moreover, the lead compounds were found suitable for blood-brain permeation in the parallel artificial membrane permeation assay. Furthermore, docking simulation experiments suggested that the potency of the lead compounds was governed by hydrogen bonds and hydrophobic interactions with the enzyme active sites. In silico drug-likeness and ADMETox prediction studies provided useful information on the compounds' oral absorption, metabolism, and toxicity profiles. In summary, this study afforded potent multifunctional carbamates with appreciable pharmacokinetic profiles meriting further investigation.
A one-pot synthesis of new variously substituted γ-chloro-γ,β-allylic carbamates have been carried out starting from β-chloro-α,β-unsaturated aldehydes. The new carbamates and the corresponding intermediates, the γ-chloro-γ,β-allylic alcohols, were fully characterized by (¹H and ¹³C) NMR, IR and HRMS spectroscopic techniques. The crystal structures of two allylic carbamates, were established by single-crystal X-ray diffraction.
A new and unique indolo[1,2-a]quinoxaline framework has been explored for the identification of potential cytotoxic agents. Thus a series of targeted indolo[1,2-a]quinoxaline derivatives were prepared via an ultrasound assisted MCR of N‐(2‐aminophenyl)indole, isatin and an appropriate alcohol using Amberlyst-15 as a catalyst. The MCR does not require the use of any additional solvent and proceeded under mild conditions to give the desired products in good yields. The presence of air in addition to ultrasound and Amberlyst-15 was necessary for the success of the MCR. All the indolo[1,2-a]quinoxaline derivatives obtained were assessed for their cytotoxic properties against three cancerous (leukemia and breast) and a non-cancerous cell lines. Compounds 4c, 4l and 4n showed significant growth inhibition of these cell lines except the non-cancerous one and inhibition of SIRT1 in vitro. Compound 4c showed good interactions with SIRT 1 in silico.
A new nano-scale Cu@salicylaldehyde-modified-chitosan (Cu@Sal-CS) was synthesized through a green, eco-friendly and cost-effective technique. The prepared catalyst was characterized using Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), Energy-dispersive X-ray spectroscopy (EDXS), and inductively coupled plasma (ICP) analysis. The synthesized Cu@Sal-CS catalyst indicated its performance in the C–O and C–N oxidative coupling using the reaction of 1,3-dicarbonyl derivatives/2- substituted phenols with amides for the preparation of carbamates, as well as in the reaction of aldehydes and various amines in the synthesis of amides. The significant features of this work are operational simplicity of catalyst synthesis, in situ and new modification method, use of an efficient, recoverable, frequently reused and stable catalyst without any loss of catalytic activity, and high yields of the products in short times.
Now-a-days carbon dioxide fixation has received much more attention for its imminent application as an abundant C1 source and a range of important fine chemicals which can be manufactured via this fixation. Here copper nanoparticles integrated triazinetriamine derived porous organic polymer-based (Cu-NPs@TzTa-POP) material was produced by a simple in-situ process. The catalyst was characterized by a variety of instrumental methods like UV-Vis spectra, FTIR spectra, HR-TEM, PXRD, N2 adsorption-desorption, TG-DTA, XPS, AAS analysis, etc. The synthesized heterogeneous catalyst was very energetic in atmospheric carbon dioxide fixation reaction to produce N-methylated products from aromatic/ heterocyclic amines in the existence of polymethyl-hydrosiloxane (PMHS) as reducing agent at 80°C within 12 h of reaction. Through this catalytic N-methylation reaction, we got up to 98% yield of the product with turnover frequency from 18 to 42 h-1. Besides, the catalyst is also very stable for the formation of primary carbamates from alcohols using eco-friendly carbonylating agent urea. A diverse type of alcohols (such as benzylic alcohols, phenols, heterocyclic alcohols as well as aliphatic alcohols) showed very much acceptance to this catalytic reaction and produced moderate to an excellent yield of respective carbamate products under ambient reaction conditions. Moreover, Cu-NPs@TzTa-POP is effortlessly recyclable and reusable without extensive loss of active copper metal centre for many catalytic rounds (up to six catalytic rounds were examined).
A series of tosyl carbamates have been synthesized and screened for their antibacterial and antifungal activities. All the synthesized compounds were characterized by spectral techniques (IR, 1H, 13C NMR and mass) and elemental analysis. in silico Molecular docking method was performed to study their antimicrobial activity against the target protein 1T9U. Compound 27 showed good antibacterial activity against Gram-positive and Gram-negative bacterial strains and compound 19 showed good antifungal activity. Molecular docking results revealed that the compound 19 exhibits minimum CDOCKER energy. Tosyl carbamate derivatives having good antimicrobial activities compared to that standard and all the synthesized compounds exhibits moderate CDOCKER scores.
Two series of 6-(1,2,3-triazolyl)-2,3-dibenzyl-l-ascorbic acid derivatives with the hydroxyethylene (8a-8u) and ethylidene linkers (10c-10p) were synthesized and evaluated for their antiproliferative activity against seven malignant tumor cell lines and antiviral activity against a broad range of viruses. Conformationally unrestricted spacer between the lactone and 1,2,3-triazole units in 8a-8u series had a profound effect on antitumor activity. Besides, the introduction of a long side chain at C-4 of 1,2,3-triazole that led to the synthesis of decyl-substituted 2,3-dibenzyl-l-ascorbic acid 8m accounted for a selective and potent antiproliferative activity on breast cancer MCF-7 cells cells in the nM range. Further analysis showed that compound 8m strongly enhanced expression of hypoxia inducible transcription factor 1 α (HIF-1α) and to some extent decreased expression of nitric oxide synthase 2 (NOS2) suggesting its role in regulating HIF-1α signalling pathway. The p-methoxyphenyl-substituted derivative 10g displayed specific anti-cytomegalovirus (CMV) potential, whereas aliphatic-substituted derivatives 8l and 8m had the most potent, yet relatively non-specific, anti-varicella-zoster (VZV) activity.
Breast cancer is the most prevalent cancer in women affecting about 12% of world's female population. It is a multifactorial disease, mostly invasive in nature. Diosgenin and related compounds are potent antiproliferative agents. Carbamate derivatives have been synthesized at C26 of furostene ring after opening spiroketal bond (F-ring) of diosgenin. Compound 10 possessed significant antiproliferative activity against human breast cancer cells by arresting the population at G1 phase of cell division cycle and induced apoptosis. Induction of apoptosis was observed through the caspase signalling cascade by activating caspase-3. Moreover, carbamate 10 exhibited moderate antiinflammatory activity by decreasing the expression of cytokines, TNF-α and IL-6 in LPS-induced inflammation in primary macrophage cells. Furthermore, compound 10 significantly reduced Ehrlich ascites carcinoma significantly in mice. It was well tolerated and safe in acute oral toxicity in Swiss albino mice. The concomitant anticancer and antiinflammatory properties of carbamate 10 are important and thus, can further be optimized for a better anti-breast cancer candidate.
