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Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine-2,5-dione Hybrids as Potential Antitumor Agents
Abstract
In search of Novel and effective antitumor agents, pyrazoline‐substituted pyrrolidine‐2,5‐dione hybrids were designed, synthesized and evaluated in silico, in vitro and in vivo for anticancer efficacy. All the compounds exhibited remarkable cytotoxic effects in MCF7 and HT29 cells. The excellent antiproliferative activity towards MCF‐7 (IC 50 = 0.78±0.01 µM), HT29 (IC 50 = 0.92±0.15 µM) and K562 (IC 50 = 47.25±1.24 µM) cell lines, prompted us to further investigate the antitumor effects of the best compound S2 . In cell cycle analysis, S2 was found to disrupt the growth phases with increased cell population in G1/G0 phase and decreased cell population in G2/M phase. The excellent in vitro effects were also supported by inhibition of anti‐apoptotic protein Bcl‐2. In vivo tumor regression studies of S2 in HT29 xenograft nude mice, exhibited equivalent and promising tumor regression with maximum TGI, 66% (i.p. route) and 60% (oral route) at 50 mg/kg dose by both the routes, indicating oral bioavailability and anti‐tumor efficacy. These findings advocate that hybridization of pyrazoline and pyrrolidine‐2,5‐dioes holds promise for the development of more potent and less toxic anticancer agents.
... Mass spectrum was documented on LC-MS Agilent Technologies 1260 Infinity instrument. Different chalcones were synthesized by procedure previously reported with minor modifications [90,104]. To ethanolic solution of NaOH (10%, 20 mL), substituted acetophenones (0.04 mol) and different aldehydes (0.04 mol) was added dropwise under ice bath and stirred for 5 h at RT. Reaction mixture was kept in refrigerator overnight, filtered and washed with cold water. ...
... Following are the unpublished chalcone intermediates, others have been reported elsewhere. [90,104] 3 ...
... Yellow crystalline solid. 81% yield (6. Various pyrazoline derivatives were synthesized by previously reported procedure with suitable modifications [90,104]. To solution of different chalcones (3a-3i, 6a-6 g, 6j, and 9b-9 g) (0.02 mol) in chloroform, hydrazine hydrate (0.04 mol) was added and refluxed for 12 h. ...
In the present study, two novel series of compounds incorporating naphthyl and pyridyl linker were synthesized and biological assays revealed 5-((6-(2-(5-(2-chlorophenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethoxy) naphthalene-2-yl)methylene)thiazolidine-2,4-dione (14b) as the most potent dual inhibitors of vascular endothelial growth factors receptor-2 (VEGFR-2) and histone deacetylase 4 (HDAC4). Compounds 13b, 14b, 17f, and 21f were found to stabilize HDAC4; where, pyridyl linker swords were endowed with higher stabilization effects than naphthyl linker. Also, 13b and 14b showed best inhibitory activity on VEGFR-2 as compared to others. Compound 14b was most potent as evident by in-vitro and in-vivo biological assessments. It displayed anti-angiogenic potential by inhibiting endothelial cell proliferation, migration, tube formation and also suppressed new capillary formation in the growing chick chorioallantoic membranes (CAMs). It showed selectivity and potency towards HDAC4 as compared to other HDAC isoforms. Compound 14b (25 mg/kg, i.p.) also indicated exceptional antitumor efficacy on in-vivo animal xenograft model of human colorectal adenocarcinoma (HT-29). The mechanism of action of 14b was also confirmed by western blot.
... The synthesis of the target molecules is depicted in Schemes 2 and 3, while Scheme 1 elicited the routes adopted for the synthesis of starting materials [17][18][19][20][21][22] . The chemical structures of the newly synthesised coumarin molecules were confirmed by elemental microanalyses and spectral data (IR, 1 H NMR and 13 C NMR). ...
... 4.1.5. Genaral procedure for synthesis of 1,3-diaryl-2-propen-1ones (4a-c) as reported [20][21][22] Equimolar amount of acetophenone and benzaldehyde derivatives (10 mmol) were dissolved in ethanol (10 mL) then 20% aqueous NaOH (10 mL) was added. The mixture was stirred for 12-18 h. ...
Persistent inflammation contributes to various inflammatory conditions. Inflammation-related diseases may be treated by inhibiting pro-inflammatory mediators and cytokines. Curcumin and coumarin derivatives can target signalling pathways and cellular factors to address immune-related and inflammatory ailments. This study involved designing and synthesising three series of coumarin-based analogs that incorporated curcumin and other heterocycles. These analogs were evaluated for their potential as anti-inflammatory agents in LPS-induced macrophages. Among the fourteen synthesised coumarin derivatives, compound 14b, which contained 3,4-dimethoxybenzylidene hydrazinyl, demonstrated the highest anti-inflammatory activity with an EC50 value of 5.32 μM. The anti-inflammatory effects of 14b were achieved by modulating signalling pathways like AKT/mTOR and Nrf2/HO-1, and downregulating NF-kβ, resulting in reduced production of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The modelling studies revealed that 14b and dexamethasone bind to the same TNF-α pocket, suggesting that 14b has potential as a therapeutic agent superior to dexamethasone for TNF-α.
... Different chalcones were synthesized using a previously reported procedure 82,83 with some minor modifications. In short, to ethanolic NaOH solution (10%, 20 mL), different acetophenones (0.04 mol-acetophenone, 4-fluoroacetophenone, and 2,4-difluoroacetophenone) were added followed by aldehydes (0.04 mol 2a-2g, 2j, and 2k) in an ice bath and stirred at room temperature (RT) for 5-6 h. ...