The use of sustainable deep eutectic solvents (DESs) as stable and green solvent/catalyst systems shows unprecedented high efficiency in the formation of carbamates and ureas from carbonates without any additional solvent. This new protocol provides a simple, fast, economically and eco‐friendly method for the synthesis of broad scope carbamates and ureas providing remarkable yields in the presence of choline chloride:Zinc(II) chloride ([ChCl][ZnCl2]2) under the mild reaction conditions. Moreover, the [ChCl][ZnCl2]2 can be reused for over five consecutive cycles without any significant loss of activity. The new protocol develops and provides an economical and eco‐friendly method for synthesis of the broad scope carbamates and ureas with providing remarkable yields in the presence of choline chloride:Zinc (II) chloride ([ChCl][ZnCl2]2).
Three series of monohalophenyl-N-pyridinylcarbamate isomer grids (CxxX) are reported (with x = para-, meta-, ortho; X = fluorine, chlorine, bromine), and Cx as the aminopyridinyl group (C5NH4NH-) and xX as -CO2C6H4X. Nine crystal structures are presented with all nine structures aggregating via N-H...N intermolecular interactions as their primary hydrogen bond; as chains in CmpX, CmmX and as dimers in the CopX triad. Halogen bonding is absent and there is a preference for N-H...N and C-H/π...π... stacking intermolecular interactions. Structural similarities abound with all three CmpX structures isomorphous in space group Pc and with CopF and CopCl isomorphous in 1 (No. 2). Differences between the monohalogenated CxxX carbamates and their CxxM and CxxOMe relatives (M, OMe = methyl, methoxy) are discussed, especially the reluctance of CxxX to form quality single crystals as most crystallise as filamentous-like fibres under a range of crystallisation conditions. Conformational analyses of the three [3 x 3] CxxX isomer grids of minimized structures in gas-phase are detailed for comparisons with the solid-state structures. Modelling results reveal inherent steric problems in CxoX associated with bulky pendant ortho-groups (i.e. bromine). Physicochemical analyses including melting point analysis and solid-state correlations are rationalised. A question is posed as to why the CxxX carbamates are reluctant to crystallise as quality single crystals and with a higher incidence of Z'>1 in comparison with related carboxamides.
Chemical fixation of carbon dioxide through suitable catalytic pathways is very demanding in the context of sustainable environment. An environmentally benign synthetic studies of N‐formylated amine derivatives by carbon dioxide fixation of amines have been investigated in presence of Merrifield resin supported palladium nanomaterial (Pd‐PS‐amtp catalyst) at ambient temperature. Poly(methylhydrosiloxane) was employed as a susceptible hydride transferring agent in the present CO2 fixation reaction. Further this catalyst exhibited an extended catalytic activity for the production of organic carbamates from dimethyl carbonate and aromatic amines. The Pd‐PS‐amtp nanomaterial has been produced by two step strategies and systematically characterized by FTIR, UV‐Vis, FE‐SEM and TGA‐DTA analysis. The benefits of this system are quite economical, high recycling efficiency and consuming short reaction time to allow significant product yield. The production of organic carbamates in presence of the present catalyst is a phosgene‐free procedure where dimethyl carbonate (DMC) is utilized both as carboxylating agent and solvent. The recovery of Pd‐PS‐amtp nanomaterial could easily be performed after the reactions and recyclable up to six times without considerable reduction in catalytic activity. N‐Formylation of amines via CO2 fixation and production of organic carbamates: An environmentally benign synthetic studies of N‐formylated amine derivatives by carbon dioxide fixation of amines have been investigated in presence of Merrifield resin supported palladium nanomaterial (Pd‐PS‐amtp catalyst) at ambient temperature. The production of organic carbamates in presence of the present catalyst is a phosgene‐free procedure where dimethyl carbonate (DMC) is utilized both as carboxylating agent and solvent.
A molecular modeling study has been carried out on two previously reported series of methylselenocarbamate derivatives that show remarkable antiproliferative and cytotoxic in vitro activity, against a panel of human cancer cell lines. These derivatives can be considered as having been constructed by a selenomethyl fragment located over a carbon atom which is decorated with two carbamate moieties, both aliphatic and aromatic, one of them attached by a single bond to the central carbon atom, while the second is connected by a double bond. According to the data obtained, these derivatives can undergo a water-mediated nucleophilic attack on the carbons with marked electrophilic character, which leads to the rupture of C-Se and carbamate C-O bonds. The aliphatic derivatives, series 1, show an early release of methylselenol and a further release of hydroxyl derivatives (alcohols), whereas the aromatic carbamates, series 2, show an early release of phenols followed by the subsequent release of methylselenol. Thus, the activity of the compounds can be related to the progressive release of active fragments. The data that support this connection are related with the overall molecular topology, volume and surface area as well as with quantum parameters as the relative electrophilic character of the target carbon atoms (measured in terms of positive charge values) or the bond order values, especially concerning the central C-SeCH3 bond and the carbamate ones. Moreover, the data obtained regarding the chromatographic behavior of some representative compounds confirm this proposal.
A simple, efficient and eco-friendly one-pot synthesis of primary, N-mono- and N-disubstituted carbamates is developed from ureas. Corresponding carbamates were produced at 120 °C, within 18 h, and in the presence of the deep eutectic solvent as a recyclable catalytic system. The catalyst can be reused for several runs without any reduction in activity. To demonstrate the utility of this approach, a wide variety of alcohols and phenols were studied to find a vast range of carbamate derivatives in moderate to high yields.
Functionalized carbon nanotubes (CNTs) have been widely employed for biomedical applications including delivery of gene, peptide and drug, imaging and biosensor design. Carbon nanotubes are well known for their fascinating properties and promising potential for versatile biological applications. Considering the importance of functionalization to improve CNTs solubility, we designed a procedure to decorate multi-walled carbon nanotubes surface with carbamate and thiocarbamate groups, since these functional groups are common in natural products with antiproliferative effects on cancer cells. To produce carbamate and thiocarbamate functional groups, the nanotubes were first hydroxylated and then reacted with different isocyanate/isothiocyanate derivatives in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give multi-walled nanotubes functionalized with carbamate/thiocarbamate functional groups. The apoptotic activity of these synthesized nanotubes was tested on neuroblastoma N2A cell line. A significant increase in the number of apoptotic cells was observed in N2A cell treated by carbamate/thiocarbamate-functionalized multi-walled nanotubes. The apoptosis level increased as the concentration of compound increased up to 0.1 µg/ml. t-But-carbamate–MWNT and 3-Br-Ph-thiocarbamate–MWNT (50 ng/ml) showed the highest apoptosis level with 1.8- and 1.7-fold increase compared to doxorubicin.
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A 3 × 3 isomer grid of nine Methylphenyl-N-pyridinylcarbamates (CxxM) is reported with seven CxxM crystal structures at 294 K (xx = pp, pm, po, mp, op, om, oo; x = para-, meta-, ortho), where Cx = pyridinyl ring (as C5NH4NH-) and xM is representative of –C(=O)OC6H4CH3. All seven carbamate crystal structures aggregate via N–H…N intermolecular interactions with the three CpxM carbamates having C(6) zigzag chains, CmpM with C(5) zigzag chains and three ortho-pyridine CoxM structures as hydrogen-bonded dimers with graph set \(R_{2}^{2}\) (8) and augmented by flanking C–H…O contacts. The CpoM crystal structure crystallises with 0.25 CHCl3 per carbamate molecule and solvent channels aligning along the a-axis direction. Conformational analyses of the nine minimised CxxM structures in gas phase are detailed for comparisons with the solid-state structures and demonstrate similarities between both structural methods. The modelling results also demonstrate the problems associated with pendant ortho-groups sterically clashing in the CmoM and CooM structures and methods to find a reasonable estimate of the CxxM conformational landscape.