... Various pyrazole derivatives were synthesized and previously reported by us. 82,83 With minor modifications in the previous procedure, we synthesized pyrazoline derivatives from their respective chalcones. To a solution of chalcones (3a, 3b, 3d-3g, 3j, 3k, 6a-6g, 6j, 9c, 9e, and 9g) (0.02 mol) in chloroform, hydrazine hydrate (0.04 mol) was added and refluxed for 12 h. ...
In anticancer drug discovery, multi-targeting compounds have been beneficial due to their advantages over single-targeting compounds. For instance, VEGFR-2 has a crucial role in angiogenesis and cancer management, whereas HDACs are well-known regulators of epigenetics and have been known to contribute significantly to angiogenesis and carcinogenesis. Herein, we have reported nineteen novel VEGFR-2 and HDAC dual-targeting analogs containing diaryl-pyrazoline thiazolidinediones and their in vitro and in vivo biological evaluation. In particular, the most promising compound 14c has emerged as a dual inhibitor of VEGFR-2 and HDAC. It demonstrated anti-angiogenic activity by inhibiting in vitro HUVEC proliferation, migration, and tube formation. Moreover, an in vivo CAM assay showed that 14c repressed new capillary formation in CAMs. In particular, 14c exhibited cytotoxicity potential on different cancer cell lines such as MCF-7, K562, A549, and HT-29. Additionally, 14c demonstrated significant potency and selectivity against HDAC4 in the sub-micromolar range. To materialize the hypothesis, we also performed molecular docking on the crystal structures of both VEGFR-2 (PDB ID: 1YWN) and HDAC4 (PDB-ID: 4CBY), which corroborated the designing and biological activity. The results indicated that compound 14c could be a potential lead to develop more optimized multi-target analogs with enhanced potency and selectivity.
... The pyrrolidinedione (succinimide) belongs to privileged scaffolds in the modern drug design and its application demonstrated promising outcomes in the search and development of new potential anticancer small molecules [15]. A series of hybrid molecules of pyrrolidine-2,5dione with the pyrazoline [16] (Compound 1, Fig. 1), benzylidene (Compound 2, Fig. 1) [17], and other scaffolds (Compound 3, Fig. 1) [15] were synthesized and reported as highly active antitumor agents. ...
The hybrid heterocyclic molecules are perspective materials in the development of anticancer drugs. Here, the pyrrolidinedione-thiazolidinone hybrid molecules were designed as potent anticancer agents. This study aimed to investigate the cytotoxic effect of three derivatives 1-(4-hydroxyphenyl)-, 1-(4-chlorophenyl)- and 1-(4-bromophenyl)-3-[5-[2-chloro-3-(4-nitrophenyl)prop-2-enylidene]-4-oxo-2-thioxothiazolidine-3-yl]pyrrolidine-2,5-diones (Les-6287, Les-6294, and Les-6328, respectively), their effect on the production of the reactive oxygen species (ROS), apoptosis induction, and expression of genes - PPARγ, AHR, and NRFL2 – whose products are important in metabolism in human tongue squamous cell carcinoma cells of SCC-15 line. The results of resazurin reduction and lactate dehydrogenase (LDH) release assays proved the toxicity of the tested derivatives for the SCC-15 cells. Les-6287, Les-6294, and Les-6328 inhibited the viability of SCC-15 cells with the half-maximal effective concentration (EC50) in the range of 10.18–32.75 µM at 24 and 48 h treatment. These derivatives reduced the metabolism of SCC-15 cells with the half-maximal inhibitory concentration (IC50) of 6.72–39.85 µM at 24 and 48 h treatment. Les-6287, Les-6294, and Les-6328 reduced the metabolism of normal human keratinocytes of HaCaT line murine fibroblasts of Balb/c 3T3 line to a lesser extent. The compounds used in a range from 50 to 100 µM concentrations decreased ROS production in the SCC-15 cells. The derivatives Les-6287 and Les-6328 decreased the level of expression of mRNA of PPARγ, AHR, and NRFL2 genes in these cells at PPARγ siRNA knockdown and without it. Thus, the anticancer effect of studied hybrid pyrrolidinedione-thiazolidinones in the SCC-15 carcinoma cells is accompanied by a reduction of their metabolic activity and ROS level, and increase in caspase 3 activity. However, these changes are not the result of direct interaction of Les-6287, Les-6294, and Les-6328 with the PPARγ molecule.
... In the past few years, numerous and diverse TZD derivatives have been synthesized and extensively studied in the discovery of anticancer therapeutics [23][24][25][26][27][28][29][30][31][32], which is evident from the piling published literature [ 2 , 12 , 33 ]. Till very recently, several researches or reviews have been published on -or including -TZD nucleus [17] , and related bio-isosteric scaffolds [34][35][36][37] . Among the published reviews, most of them revolves around their structures, synthetic strategies [38] , anticancer mechanism of action (PPAR γ -dependent or PPAR γ -independent) [39][40][41] and their biological applications in general [42] . ...
Thiazolidinedione (TZD) containing derivatives have been proved to be promising anticancer agents in preclinical and clinical evaluation phases. Hybrid molecules not just offer the benefits such as enhanced therapeutic effects and improved specificity, but in addition could beat drug resistance, so hybridization of thiazolidinedione scaffold with other anticancer pharmacophoric scaffolds may constitute a hopeful strategy to develop newer and more efficacious anticancer agents. Based on this approach, in past decade, several such hybrids containing TZD scaffold have been reported and evaluated for their antitumor activity, and some of them revealed excellent in vitro potency, indicating their potential as presumed anticancer drugs. In this review, we will summarize the recent advances of TZD hybrids as potential anticancer agents, highlighting their antitumor activity and possible mechanism of action. Structure‐activity relationship (SAR) studies will also be discussed to direct the rational molecular hybridization of TZD scaffolds to design of more effective candidates.
... 13 Figure 6 describes the synthesis of final compounds B1-B8. The intermediates 4 (4b, 4c, 4e, 4g, 4i), 7 (7b, 7e, 7g), 13 (13b, 13c, 13e, 13g, 13i), and 14 (14b, 14e, 14g) were synthesized by previously reported procedure [42,50,51]. Cellular migration assay HUVEC cells were grown to 90% confluency in 6-well plates in DMEM, 10% FCS. ...
Background: Angiogenesis deregulation is often linked to cancer and is thus an essential target. Materials and methods: Twenty-nine compounds were developed as VEGFR-2 inhibitors. Compounds were evaluated to determine their antiangiogenic activity. Results: B1, PB11 and PB16 showed HUVEC's IC 50 scores in the submicromolar range. B1, B2 and PB16 reduced cellular migration and capillary tube formation of HUVECs. VEGFR-2 inhibitory activity was found in the nanomolar range: 200 nM of B1, 500 nM of B2 and 600 nM of PB16. B1 and PB16 suppressed the formation of new capillaries on growing CAMs. B1 and PB16 occupied the ATP site and allosteric pocket of VEGFR-2 in docking studies. Conclusion: These compounds can target VEGFR-2 and are endowed with in vitro and in vivo antiangiogenic activity.
... To escape the problem of drug resistance, Tilekar et al. [81] recently published new pyrazoline-substituted pyrrolidine-2,5-dione hybrids 116a-m (Fig. 24), with anticancer activity against MCF7, HT29, and K562 cancer cells. Compounds 116b,f,g, showed nanomolar activity against MCF7 with IC 50 values in the range of 0.42 and 0.78 µM. ...
The five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp ³ -hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring—a phenomenon called “pseudorotation”. In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2,5-diones and prolinol described in the literature from 2015 to date. After a comparison of the physicochemical parameters of pyrrolidine with the parent aromatic pyrrole and cyclopentane, we investigate the influence of steric factors on biological activity, also describing the structure–activity relationship (SAR) of the studied compounds. To aid the reader’s approach to reading the manuscript, we have planned the review on the basis of the synthetic strategies used: (1) ring construction from different cyclic or acyclic precursors, reporting the synthesis and the reaction conditions, or (2) functionalization of preformed pyrrolidine rings, e.g., proline derivatives. Since one of the most significant features of the pyrrolidine ring is the stereogenicity of carbons, we highlight how the different stereoisomers and the spatial orientation of substituents can lead to a different biological profile of drug candidates, due to the different binding mode to enantioselective proteins. We believe that this work can guide medicinal chemists to the best approach in the design of new pyrrolidine compounds with different biological profiles.
Chemotherapeutics occupy a pivotal role in the medication of different types of cancers, but the prevalence and mortality rates of cancer remain high. The drug resistance and low specificity of current available chemotherapeutics are the main barriers for the effective cancer chemotherapy, evoking an immediate need for the development of novel anticancer agents. Pyrazole is a highly versatile five-membered heterocycle with two adjacent nitrogen atoms and possesses remarkable therapeutic effects and robust pharmacological potency. The pyrazole derivatives especially pyrazole hybrids have demonstrated potent in vitro and in vivo efficacies against cancers through multiple mechanisms, inclusive of apoptosis induction, autophagy regulation, and cell cycle disruption. Moreover, several pyrazole hybrids such as crizotanib (pyrazole-pyridine hybrid), erdafitinib (pyrazole-quinoxaline hybrid) and ruxolitinib (pyrazole-pyrrolo [2,3-d]pyrimidine hybrid) have already been approved for the cancer therapy, revealing that pyrazole hybrids are useful scaffolds to develop novel anticancer agents. The purpose of this review is to summarize the current scenario of pyrazole hybrids with potential in vivo anticancer efficacy along with mechanisms of action, toxicity, and pharmacokinetics, covering papers published in recent 5 years (2018-present), to facilitate further rational exploitation of more effective candidates.
Pyrrolidine molecules are a significant class of synthetic and natural plant metabolites, which shows the diversity of pharmacological activities. An extensive variety of synthetic pyrrolidine compounds with numerous derivatization like spirooxindole, thiazole, metal complexes, coumarin, etc have revealed significant anticancer activity. Pyrrolidine molecules are found not only as potential anticancer candidates but also retain the lowest side effects. Depending upon the diverse substitution patterns of the derivatives, these molecules have demonstrated an incredible ability to regulate the various targets to give excellent anti-proliferative activities. Taking these into consideration, efforts have been taken by the scientific fraternity to design and develop a potent anticancer scaffold with negligible side effects. In the present review, we cover the latest advancements in the synthesis of pyrrolidine molecules which have promising anticancer activity toward numerous cancer cell lines. Additionally, it also highlights the effectiveness of derivatives via elucidation of Structural-Activity-Relationship (SAR) which is discussed in detail.
A new series of sulfonamides, 8a-b, 10, 12, and 14a-b, were synthesized by N-sulfonation reaction with sulfonyl chlorides 6a-b. Five new series of chalcone-sulfonamide hybrids (16-20)a-f were prepared via Claisen–Schmidt condensation of the newly obtained sulfonamides with aromatic aldehydes 15a-f in basic medium. Chalcones substituted with chlorine at position 4 of each series were used as precursors for the generation of their five-membered heterocyclic pyrazoline (22-23)a-d, (24-25)a-b and carbothioamide 27a-f derivatives. The synthesized compounds were evaluated for their anticancer and antituberculosis activities. To determine their anticancer activity, compounds were screened against sixty human cancer cell lines at a single dose (10 μM). Compounds 17a-c were highly active against LOX IMVI (melanoma), with IC50 values of 0.34, 0.73 and 0.54 μM, respectively. Chalcone 18e showed remarkable results against the entire panel of leukemia cell lines with IC50 values between 0.99–2.52 μM. Moreover, compounds 20e and 20f displayed growth inhibition of Mycobacterium tuberculosis H37Rv at concentrations below 10 μM. Although they showed low selectivity in cytotoxicity tests against the Vero cell line, further optimization could advance the potential biological activity of the selected compounds.