Heterobimetallic dinuclear lanthanide alkoxide complexes Ln2Na8(OCH2CH2NMe2)12(OH)2 [Ln: I (Nd), II (Sm), III (Yb) and IV (Y)] were used as efficient acid-base bifunctional catalysts for the synthesis of carbamates from dialkyl carbonates and amines as well as the N-Boc protection of amines. The cooperative catalysts showed high catalytic activity and a wide scope of substrates with good to excellent yields under solvent-free conditions. The systems have shown higher catalytic activities due to the noteworthy synergistic interactions of Lewis acid center-Brønsted basic center. The comparison of catalytic efficiency between mono- and dinuclear heterobimetallic lanthanide alkoxide analogues was also investigated.
A general study of the iron-catalyzed reaction of urea with nucleophiles is here presented. The carbamoylation of alcohols allows for the synthesis of N-unsubstituted (primary) carbamates, including present drugs (Felbamate and Meprobamate), without the necessity to apply phosgene and related derivatives. Using amines as nucleophiles gave rise to the respective mono- and disubstituted ureas via selective transamidation reaction. These atom-economical transformations provide a direct and selective access to valuable compounds from cheap and readily available urea using a simple Lewis-acidic iron(II) catalyst.
Organic carbamates are the stable class of compounds derived from the unstable carbamic acid (H2N-COOH) by the substitution of amino and acid ends through various kinds of structurally diverse alkyl/aryl, aryl-alkyl or substituted alkyl/aryl, and aryl-alkyl groups, and are identified by the presence of the linkage -O-CO-NH- (Adams and Baron 1965; Chaturvedi 2003, 2011, 2012; Chaturvedi and Ray 2007a, b). When the carbamate linkage is present in a cyclic system, this class of compounds is referred to as cyclic carbamates (Ager et al. 1996; Arya and Qin 2000; Johnson and Evans 2000). When the carbamate group is attached to any inorganic atom, either metal or nonmetal, such compounds are referred to as inorganic carbamates (Aoki et al. 2001; Boyle et al. 1992).
Cancerous tumors of the liver can be primary cancer - cancer starting in the liver itself or secondary or metastatic cancer - cancer which started in another part of the body and has spread to the liver. Surgery is the most effective treatment for primary liver cancer, but this is not always possible due to the size or position of the tumor and hence chemotherapy is used sometimes to treat these cancerous tumors that cannot be removed. Chemotherapy is also given following surgery to prevent relapse of the cancer. Chemotherapeutic agents used in treatment of liver cancer are not specific for the treatment of liver cancer and suffers from the problem of serious toxicities to the normal cell of the liver as well as to other cells. This can be overcome by targeting drug to the liver by different approaches such as by designing prodrugs which may be distributed to all body tissues but cleaved only in liver or tethering a moiety which binds with the receptor on liver cells. New drugs are being developed that work in a different way from standard chemotherapeutic drugs.
Many alkaloids derived from plant origins are bioactive and play a significant role in human health and emerging medicine. Noscapine, a phthalideisoquinoline alkaloid derived from Papaver somniferum, has been used as a cough suppressant since the mid 1950s, illustrating a good safety profile. Noscapine has since been discovered to arrest cells at mitosis, albeit with moderately weak activity. Immunofluorescence staining of microtubules after 24 hours of noscapine exposure at 20 μM elucidated chromosomal abnormalities and the inability of chromosomes to complete congression to the equatorial plane for proper mitotic separation.1 A number of noscapine analogs possessing various modifications have been described within the literature and have shown significantly improved anti-prolific profiles for a large variety of cancer cell lines. Several semi-synthetic antimitotic alkaloids are emerging as possible candidates as novel anticancer therapies. This perspective discusses the advancing understanding of noscapine and related analogs in the fight against malignant disease.
In the present work, novel chromene derivatives fused with the imidazo[1,2-a]pyridine nucleus were tested for their anticancer potential in the human colorectal cancer HCT116 cells. Compounds 2a and 2c showed significant growth inhibitory activity with GI50 of 15 μM and 11 μM, respectively. Compound 2c, the most potent, has a carbamate group in position 8 of the pyridine ring, and showed significant cell cycle arrest and induction of cell death by apoptosis, even at 5 μM. Besides different potencies, chromene analogues 2a and 2c showed different mechanisms of action. Whereas the carbamate-free chromene 2a induced cell cycle arrest at G1/G0 phase, compound 2c showed to arrest cell cycle at both S and G2 phases. Chromene derivative 2a at concentrations higher than its GI50 remarkably induced caspases-dependent apoptosis in a p53-independent manner. On the other hand, compound 2c increased significantly p53 levels and induced apoptosis in a p53- and caspases-dependent manner, even at concentrations lower than its GI50. Both compounds increased the Bax/Bcl-2 ratio, induced mitochondria depolarization and activated MAP kinases. In conclusion, two novel and structurally similar chromene derivatives showed cytotoxicity to HCT16 cells through opposing effects on p53 levels and apoptosis mechanisms, which may be relevant for further development of drugs acting on distinct molecular targets useful in the treatment of cancers with different genetic profiles and for personalized medicine.
Copyright © 2015. Published by Elsevier B.V.
The two-step one-pot procedure allows the synthesis of different types of carbamates via pyridine-catalyzed reaction of alcohols with carbonate (II) and subsequent treatment with hindered amino acids or amino esters.
A mild and efficient synthesis of N-arylcarbamates was achieved by reacting azidoformates with boronic acids in the presence of 10 mol % of copper chloride catalyst. The reaction proceeds readily in an open flask at room temperature without additional base, ligand or additive. Rapid access to urea analogues via a two-step one-pot procedure is enabled by reacting N-arylcarbamates with aluminium-amine complex-es. In addition, among several boronic acid derivatives prepared, dimethylphenyl boronate was found to react rapidly in its reaction with benzyl azidoformate, invoking in situ generation of this species in the catalytic cycle.
Kinetic evidence has indicated that methanolysis of synthesized 4-acetoxybenzyl carbamates proceeds via a one-step (concerted) mechanism. Concerted 1,6-elimination produces the very reactive 1,4-quinonemethide, which was trapped in the form of 4-methoxymethylphenol. The inhibition activity of benzyl N-phenylcarbamates to acetylcholinesterase (ACHE) and butyrylcholinesterase (BCHE) was also tested. The found IC 50 values varied within the limits of 199-535 µmol·l –1 for ACHE and 21-177 µmol·l –1 for BCHE. The found values of partition coefficient (P ow) in the range of 1.5-11.5 represent a prerequisite of good transport of benzyl N-phenylcarbamates through haemato-encephalic barrier.
The reaction of amines and dimethyl carbonate (DMC) in the presence of catalytic amounts of L-proline and tetrabutylammonium bromide (TBAB) afforded methyl carbamates in good to excellent yields under mild conditions. The presence of both L-proline and TBAB co-catalysts is vital for this transformation.