Breast cancer is a disease in which cells in the breast divide continuously without control. There are great limitations in cancer chemotherapy. Hence, it is essential to search for new cancer therapeutics. Herein, a novel series of EGFR/HER2 dual inhibitors has been designed based on the hybridization of thiazole and pyrazoline fragments. The synthesized compounds were screened for their anti-proliferative activity against MCF-7 breast cancer cell line and MCF-10 normal breast cell line. Interestingly, synthesized compounds 6e and 6k showed very potent antiproliferative activity towards MCF-7 with IC50 values of 7.21 and 8.02 µM, respectively. Furthermore, enzymatic assay was performed against EGFR and HER2 to prove the dual inhibitory action. Compounds 6e and 6k showed potent inhibitory activity for EGFR with IC50 of 0.009 and 0.051 µM, respectively, and for HER2 with IC50 of 0.013 and 0.027 µM, respectively. Additionally, compounds 6e and 6k significantly stimulated apoptotic breast cancer cell death. Compound 6e was further explored for its anticancer activity in vivo using a Xenograft model. Moreover, computational modeling studies, ADMET studies and toxicity prediction were performed to investigate their potential drug candidates.
In search for new and safer anti-cancer agents, a structurally guided pharmacophore hybridization strategy of two privileged scaffolds, namely diaryl pyrazolines and imidazolidine-2,4-dione (hydantoin), was adopted resulting in a newfangled series of compounds (H1-H22). Herein, a bio-isosteric replacement of “pyrrolidine-2,5-dione” moiety of our recently reported antitumor hybrid incorporating diaryl pyrazoline and pyrrolidine-2,5-dione scaffolds with “imidazoline-2,4-dione” moiety has been incorporated. Complete biological studies revealed the most potent analog among all i.e. compound H13, which was at-least 10-fold more potent compared to the corresponding pyrrolidine-2,5-dione, in colon and breast cancer cells. In-vitro studies showed activation of caspases, arrest of G0/G1 phase of cell cycle, decrease in the expression of anti-apoptotic protein (Bcl-2) and increased DNA damage. In-vivo assay on HT-29 (human colorectal adenocarcinoma) animal xenograft model unveiled the significant anti-tumor efficacy along with oral bioavailability with maximum TGI 36% (i.p.) and 44% (per os) at 50 mg/kg dose. These findings confirm the suitability of hybridized pyrazoline and imidazolidine-2,4-dione analog H13 for its anti-cancer potential and starting-point for the development of more efficacious analogs.
Succinimides are well recognized heterocyclic compounds in drug discovery which produce diverse therapeutically related applications in pharmacological practices. Researches in medicinal chemistry field have isolated and synthesized succinimide derivatives with multiple medicinal properties including anticonvulsant, anti-inflammatory, antitumor and antimicrobial agents, 5-HT receptor ligands and enzyme inhibitors. Simultaneously, SAR (Structure-Activity Relationship) analysis has been gradually possessed, along with a great deal of derivatives have been derived for potential targets. In this article, we comprehensively summarize the biological activities and SAR for succinimide derivatives, along with the featuring bioactive molecules reported in patents, wishing to provide an overall retrospect and prospect on the succinimide analogues.
Genetic abnormalities have been conventionally considered as hallmarks of cancer. However, recent studies have demonstrated that epigenetic mechanisms are also implicated in the insurgence and development of cancer. Patterns of the epigenetic component include DNA methylation and histone modifications. Acetylation of histones is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). Imbalance of these two enzymatic systems is known to be a key factor in tumor progression. Because HDACs have been found to function incorrectly in cancer, various HDAC inhibitors (HDACIs) are being investigated to act as cancer chemotherapeutics. Herein, we report the synthesis, docking studies and biological activity of a series of hydroxamic acid-based HDACIs bearing an N1-aryl or N1-H pyrazole nucleus as surface recognition motif and a cinnamoyl group as a linker to the hydroxamic acid zinc-binding group (ZBG). Some of the tested compounds exhibited inhibitory properties towards HDACs and antiproliferative activity against neuroblastoma SH-SY5Y tumor cell line both at micromolar concentrations.
To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
Apart from efficacy and toxicity, many drug development failures are imputable to poor pharmacokinetics and bioavailability. Gastrointestinal absorption and brain access are two pharmacokinetic behaviors crucial to estimate at various stages of the drug discovery processes. To this end, the Brain Or IntestinaL EstimateD permeation method (BOILED-Egg) is proposed as an accurate predictive model that works by computing the lipophilicity and polarity of small molecules. Concomitant predictions for both brain and intestinal permeation are obtained from the same two physicochemical descriptors and straightforwardly translated into molecular design, owing to the speed, accuracy, conceptual simplicity and clear graphical output of the model. The BOILED-Egg can be applied in a variety of settings, from the filtering of chemical libraries at the early steps of drug discovery, to the evaluation of drug candidates for development.
With the aim of developing novel antitumor scaffolds, a novel series of polysubstituted pyrazole derivatives linked to different nitrogenous heterocyclic ring systems at the C-4 position were synthesized through different chemical reactions and characterized by means of spectral and elemental analyses and their antiproliferative activity against 60 different human tumor cell lines was validated by the U.S. National Cancer Institute using a two stage process. The in vitro anticancer evaluation revealed that compound 9 showed increased potency toward most human tumor cell lines with GI50MG-MID = 3.59 µM, as compared to the standard drug sorafenib (GI50 MG-MID = 1.90 µM). At the same time, compounds 6a and 7 were selective against the HOP-92 cell line of non-small cell lung cancer with GI50 1.65 and 1.61 µM, respectively.
Virtual molecular screening is used to dock small-molecule libraries to a macromolecule in order to find lead compounds with desired biological function. This in silico method is well known for its application in computer-aided drug design. This chapter describes how to perform small-molecule virtual screening by docking with PyRx, which is open-source software with an intuitive user interface that runs on all major operating systems (Linux, Windows, and Mac OS). Specific steps for using PyRx, as well as considerations for data preparation, docking, and data analysis, are also described.
Angiogenesis is a mulit-step process by which new blood vessels are formed from preexisting vasculature. It is a key rate limiting factor in tumor growth since new blood vessels are necessary to increase tumor size. In this context it has been shown that anti-angiogenic factors can be used in cancer therapy. Among the plethora of heterocyclic compounds administered as anti-angiogenesis agents, pyrazoles constitute one of the bottlenecks of this category. Currently, several pyrazole based compounds are administered or are in Phase II and III trials and new targets emerge. It is highly possible that the advent of the next two decades will lead to the discovery and use of additional pyrazoles whose anti-angiogenic profile will position them in the forefront of the battle of various malignancies. The present review is an attempt to focus on those pyrazoles that arise as anti-angiogenesis agents commenting both on the chemistry and bioactivity that these exhibit aiming to contribute to the perspectives that they hold for future research.
In the past few years pyrazole derivatives have attracted increasing attention because of their numerous potential pharmacological applications. Changes in their structure have offered a high degree of diversity that has proven useful for the development of new medicinal agents with improved potency and less toxicity. This review focuses on the recent developments in pyrazole along with their structure–activity relationship (SAR), particularly for anticancer activity. The review covers SAR for active pyrazole molecules such as cyclin dependent kinase (CDK) inhibitor (modulator), aurora kinase inhibitors (modulator), break point cluster region-Abelson (BCR-ABL) tyrosine kinase inhibitors (modulator), heat shock protein (HSP 90) inhibitors (modulator), polo-like kinase inhibitors (modulator), cyclo-oxygenase (COX) and lypo-oxygenase (LOX) inhibitors (modulator), epithelial growth factor receptor (EGFR) inhibitors (modulator), reticular activating system–neuro endocrine tumor (Ras-Net) ETS-like transcription factor (Elk-3) pathway inhibitors (modulator), and DNA binding agent.
Export Date: 16 April 2014, Source: Scopus
P-glycoprotein (P-gp), an efflux membrane transporter, is widely distributed throughout the body and is responsible for limiting cellular uptake and the distribution of xenobiotics and toxic substances. Hundreds of structurally diverse therapeutic agents are substrates to it and it impedes the absorption, permeability, and retention of the drugs, extruding them out of the cells. It is overexpressed in cancer cells and accountable for obstructing cell internalization of chemotherapeutic agents and for developing transporter mediated resistance by cancer cells during anti-tumor treatments. As it jeopardizes the success of drug delivery and cancer targeting, strategies are being developed to overcome P-gp mediated drug transport. This concise review represents a brief discussion on P-gp mediated drug transport and how it hinders the success of various therapies. Its main focus is on various strategies used to tackle this curb in the field of drug delivery and targeting.
The aim of present research was investigation of anticancer activity of 4-azolidinone-3-carboxylic acids derivatives, and studies of structure–activity relationships (SAR) aspects. Methods. Organic synthesis; spectral methods; anticancer screening was performed according to the US NCI protocol (Developmental Therapeutic Program). Results. The data of new 4-thiazolidinone-3-alkanecarboxylic acids derivatives in vitro anticancer activity were described. The most active compounds which belong to 5-arylidene-2,4- thia(imida)zolidinone-3-alkanecarboxylic acids; 5-aryl(heteryl)idenerhodanine-3-succinic acids derivatives were selected. Determination of some SAR aspects which allowed to determine directions in leadcompounds structure optimization, as well as desirable molecular fragments for design of potential anticancer agents based on 4-azolidinone scaffold were performed. 5-Arylidenehydantoin-3-acetic acids amides were identified as a new class of significant selective antileukemic agents. Possible pharmacophore scaffold of 5-ylidenerhodanine-3-succinic acids derivatives was suggested. Conclusions. The series of active compounds with high anticancer activity and/or selectivity levels were selected. Some SAR aspects were determined and structure design directions were proposed.
Epigenetics plays a fundamental role in cancer progression, and developing agents that regulate epigenetics is crucial for cancer management. Among Class I and Class II HDACs, HDAC8 is one of the essential epigenetic players in cancer progression. Therefore, we designed, synthesized, purified, and structurally characterized novel compounds containing N-substituted TZD (P1-P25). Cell viability assay of all compounds on leukemic cell lines (CEM, K562, and KCL22) showed the cytotoxic potential of P8, P9, P10, P12, P19, and P25. In-vitro screening of different HDACs isoforms revealed that P19 was the most potent and selective inhibitor for HDAC8 (IC50 – 9.3 μM). Thermal shift analysis (TSA) confirmed the binding of P19 to HDAC8. In-vitro screening of all compounds on the transport activity of GLUT1, GLUT4, and GLUT5 indicated that P19 inhibited GLUT1 (IC50 – 28.2 μM). P10 and P19 induced apoptotic cell death in CEM cells (55.19% and 60.97% respectively) and P19 was less cytotoxic on normal WBCs (CC50 – 104.2 μM) and human fibroblasts (HS27) (CC50 – 105.0 μM). Thus, among this novel series of TZD derivatives, compound P19 was most promising HDAC8 inhibitor and cytotoxic on leukemic cells. Thus, P19 could serve as a lead for further development of optimized molecules with enhanced selectivity and potency.