Organic carbamates represent an important class of compounds showing various interesting properties. They find wide utility in various areas as pharmaceuticals, agrochemicals (pesticides, herbicides, insecticides, fungicides etc.), intermediates in organic synthesis, protection of amino group in synthetic organic chemistry, as linkers in combinatorial chemistry etc. Classical synthesis of carbamates involves use of harmful reagents such as phosgene, its derivatives and carbon monoxide. Recently, carbon dioxide has frequently been employed as a green reagent in its various conditions and forms for the synthesis of organic carbamates employing diversity of starting materials, reagents and catalytic systems. In the present review, we would like to highlight the recent developments on the synthesis of organic carbamates using various conditions and forms of carbon dioxide.
In the present study, we explore the application of several theoretically estimated indices that characterize the reactivity of a series of phenyl N-phenylcarbamates in the alkaline hydrolysis reaction. The rate constants (at 25 °C) for the hydrolysis of several derivatives were spectrophotometrically determined. The obtained kinetic data in this study, combined with literature data for other derivatives, were then correlated with theoretically estimated reactivity indices: Hirshfeld and NBO atomic charges, the Parr electrophilicity index (ω), and the electrostatic potential at the carbon and oxygen atoms of the reaction centre (VC, VO). The predictive ability of these quantities is discussed in a comparative context. Copyright © 2011 John Wiley & Sons, Ltd.
A series of carbamate derivatives of 4'-demethylepipodophyllotoxin have been synthesized, and their cytotoxicities against several human cancer cell lines, including HeLa, A549, HCT-8, and HL-60 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4β-4'-Demethylepipodophyllotoxin 1-(4-nitrophenyl) piperazinyl carbamate (19) was found to be the most potent compound of those synthesized in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of Bax, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form.
A new nanostarch functionalized ionic liquid containing imidazolium cation and cobalt chelate anion was synthesized and tested for the one pot synthesis of carbamates by the reaction of amines and dimethyl carbonate (DMC), affording excellent yield of the products under solvent free mild reaction conditions. The synthesized ionic liquid was easily recovered and reused several times without any loss in catalytic efficiency.
Twenty-one novel urea derivatives were synthesized and their structures characterized by mass, NMR, IR, and UV spectroscopy. These compounds were evaluated for their antiproliferative profile against human PC-3 (prostate) and NCI-H460 (lung) cancer cell lines. Among them, compound 21
N-(3-nitrophenyl)-N′-(1-phenylethyl)urea was found to be active against both PC-3 (IC50 ± SEM: 20.13 ± 0.91 μM) and NCI-H460 (GI50: 22 ± 2.6 μM) cell lines; hence has the potential to be further studied as anticancer agent. These compounds were also investigated for their ability to inhibit urease, β-glucuronidase, and phosphodiesterase enzymes. N-(2,6-Dimethylphenyl)-N′-(4′-nitrophenyl)urea (1) demonstrated 90 % inhibition of β-glucuronidase enzyme (IC50 ± SEM: 3.38 ± 0.043 μM).
In this review, various kinds of synthetic methodologies for the synthesis of organic carbamates employing diversity of reagents and catalytic systems have been reviewed, from the beginning to the recent reports (covering till December 2010). Figure optionsView in workspaceDownload full-size imageDownload as PowerPoint slide
Hydrogen bonding between protonated monoethanolamine and chloride ion can benefit the capture and thermal stabilisation of carbon dioxide in hydroxyl imidazolium based ionic liquids for potential reclamation of the captured carbon by, for example, electrolysis and catalytic synthesis.
A convenient, efficient, one-pot, novel process has been developed for the synthesis of carbamates from corresponding amines and alcoholic tosylates using basic resin/CO2 system is described.
Organic carbamates represent an important class of compounds showing various interesting properties. They find wide utility in various areas as pharmaceuticals, agrochemicals (pesticides, herbicides, insecticides, fungicides etc.), intermediates in organic synthesis, protection of amino group in peptide chemistry, and as linker in combinatorial chemistry etc. Classical synthesis of carbamates involves use of harmful reagents such as phosgene, its derivatives and carbon monoxide. Recently, various kinds of synthetic methods have been developed for the synthesis of organic carbamates. In the present review, I would like to highlight the recent developments on the synthesis of organic carbamates using variety of reagents.
Attempts to improve the selectivity of anti-cancer agents by conjugating them to antibodies directed at tumour associated antigens have demonstrated tumour localisation but only limited therapeutic success. We report here the advantage of a 2-stage approach in which the first component combines the selective delivery of antibody with a capability to generate a cytotoxic agent from a second subsequently administered component. A bacterial enzyme, carboxypeptidase G2 (CPG2) was conjugated with F(ab')2 fragment of a monoclonal antibody directed at beta subunit of human chorionic gonadotrophin (beta-hCG) and injected into nude mice bearing hCG producing CC3 xenografts of human choriocarcinoma. Time was allowed for the conjugate to localise at tumour sites and clear from blood before injecting para-N-bis (2-chloroethyl) aminobenzoylglutamic acid. Cleavage of the glutamic acid moiety from this molecule by CPG2 released a benzoic acid mustard. Growth of the tumour which is resistant to conventional chemotherapy was markedly depressed by a single course of treatment. This demonstrates for the first time the potential of an antibody directed enzyme to activate an alkylating agent and to eradicate an established human cancer xenograft.
Two anti-tumor monoclonal antibodies, L6 (anticarcinoma) and 1F5 (anti-B lymphoma), were covalently linked to alkaline phosphatase (AP), forming conjugates that could bind to the surface of antigen-positive tumor cells. The conjugates were capable of converting a relatively noncytotoxic prodrug, etoposide phosphate (EP), into etoposide--a drug with significant antitumor activity. In vitro studies with a human colon carcinoma cell line, H3347, demonstrated that while EP was less toxic than etoposide by a factor of greater than 100, it was equally toxic when the cells were pretreated with L6-AP, a conjugate that bound to the surface of H3347 cells. The L6-AP conjugate localized in H3347 tumor xenografts in nude mice and histological evaluation indicated that the targeted enzyme (AP) was distributed throughout the tumor mass. A strong antitumor response was observed in H3347-bearing mice that were treated with L6-AP followed 18-24 hr later by EP. This response, which included the rejection of established tumors, was superior to that of EP (P less than 0.005) or etoposide (P less than 0.001) given alone. The IF5-AP conjugate did not bind to H3347 cells and did not enhance the toxicity of EP on these cells in vitro. In addition, IF5-AP did not localize to H3347 tumors in nude mice and did not demonstrate enhanced antitumor activity in combination with the prodrug.
The synthesis of a differentially protected dipeptide mimic 10 in enantiomerically pure form is described. The key step involves the epimerization of the C-2 center of the lactone 4, hydrolysis and protection of the resulting hydroxy acid, followed by Curtius rearrangement to introduce the urethane functionality. The scope and versatility of this isostere has been demonstrated by its conversion to potent HIV-1 protease inhibitors with nanomolar potencies. Also, established through the synthesis of compound 13 and 14, the 3S hydrozyl configuration of the dipeptide isostere 1 is the preferred configuration for its potency. The present synthesis is efficient and provides an access to other dipeptide mimics with a great deal of structural diversity.