Histone deacetylases (HDACs) are being explored as a therapeutic target for interventions in different types of cancer. HDAC8 is a class I HDAC that is implicated as a therapeutic target in various indication areas, including different types of cancer and particularly childhood neuroblastoma. Most previously described HDAC8-selective inhibitors contain a hydroxamate function as zinc binding group (ZBG) to confer potency. However, hydroxamate class HDAC inhibitors have raised increasing concerns about their mutagenic character. Therefore, non-hydroxamate based inhibitors could prove to be safer than hydroxamates. In the present work, a series of novel 5-naphthylidene-2,4-thiazolidinedione was designed and evaluated as potential antiproliferative agents targeting selectively HDAC8 enzyme. Eleven novel derivatives were synthesized, purified and characterized by spectroscopic techniques. Compounds 3k and 3h was found to be most potent selective inhibitors of HDAC8 with IC50 values of 2.7 μM and 6.3 μM respectively. 3a to 3i was found to be most cytotoxic in leukemic cell lines. 3a and 3 h both were found to induce apoptosis and cause cell cycle arrest in G2/M phase.
The investigations of stabilization energy, bond order, intra-molecular interactions and energy gap of pharmaceutical drugs are useful for understanding their behaviour. A new Mannich base molecule 1-((dibenzylamino)methyl)-pyrrolidine-2,5-dione (SBF) was synthesized through sequential Mannich reactions of an imide with an aldehyde and the intermediate obtained are reacted with secondary amine to get the desired product. The entire molecular geometry of the SBF molecule was confirmed by single crystal XRD studies. The crystal structure of SBF molecule was found symmetrical and planar with anti-periplanar orientation of CO group and nitrogen atom. The theoretical computations were performed using B3LYP/6-31G(d, p) level of basis set. The chemical environment of carbon and protons were shown with ¹³C and ¹H NMR spectral analysis, respectively. The molecular weight of the title molecule was determined by mass spectrum. The thermal stability of the SBF molecule up to 270 °C was exposed by thermogravimetric (TG) and differential scanning analysis (DSC). The natural bonding orbital (NBO) analysis data revealed the highest stabilization value of E(2) for transfer of electron density from succinimide to the antibonding molecular orbital of the dibenzyl ring were found to be 51.51 and 50.31 kJ/mol. The energy of HOMO-LUMO, PDOS, OPDOS, RDG of the title molecule have also been carried out. The protein-ligand relationship was well revealed by molecular docking studies. The cytotoxic activity of the SBF molecule was evaluated by MTT assay on cell line A549.
Exosomes are a class of extracellular vesicles ranging in size from 40 to 100 nm, which are secreted by both cancer cells and multiple stromal cells in the tumor microenvironment. Following their secretion, exosomes partake in endocrine, paracrine and autocrine signaling. Internalization of exosomes by tumor cells influences several cellular pathways which alter cancer cell physiology. Tumor-derived exosomes secreted by cancer or stromal cells can also confer anticancer drug-resistant traits upon cancer cells. These exosomes promote chemoresistance by transferring their cargo which includes nucleic acids, proteins, and metabolites to cancer cells or act as a decoy for immunotherapeutic targets. Depletion of exosomes can reverse some of the detrimental effects on tumor metabolism and restore drug sensitivity to chemotherapeutic treatment. Herein we discuss various approaches that have been developed to deplete exosomes for therapeutic purposes. The natural composition, low immunogenicity and cytotoxicity of exosomes, along with their ability to specifically target tumor cells, render them an appealing platform for drug delivery. The ability of exosomes to mediate autocrine and paracrine signaling in target cells, along with their natural structure and low immunogenicity render them an attractive vehicle for the delivery of anticancer drugs to tumors.
Background:
Cancer being a complex disease, single targeting agents remain unsuccessful. This calls for "multiple targeting", wherein a single drug is so designed that it will modulate the activity of multiple protein targets. Topoisomerase 2 (Top2) helps in removing DNA tangles and super-coiling during cellular replication, Casein Kinase 2 (CK2) is involved in the phosphorylation of a multitude of protein targets. Thus, in the present work, we have tried to develop dual inhibitors of Top2 and CK2.
Objective:
With this view, in the present work, 2 human proteins, Top2 and CK2 have been targeted to achieve the anti-proliferative effects.
Methods:
Novel 1-acetylamidoanthraquinone (3a-3y) derivatives were designed, synthesized and their structures were elucidated by analytical and spectral characterization techniques (FTIR, 1H NMR, 13C NMR and Mass Spectroscopy). The synthesized compounds were then subjected to evaluation of cytotoxic potential by the Sulforhodamine B (SRB) protein assay, using HL60 and K562 cell lines. Ten compounds were analyzed for Top2, CK2 enzyme inhibitory potential. Further, top three compounds were subjected to cell cycle analysis.
Results:
The compounds 3a to 3c, 3e, 3f, 3i to 3p, 3t and 3x showed excellent cytotoxic activity to HL-60 cell line indicating their high anti-proliferative potential in AML. The compounds 3a to 3c, 3e, 3f, 3i to 3p and 3y have shown good to moderate activity on K-562 cell line. Compounds 3e, 3f, 3i, 3x and 3y were found more cytotoxic than standard doxorubicin. In cell cycle analysis, the cells (79-85%) were found to arrest in the G0/G1 phase.
Conclusion:
We have successfully designed, synthesized, purified and structurally characterized 1- acetylamidoanthraquinone derivatives. Even though our compounds need design optimization to further increase enzyme inhibition, their overall anti-proliferative effects were found to be encouraging.
A series of hybrid Aldimine-type Schiff base derivatives including trimethoxyphenyl ring and 1,2,4-triazle-3-thiol/thione were designed as tubulin inhibitors. The molecular docking simulations on tubulin complex (PDB: 1SA0) revealed that derivatives with nitro and /or chloro or dimethylamine substitutes (4-Nitro, 2-Nitro, 3-Nitro, 4-Cl-3-nitro, and 4-N(CH3)2) on the aldehyde ring were the best compounds with remarkable binding energies (-9.09, -9.07, -8.63, -8.11, and -8.07 kcalmol⁻¹, respectively) compared to Colchicine (-8.12 kcalmol⁻¹). These compounds were also showed remarkable binding energies from -10.66 to -9.79 and -10.12 to -8.95 kcalmol⁻¹ on human (PDB: 1PD8) and Candida albicans (PDB: 3QLS) DHFR, respectively. The obtained results of cytotoxic activities against HT1080, HepG2, HT29, MCF-7, and A549 cancer cell lines indicated that 4-Nitro and 2-Nitro substituted compounds were the most effective agents by mean IC50 values of 11.84±1.01 and 19.92±1.36 μM, respectively. 4-Nitro substituted compound (5 μM) and 2-Nitro substituted compound (30 μM) were able to strongly inhibit the tubulin polymerization compared to Colchicine (5 μM) and 4-Nitro substituted compound displayed IC50 values of 0.16±0.01 μM compared to that of colchicine (0.19±0.01 μM). This compound also showed the lowest MIC values on all tested microbial strains including three Gram-positive, four Gram-negative, and three yeast pathogens.
In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti-cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A series of hydroxamic acid derivatives bearing phenylpyrazol moiety were designed and synthesized as HDAC6 inhibitors. Most compounds showed potent HDAC6 inhibition activity. 11i was the most selective compound against HDAC6 with IC50 values of 0.020 µM and selective factor of 101.1. Structure-activity relationship analysis indicated that locating the linker group at 1’ of pyrazol gave the most selectivity. The most compounds 11i (GI50 = 3.63 μM) exhibited 6-fold more potent than vorinostat in HepG2 cells. Considering of the high selectivity against HDAC6 and anti-proliferation activity, such compounds have potential to be developed as anti-cancer agents.
The current research article reports the synthesis of coumarinyl pyrazolinyl thioamide derivatives and their biological activity as inhibitors of jack bean urease. The coumarinyl pyrazolinyl thioamides were synthesized by reacting thiosemicarbazide with newly synthesized chalcones to afford the products in good yields and the synthesized compounds were purified by recrystallization. Coumarinyl pyrazolinyl thioamide derivatives 5a-5q showed significant activity against Urease enzyme and also exhibited good antioxidant potential. The compound 3-(2-Oxo-2H-chromen-3-yl)-5-phenyl-4,5-dihydro-1H-pyrazole-1-carbothioamide 5n was found to be superior agent in the series with an IC50 = 0.358±0.017μM compared to standard thiourea with an IC50 = 4720±174μM. To undermine the binding mode of inhibition kinetic studies were performed for most potent derivative and it was found that compound 5n inhibits urease enzyme by non-competitive mode of inhibition. Molecular docking studies were carried out to delineate the binding affinity of the synthesized derivatives. This article is protected by copyright. All rights reserved.
Introduction: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with a poor prognosis due to late diagnosis in the majority of cases. Physicians are frequently confronted with patients who are not eligible for curative or locoregional treatments any more. In this scenario, the multi-tyrosine kinase inhibitor sorafenib remains the only systemic first-line treatment option providing modest survival benefit compared to placebo with significant but for most patients acceptable adverse effects.
Areas covered: Tivantinib was the first antiproliferative agent to be been applied in a phase III trial based on receptor overexpression analyses after disease progression on sorafenib. While phase I and II trials with tivantinib in second line showed encouraging results, a recent press release announced that the METIV-HCC phase III study of tivantinib in HCC did not meet its primary endpoint of improving overall survival.
Expert commentary: Evidence for antiangiogenetic therapy inducing tumor hypoxia leading to overexpression of proliferative genes, including cMET, underlines the potential of tivantinib as second-line treatment. However, as the mechanism of action of tivantinib through cMET inhibition has recently been questioned by several groups, identification of alternative proliferative markers or targets is mandatory.
Design of a new drug entity is usually preceded by analysis of quantitative structure activity (properties) relationships, QSA(P)R. Six newly synthesized succinimide derivatives have been determined for i) in silico physico-chemical descriptors, pharmacokinetic and toxicity predictors, ii) in vitro biological activity on four different carcinoma cell lines and on normal fetal lung cells and iii) lipophilicity on liquid chromatography. All compounds observed were predicted for good permeability and solubility, good oral absorption rate and moderate volume of distribution as well as for modest blood brain permeation, followed by acceptable observed toxicity. In silico determined lipophilicity, permeability through jejunum and aqueous solubility were correlated with experimentally obtained lipophilic constants (by use of high pressure liquid chromatography) and linear correlations were obtained. Absorption rate and volume of distribution were predicted by chromatographic lipophilicity measurements while permeation through blood bran barrier was predicted dominantly by molecular size defined with molecular weight. Five compounds have demonstrated antiproliferative activity toward cervix carcinoma HeLa cell lines; three were cytotoxic against breast carcinoma MCF-7 cells, while one inhibited proliferation of colon carcinoma HT-29 cell lines. Only one compound was cytotoxic toward normal cell lines, while other compounds were proven as safe. Antiproliferative potential against HeLa cells was described as exponential function of lipophilicity. Based on obtained results, lead compounds were selected.
The weakly coordinating ketone group-directed C–H functionalizations of chromones, 1,4-naphthoquinones and xanthones with various maleimides under rhodium(III) catalysis are described. These protocols efficiently provide a range of succinimide-containing chromones, naphthoquinones and xanthones with excellent site-selectivity and functional group compatibility. All synthetic compounds were screened for in vitro anticancer activity against human breast adenocarcinoma cell lines (MCF-7). In particular, compounds 7aa and 7ca with a naphthoquinone scaffold were found to be highly cytotoxic, with an activity competitive with anticancer agent doxorubicin.