Various 2-amido docetaxel analogues were prepared and evaluated for their cytotoxicities. Among them, m-methoxy and m-chlorobenzoylamido analogues were most active but not superior to docetaxel and paclitaxel, and d-seco analogues inactive. Change of 2-benzoate to 2-benzamide may not improve their activities to drug-resistant cell lines.
The design, synthesis and biological actions of a novel, non-peptide CCK1 receptor agonist (PD 170292) which exhibits a similar pharmacological profile to the CCK analogue JMV180 is reported. PD 170292 was designed based on a consideration of the structures of a peptide based CCK1 receptor selective agonist and a peptoid CCK2 receptor selective antagonist.
A prodrug consisting of a β-D-glucuronic acid linked to a self-immolative spacer (a N-(ortho-hydroxyphenyl)-N-methylcarbamate) and a phenolic nitrogen mustard was synthesised. As this prodrug was easily cleaved by a β-glucuronidase enzyme and displayed low cytotoxicity, it must be considered as appropriate for an ADEPT approach.
We designed and synthesized several brefeldin A (BFA) analogs. These compounds were evaluated for the ability to induce differentiation and apoptosis in human colonic carcinoma cell line HCT116. Diacetyl BFA (2a), 4-acetyl BFA (2b), 7-acetyl BFA (2c), and 10,11-epoxy BFA (3b) were active but tetrahydro BFA (3a) and other analogs could not induce the malignant cells to differentiate. The results suggested that the moiety from 1- to 4-position in BFA as well as its conformational rigidity is essential for its biological activity.
Carbohydrate based analogues of the natural product (−)-Ovalicin have been synthesized, and shown to be potent inhibitors of angiogenesis.
The synthesis of a novel enediyne 2, and its cytotoxicity and activation by the nitroreductase enzyme NR2 from Esherichia coli B, are described. In contrast to closely related analogues, 2 exhibits a 90-fold increase in cytotoxicity against UV4 cells in the presence of the enzyme and NADH, suggesting its potential as a prodrug for Antibody-Directed Enzyme Prodrug Therapy in conjunction with E. coli nitroreductase.
The design and synthesis of carbamate-daunomycin prodrug 11 that can release free daunomycin by the reaction with sulfhydryl compounds is described. The compound 11 is more sensitive to adriamycinresistant L1210 cell line than free daunomycin with relative resistance of 3.7 and 9.2, respectively.
A general method for the solid-phase synthesis of ureas has been developed. The key intermediate being a p-nitrophenylcarbamate which is transformed into the urea by reaction with primary or secondary amines. The products obtained are of high chemical purity.
A scheme for the design of dynemicin analogs and a concise, efficient route for their synthesis are described. A photochemically activatable analog was prepared and shown to undergo cycloaromatization upon irradiation with wavelengths greater than 300 nm. The ability of this compound to function as a competent DNA cleaving agent is demonstrated.
The first synthesis of seco-CBI-TMI alkylating agents with 5-nitrogen substituents is reported. The parent 5-amino compound was prepared in a 15-step synthesis from 1-hydroxynaphthalene-2-carboxylic acid. Reductive alkylation of the 5-amino compound gave the corresponding 5-methylamino and 5-dimethylamino analogues, while resolution of an intermediate by chiral HPLC allowed preparation of the R and S enantiomers of the 5-amino analogue. Absolute configuration was assigned by X-ray crystallography. The S enantiomer was about 65-fold more cytotoxic than the R enantiomer in cell line assays. The 5-amino and 5-methylamino compounds had in vitro cytotoxicities comparable to that of the known 5-hydroxy analogue (0.2−0.5 nM), while the 5-dimethylamino derivative was about 10-fold less potent. The high potencies of the 5-amino and 5-methylamino analogues make them of interest for the formation of relatively stable amine-based prodrugs.
An improved procedure for the fluoride-induced desilylative condensation of a silyl-protected alkyne with an aldehyde provides the first example of dynemicin analogs (11) that can be activated by photochemical deprotection on nitrogen, leading to DNA cleavage under neutral conditions in the absence of chemical activators.
The synthesis of a differentially protected dipeptide mimic 10 in enantiomerically pure form is described. The key step involves the epimerization of the C-2 center of the lactone 4, hydrolysis and protection of the resulting hydroxy acid, followed by Curtius rearrangement to introduce the urethane functionality. The scope and versatility of this isostere has been demonstrated by its conversion to potent HIV-1 protease inhibitors with nanomolar potencies. Also, established through the synthesis of compound 13 and 14, the 3S hydroxyl configuration of the dipeptide isostere 1 is the preferred configuration for its potency. The present synthesis is efficient and provides an access to other dipeptide mimics with a great deal of structural diversity.
A general methodology for synthesizing poly(ethylene glycol) (PEG) prodrugs of amino-containing compounds has been developed and constitutes the basis for solubilization of insoluble drugs, extending plasma circulating half-lives and, in the case of anticancer agents, apparent tumor accumulation. Thus, we have successfully designed PEG conjugated specifiers or “triggers” as part of a double-prodrug strategy that relies, first, on enzymatic separation of PEG followed by the classical and rapid 1,4- or 1,6-benzyl elimination reaction releasing the amine (drug) bound in the form of a carbamate. The prodrug trigger was comprised of ester, carbonate, carbamate, or amide bonds in order to secure predictable rates of hydrolysis. Further refinement of the hydrolysis was accomplished by the introduction of steric hindrance through the use of ortho substituents on the benzyl component of the prodrug. This modification led to longer circulating plasma half-lives of the final tripartate form. The “ortho” effect also had the beneficial effect of directing nucleophilic attack almost exclusively to the activated benzyl 6-position of the heterobifunctional intermediates. In vivo testing of the PEG daunorubicin prodrugs (transport forms) prepared in the course of this study ultimately identified the type 1 carbamate (34b), with a circulating t1/2 of 4 h, as the most effective derivative for solid tumor growth inhibition.
Water-soluble analogues of the antitumor alkaloid camptothecin (1) were prepared in which aminoalkyl groups were introduced into ring A or B. Most of the analogues were prepared by oxidation of camptothecin to 10-hydroxy-camptothecin (2) followed by a Mannich reaction to give N-substituted 9-(aminomethyl)-10-hydroxycamptothecins (4-12) or by subsequent modification of Mannich product 4 (13, 15, 17, 19, 21). Others were obtained by modification of the hydroxyl group of 2 (25, 26) or by total synthesis (35, 42, 43). These analogues, as well as some of their synthetic precursors, were evaluated for inhibition of topoisomerase I, cytotoxicity, and antitumor activity. Although there was not a quantitative correlation between these assays, compounds that inhibited topoisomerase I were also cytotoxic and demonstrated antitumor activity in vivo. Further evaluation of the most active water-soluble analogue led to the selection of 9-[(dimethylamino)methyl]-10-hydroxycamptothecin (4, SK&F 104864) for development as an antitumor agent. In addition to its water solubility, ease of synthesis from natural camptothecin, and high potency, 4 demonstrated broad-spectrum activity in preclinical tumor models and is currently undergoing Phase I clinical trials in cancer patients.
3'-(tert-Butyl) 3'-dephenyl analogs of paclitaxel were synthesized from 10-deacetylbaccatin III and oxazolidinecarboxylic acid 7 followed by acylation of intermediate amines 10 and 11. Oxazolidinecarboxylic acid 7 was prepared in five steps and in good overall yield from L-tert-leucine. Twelve analogs were synthesized and evaluated for their in vitro ability to stimulate the formation of microtubules and for their cytotoxicity against B16 melanoma cells. Amide, carbamate, urea, and thiourea congeners were prepared. The most potent derivatives found in this study are the docetaxel analog 13, the N-[(tert-amyloxy)carbonyl] analog 17, and the 3'-phenylurea and 3'-tert-butylurea derivatives 20 and 23. Six of these analogs were shown to be ca. 90 times more soluble in water than paclitaxel and ca. 4-5 times more water-soluble than docetaxel.
The synthesis and biological profile of the new daunomycin derivative 2 as an antitumor agent is described.
In an attempt to det. some of the structural features of geiparvarin (I; R = H) that account for its cytostatic activity in vitro, a series of analogs II (R1 = Ph, cyclohexyl, CHMe2, Bu, MeC, PhCH2, CH2:CHCH2, ClCH2CH2, octyl), I (R = OMe), III (R2 = 4-MeO, C6H4, Ph, coumarin), and IV, which contain novel modifications in the region of the olefinic double bond and of the coumarin moiety were designed and synthesized. Among the derivs. contg. a carbamate moiety, only the analogs contg. a carbamate group linked to an alkyl moiety II were endowed with potent cytostatic activity, whereas the corresponding benzene deriv. II (R1 = Ph) was devoid of any antiproliferative activity. 6-Methoxygeiparvarin (I; R = OMe) proved equally effective as I (R = H), while compds. contg. an addnl. double bond at the side chain III (R2 = 4-MeOC6H4, Ph, coumarin)) and IV were invariably 5-100-fold less effective than I (R = H). Diene deriv. III (R = coumarin) bearing a coumarin moiety, was essentially inactive against murine (L1210, FM3A) tumor cells but exhibited good activity against human (Molt/4F, MT-4) tumor cells. [on SciFinder(R)]
Two approaches to prodrugs of alkylating agents based on an imidazolylmethyl carbamate nucleus were explored. A 2-azido analogue (3) of the bis-carbamate carmethizole (1) displayed similar aerobic cytotoxicity to 1 in a panel of human and murine cell lines. Approaches to the 2-amino and 2-carbamoyl analogues are described. In the second approach an imidazolylmethanol was used as a ‘trigger’ linked via a carbamate to the alkylating agent N,N-bis(2-chlorethyl)amine (BCEA). Nitroimidazole and methylsulphinylimidazole carbamate prodrugs 6–8 were 5–20-fold less toxic than BCEA. Despite this deactivation in the prodrug form, little increase in cytotoxicity was observed under hypoxia. The data suggest that BCEA released on bioreduction is not sufficiently potent to contribute significant additional cytotoxicity.
The synthesis and evaluation of the 4-nitrobenzylcarbamate enediyne 6 and related compounds as prodrugs activated by a nitroreductase enzyme (NTR) from E. coli B is described. Expression of NTR in three different cell lines gives increases in cytotoxicity of 21- to 135-fold for 6 (IC50 values 13-24 nM in the NTR-expressing lines), indicating its potential as a prodrug for NTR-mediated Gene-Directed Enzyme Prodrug Therapy. The cytotoxicity of 6 and related enediynes is shown to be oxygen-dependent, especially in nucleotide excision repair-proficient cells, which might limit activity in hypoxic regions of tumours.
This chapter discusses those aspects of Adriamycin that are relevant to the design of analogues. As Adriamycin is not a unique antibiotic but is a member of the large anthracycline group of antibiotics, a discussion of other anthracyclines has been included. Adriamycin probably has the widest spectrum of activity of any present antitumor drug but its cardiotoxicity limits the total cumulative dose that can be administered; the analogues of Adriamycin and daunomycin clinically evaluated to date (for example rubidazone and duborimycin) show no clear advantage over Adriamycin. The use of masking groups to achieve the required distribution properties also appears feasible. Comparing daunomycin and Adriamycin, the former is more rapidly accumulated by cells, but the latter has a slightly lower rate of dissociation from DNA and its half-life in cells is considerably longer than that of daunomycin.
The synthesis of ring analogues and derivatives of the S isomer of ethyl [5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 - yl[carbamate, (S)-1, a potent antimitotic agent with anticancer activity, was directed toward the determination of the contribution of several structural features of this compound to biological activity. Replacement of the 5-amino with a 5(6H)-oxo group and either transposing the 6-ring nitrogen to or incorporation of a ring nitrogen at the 8-position caused a significant decrease in in vitro activity and destroyed in vivo activity. Although in vivo cytotoxicity was reduced, in vitro activity at higher doses relative to (S)-1 was retained by replacement of the 5-amino group with hydrogen and by expansion of the 1,2-dihydropyrazine to give a dihydro-1,4-diazepine ring.
Metabolism studies with ethyl [5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 - yl]carbamate (1) in mice were reported previously to give a hydroxylated metabolite, which was methylated to give a methoxy derivative. The metabolite and its derivatives were considered to be 4-(substituted)phenyl compounds, which have been confirmed by the synthesis of the [1,2-dihydro-3-(4-hydroxyphenyl)- and [1,2-dihydro-3-(4-methoxyphenyl)pyrido[3,4-b]-pyrazin-7-yl]carbama tes (17 and 16). Both the S- and R-isomers of 17 are active in several biological systems, but the S-isomer is more potent then the R-isomer. The difference in activity between the S- and R-isomers of 17 is similar with that observed for S- and R-isomers of 1. As model reactions, several O-substituted derivatives were prepared by alkylation of (RS)-17 with benzyl chloride and condensation of (RS)-17 with butyl isocyanate and (S)-17 with 2-chloroethyl isocyanate.
The rational design and biological actions of a new class of DNA-cleaving molecules with potent and selective anticancer activity are reported. These relatively simple enediyne-type compounds were designed from basic chemical principles to mimic the actions of the rather complex naturally occurring enediyne anticancer antibiotics, particularly dynemicin A. Equipped with locking and triggering devices, these compounds damage DNA in vitro and in vivo on activation by chemical or biological means. Their damaging effects are manifested in potent anticancer activity with remarkable selectivities. Their mechanism of action involves intracellular unlocking and triggering of a Bergman reaction, leading to highly reactive benzenoid diradicals that cause severe DNA damage. The results of these studies demonstrate the potential of these de novo designed molecules as biotechnology tools and anticancer agents.
A variety of synthetic analogues of taxol, a naturally occurring antitumor diterpene, were examined for their potency to inhibit microtubule disassembly. For some of the compounds, the in vitro cytotoxic properties showed a good correlation with the tubulin assay. This structure-activity relationship study shows that inhibition of microtubule disassembly is quite sensitive to the configuration at C-2' and C-3'. A correlation between the conformation of the side chain at C-13 and the activity is suggested. Of all the compounds examined, one of the most potent in inhibiting microtubule disassembly and in inhibiting murine P388 leukemic cells, N-debenzoyl-N-tert-(butoxycarbonyl)-10-deacetyltaxol, named taxotere, was selected for evaluation as a potential anticancer agent.
RP 56976 (taxotere), a new semisynthetic analogue of taxol, is a potentially important chemotherapeutic agent for the treatment
of cancer. We report here that this drug is a potent inhibitor of cell replication and, like taxol, Promotes the in vitro
assembly of stable microtubules in the absence of guanosine triphosphate and induces microtubule-bundle formation in cells.Compared
with taxol, RP 56976 is slightly more active as a promoter of tubulin polymerization. As an inhibitor of cell replication,
RP 56976 is 2.5-fold more potent than taxol in J774.2 and P388 cells and at least 5-fold more potent in taxol-resistant cells.
[J Natl Cancer Inst 83:288–291, 1991]
Neovascularization is critical for the growth of tumours and is a dominant feature in a variety of angiogenic diseases such as diabetic retinopathy, haemangiomas, arthritis and psoriasis. Recognition of the potential therapeutic benefit of controlling unabated capillary growth has led to a search for safe and effective angiogenesis inhibitors. We report here the synthesis of a family of novel inhibitors that are analogues of fumagillin, a naturally secreted antibiotic of Aspergillus fumigatus fresenius. We first isolated this fungus from a contaminated culture of capillary endothelial cells. Purified fumagillin inhibited endothelial cell proliferation in vitro and tumour-induced angiogenesis in vivo; it also inhibited tumour growth in mice, but prolonged administration was limited because it caused severe weight loss. Synthesis of fumagillin analogues yielded potent angiogenesis inhibitors ('angioinhibins') which suppress the growth of a wide variety of tumours with relatively few side-effects.
The reaction of ethyl (6-amino-4-chloro-5-nitropyridin-2-yl)carbamate (2) with alpha-amino ketone oximes gave 4-[(2-oxoethyl)amino]pyridine oximes 3, which were reductively cyclized to give a series of ethyl (1,2-dihydro-pyrido[3,4-b]pyrazin-7-yl)carbamates (6). In another approach, alpha-nitro ketones, alpha-oximino ketones, and alpha-nitro alcohols were reduced to give alpha-amino alcohols, which were reacted with 2 to give 4-[(2-hydroxyethyl)amino]pyridines (5). Oxidation of these alcohols with the chromium trioxide-pyridine reagent gave the corresponding ketones (4), which were also reductively cyclized to give 6. Structure-activity relationship studies indicated that alterations at the 2- and 3-positions of the pyrazine ring of 6 had a significant effect on cytotoxicity and the inhibition of mitosis in cultured lymphoid leukemia L1210 cells. Compounds that exhibited in vitro cytotoxicities at less than 1 nM showed the same level of in vivo activity, whereas the less potent compounds showed wide variations in their in vivo activity.
In an attempt to determine some of the structural features of geiparvarin (1) that account for its cytostatic activity in vitro, a series of geiparvarin analogues (10a-i, 1, 12, and 14-16) which contain novel modifications in the region of the olefinic double bond and of the coumarin moiety have been designed and synthesized. Among the derivatives containing a carbamate moiety, only the analogues containing a carbamate group linked to an alkyl moiety 10b-i were endowed with potent cytostatic activity, whereas the corresponding benzene derivative 10a was devoid of any antiproliferative activity. 6-Methoxygeiparvarin 101 proved equally effective as geiparvin (1), while compounds containing an additional double bond at the side chain (12 and 14-16) were invariably 5-100-fold less effective than geiparvarin. Diene derivative 15, bearing a coumarin moiety, was essentially inactive against murine (L1210, FM3A) tumor cells but exhibited good activity against human (Molt/4F, MT-4) tumor cells.
A number of 4-demethoxyanthracyclines having hydroxylalkyl functions at the 9-position have previously been synthesized and shown to have potent antitumor activity. A series of carbamate derivatives of these (hydroxyalkyl)anthracyclines have now been prepared, many of which possess considerably greater efficacy in an L-1210 leukemia test system than do the parent alcohols or the known anthracyclines daunorubicin (1), doxorubicin (2), and 4-demethoxydaunorubicin (3). Phenylcarbamate 8a was more active than methyl analogue 8b, while the 4'-deoxy and 4'-epi phenylcarbamates 17 and 18 showed particularly high efficacy at optimal dose levels similar to that of doxorubicin. Secondary carbamates were more potent, with the 13R isomer 23 having significantly higher efficacy than 13S analogue 24.
Racemic ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazine-7- carbamate (1a) has shown antitumor activity in a variety of in vivo experiments. The preparation of the R and S isomers gave compounds with significant differences in potency in several biological tests.
The ethyl (1,2-dihydropyrido[3,4-b]pyrazin-7-yl)carbamates have been reported to bind with cellular tubulin, to produce an accumulation of cells at mitosis, and to exhibit cytotoxic activity against experimental neoplasms in mice. Studies on the disposition of ethyl (5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 -yl)carbamate (8) in mice showed that one metabolite was formed by cleavage of the ethyl carbamate moiety. Analogues with alterations in the carbamate group were prepared by transformations at the carbamate of 8, by reductive cyclization of nitropyridine intermediates, and by hydride reduction of the ring of heteroaromatic compounds. In vitro and in vivo evaluations of analogues indicated that a carbamate group was required for activity. No significant change in activity was observed when ethyl was replaced by methyl. However, activity was reduced when ethyl was replaced with bulky aliphatic groups and when ethoxy was replaced with a methylamino group. Also, the activity of 8 was decreased by acetylation of the 5-amino group and was destroyed by substitution of an amino group at the 8-position.
The development of acquired resistance to antineoplastic drugs and the associated broad cross-resistance to other agents frequently limits the effectiveness of chemotherapy. Ling and coworkers have demonstrated that Chinese hamster ovary (CHO) cells develop the phenotype of pleiotropic drug resistance which is manifest by a decrease in drug accumulation in these cells and hence a decrease in cytotoxicity (1). The role of drug accumulation and membrane glycoproteins in the expression of primary resistance and cross-resistance in human tumors is an area of active investigation (2–4). We have developed a series of human ovarian cancer cell lines with acquired resistance to melphalan, cisplatin, or adriamycin (5). These cell lines exhibit sensitivity/resistance profiles characteristic of pleiotropic drug resistance. In addition, the melphalan and cisplatin resistant variants are also cross-resistant to irradiation (6). Both the primary resistance to melphalan and the cross-resistance to irradiation in these cell lines can be reversed by lowering glutathione (GSH) levels in the cells with buthionine sulfoximine (BSO) (6,7). In the present study, the role of GSH in the expression of sensitivity to agents other than melphalan was examined by BSO-mediated depletion of GSH. In addition, the patterns of both primary resistance and cross-resistance were compared following GSH depletion in these cell lines.
Although benzimidazole is one of the oldest and chemically well-studied nitrogen heterocyclics, it has been quite lately recognized as the versatile nucleus for building molecules possessing broad spectrum of biological activity. The polyfunctionality associated with benzimidazole nucleus, the ease to carry out various organic reactions and its association with bio-molecules stimulated several laboratories of the world to explore its synthetic and biological avenues. This, not only, disclosed various fascinating aspects of benzimidazole chemistry but also led to the synthesis of a large variety of benzimidazole derivatives of which many have been demonstrated to exhibit powerful anthelmintic, antimicrobial, pesticidal, anticancer and pharmcological activities. Among the above areas of drug research, a newer dimension has been given to the chemotherapy of helminthiasis where modern drug design is chiefly directed towards searching potent veterinary and human anthelmintics derived from benzimidazoles.
3'-(tert-Butyl) 3'-dephenyl analogs of paclitaxel were synthesized from 10-deacetylbaccatin III and oxazolidinecarboxylic acid 7 followed by acylation of intermediate amines 10 and 11. Oxazolidinecarboxylic acid 7 was prepared in five steps and in good overall yield from L-tert-leucine. Twelve analogs were synthesized and evaluated for their in vitro ability to stimulate the formation of microtubules and for their cytotoxicity against B16 melanoma cells. Amide, carbamate, urea, and thiourea congeners were prepared. The most potent derivatives found in this study are the docetaxel analog 13, the N-[(tert-amyloxy)carbonyl] analog 17, and the 3'-phenylurea and 3'-tert-butylurea derivatives 20 and 23. Six of these analogs were shown to be ca. 90 times more soluble in water than paclitaxel and ca. 4-5 times more water-soluble than docetaxel.
The synthesis and antitumor activities of the novel water soluble camptothecin derivatives 7-[(4-methylpiperazino)methyl]-10,11-(methylenedioxy)-(20S)-campto thecin trifluoroacetate (6) and 7-[(4-methylpiperazino)methyl]-10,11-(ethylenedioxy)-(20S)-camptot hecin trifluoroacetate (7) are described. The solubilities of compounds 6 and 7 were measured to be 4.5 and 5.8 mg/mL, respectively, in pH 5 acetate buffer in contrast to < 0.003 mg/mL for camptothecin in the same buffer. In the purified topoisomerase I cleavable complex enzyme assay, compounds 6 and 7 demonstrated potent inhibition of topoisomerase I with IC50's of 300 and 416 nM, respectively, in comparison to 679 nM for camptothecin and 1028 nM for topotecan. In human tumor cell cytotoxicity assays, compounds 6 and 7 demonstrated potent antitumor activity against ovarian (SKOV3), ovarian with upregulated MDRp-glycoprotein (SKVLB), melanoma (LOX), breast (T47D), and colon (HT29) with IC50's ranging from 0.5 to 102 nM. Compounds 6 and 7 induced tumor regressions in the HT29 human colon tumor xenograft model and demonstrated similar rank order of potency compared to in vitro assay results.
Methyl 4-(isothiocyanatomethyl)thiazole-2-carbamate and methyl 4-(isothiocyanatomethyl)selenazole-2-carbamate have been prepared via chemical transformations involving 2-amino-4-(chloromethyl)thiazole (1) and 2-amino-4-(chloromethyl)selenazole (2), respectively, as starting materials. The homoanalog, methyl 4-(2-isothiocyanatoethyl)thiazole-2-carbamate, was prepared from (2-aminothiazol-4-yl)acetic acid. All compounds prepared were evaluated for their ability to inhibit leukemia L1210 cell proliferation. Methyl 4-(isothiocyanatomethyl)thiazole-2-carbamate (7) was the most active compound in this screen, inhibiting the growth of L1210 leukemic cells with an IC50 = 3.2 microM. Mitotic blocking appears to be its primary mechanism of cytotoxic activity. Compound 7 also was the only compound which demonstrated significant in vivo antifilarial activity against the adult worms of Acanthocheilonema viteae in experimentally infected jirds. This compound was inactive against Brugia pahangi at a dosage of 100 mg/kg x 5 days.
Antibody-directed enzyme prodrug therapy (ADEPT) is a two-step approach for the treatment of cancer which seeks to generate a potent cytotoxic agent selectively at a tumor site. In this work described the cytotoxic agent is generated by the action of an enzyme CPG2 on a relatively nontoxic prodrug. The prodrug 1 currently on clinical trial is a benzamide and is cleaved by CPG2 to a benzoic acid mustard drug 1a. We have synthesized a series of new prodrugs 3-8 where the benzamide link has been replaced by, for example, carbamate or ureido. Some of these alternative links have been shown to be good substrates for CPG2 and therefore new candidates for ADEPT. The active drugs 3a and 4a derived from the best of these prodrugs are potent cytotoxic agents (1-2 microM) some 100 times more than 1a. The prodrugs 3 and 4 are some 100-200-fold less cytotoxic, in a proliferating cell assay, than their corresponding active drugs 3a and 4a.
A series of new 3'-(2-methyl-1-propenyl) and 3'-(2-methylpropyl) taxoids with modifications at C-10 was synthesized by means of the beta-lactam synthon method using 10-modified 7-(triethylsilyl)-10-deacetylbaccatin III derivatives. The new taxoids thus synthesized show excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines. All but one of these new taxoids possess better activity than paclitaxel and docetaxel in the same assay, i.e., the IC50 values of almost all the taxoids are in the subnanomolar level. It is found that a variety of modifications at C-10 is tolerated for the activity against normal cancer cell lines, but the activity against a drug-resistant human breast cancer cell line expressing MDR phenotype (MCF7-R) is highly dependent on the structure of the C-10 modifier. A number of the new taxoids exhibit remarkable activity (IC50 = 2.1-9.1 nM) against MCF7-R. Among these, three new taxoids, SB-T-1213 (4a), SB-T-1214 (4b), and SB-T-1102 (5a), are found to be exceptionally potent, possessing 2 orders of magnitude better activity than paclitaxel and docetaxel. The observed exceptional activity of these taxoids may well be ascribed to an effective inhibition of P-glycoprotein binding by the modified C-10 moieties. The new taxoid SB-T-1213 (4a) shows an excellent activity (T/C = 0% at 12.4 and 7.7 mg/kg/dose, log10 cell kill = 2.3 and 2.0, respectively) against B16 melanoma in B6D2F1 mice via intravenous administration.
The enediyne compounds 9-14, simple dynemicin A (1) analogues equipped with aryl carbamate moieties with various aliphatic amino or hydroxy groups at the C9 position, were synthesized and evaluated for DNA-cleaving ability, in vitro cytotoxicity, and in vivo antitumor activity. We found that the water-soluble compounds, in which the tert-amines such as the 2-(dimethylamino)ethyl (10b, 14b), 2-(pyrrolidino)ethyl (10c), or 1-azabicyclo[3.3.0]oct-5-ylmethyl (10d, 12d, 14d) group were attached, showed not only the enhanced in vivo antitumor activity but also the decreased toxicity compared to the corresponding 9-acetoxy enediyne compounds 6-8. In particular, compound 10c showed the most enhanced in vivo antitumor activity (T/C = 222% at a daily dose of 1.25 mg/kg for 4 days) at about half of the dose of 6. These results suggest that both the enhanced antitumor activity and the reduced toxicity might be due to the improved bioavailability or disposition of compounds 6-8 by their water-solubilization.