Background:
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that regulates the expression of many genes relevant to carcinogenesis. By analogy to selective estrogen receptor modulator for treatment of cancer, selective or partial PPARγ agonists are considered clinically important for chemotherapy of cancer.
Objective:
In this study we have rationally modified the structure of existing p-coumaric acid and ferulic acid, which would selectively activate PPARγ and exert their anti-proliferative effect at lower dose as compared to natural phytoconstituents.
Method:
A series of p-coumaric (3a-3y) and ferulic acid (4a-4y) derivatives were designed as docked and virtually studied for their molecular properties using suitable software. Synthesized derivatives were assessed to check their effect on non-transformed hepatocytes using MTT assay. The final products, 3a-3y and 4a-4y, substituted 4- hydroxycinnamic acid derivatives and ferulic acid derivatives respectively were synthesized by stirring compound 1a or 1b with compounds 2a-2y (molar ratio- 1:2) for 24 hours, in presence of K2CO3, using dimethyl formamide (DMF) as the solvent. Synthesized molecules were characterized by 1HNMR, 13C NMR, Mass and elemental analysis. Synthesized molecules were studied for their antiproliferative activity by SRB assay. Compounds were screened further evaluated for PPARγ activating assay, cell cycle analysis (propidium iodide) and westernblot analysis.
Results:
Molecules 3c, 3m, 4c and 4m were found to have GI50 value less than 50μM. These molecules were found to block G0/G1 phase of cell cycle in dose dependent manner. Western blot analysis revealed that these molecules inhibit proliferating cell nuclear antigen (PCNA) and cyclin D1 expression.
Conclusion:
Collectively, these results suggest that these molecules could play a role as a novel therapeutic strategy for chronic myeloid leukemia.
The cyclization of chalcones 3a-3u with 3-hydrazinyl-6-phenylpyridazine 7 under basic condition led to the formation of new pyrazoline derivatives 8a-8u. All final compounds were characterized by spectral and elemental analyses. They were screened for their antiproliferative activities against A549 (lung), HepG-2 (liver), CaCo-2 (intestinal) and MCF-7 (breast) cancer cell lines. Some of the synthesized compounds exhibited promising antiproliferative activities especially compound 8k with IC50 values of 8.33, 1.67 and 10 μM against HepG-2, MCF-7 and CaCo-2 cancer cell lines, respectively. Moreover, their antiproliferative activity was due to apoptosis rather than necrosis induction except compound 8h which exhibited equal apoptotic and necrotic properties. Compound 8k showed 5 fold increase in caspase-3 activity indicating that the apoptosis proceeds via caspase-3 activation.
Novel fluorine-containing pyrazolines (2a-2g) and pyrazoles (5a-5e) were synthesized and evaluated for their cytotoxicity in vitro in a panel of four human cancer cell lines using Sulforhodamine B (SRB) assay. Though the compounds showed varying degrees of cytotoxicity in different cell lines, it was noteworthy that the 4H pyrazoles (5a-5e) were distinguished by their potent and selective action against MCF7 breast cancer cell line.
A series of novel thiol-based histone deacetylase (HDAC) inhibitors bearing 3-phenyl-1H-pyrazole-5-carboxamide scaffold as surface recognition motif was designed, synthesized, and evaluated for their HDAC inhibition activity. Among them, 15j (IC50=0.08μM) was identified as a better inhibitor than Vorinostat (IC50=0.25μM) against total HDACs. In addition, Structure-activity relationships (SAR) analyses indicated that (i) compounds with different substituents on pyrazole N-1 position exhibited superior activities than those on pyrazole N-2 position, (ii) variation of functional groups on N-1'-alkyl chain terminus followed the trends of carboxyl group>hydroxyl group≫alkyl group, and (iii) methylation on pyrazole C-4 position diminished the HDAC inhibition activity. The SAR will guide us to further refine compounds bearing 3-phenyl-1H-pyrazole-5-carboxamide scaffold to achieve better HDAC inhibitors.
Apremilast (Otezla(®)) is an oral phosphodiesterase 4 inhibitor indicated for the twice-daily treatment of adults with psoriasis and psoriatic arthritis (PsA). Its use in these patient populations has been assessed in two phase III clinical trial programmes (ESTEEM and PALACE). At 16 weeks in the two ESTEEM trials, apremilast reduced the severity and extent of moderate to severe plaque psoriasis, including nail, scalp and palmoplantar manifestations, versus placebo in adults, with these benefits generally being sustained over 52 weeks of treatment. Similarly, in three PALACE trials (PALACE 1-3), apremilast improved the signs and symptoms of PsA relative to placebo at 16 weeks in adults with active disease despite treatment with conventional synthetic and/or biologic disease-modifying anti-rheumatic drugs. These PsA benefits were generally sustained for up to 104 weeks of treatment; skin involvement, enthesitis and dactylitis also improved with the drug. Apremilast was generally well tolerated, with the most common adverse events being diarrhoea and nausea in the first year of treatment (usually occurring in the first 2 weeks after the first dose and resolving within 4 weeks) and nasopharyngitis and upper respiratory tract infection with continued treatment. Although further longer-term and comparative efficacy and tolerability data would be beneficial, the current clinical data indicate that apremilast is an effective and well tolerated option for the management of psoriasis and PsA in adults.
A series of novel pyrazoline-containing derivatives (15-47) has been designed, synthesized and evaluated for their biological activities. Among them, compound 18 displayed the most potent antiproliferative activity against A549, MCF-7 and HepG-2 cells line (IC50 = 0.07 μM, 0.05 μM, 0.03 μM, respectively) and the tubulin polymerization inhibitory activity (IC50 = 1.88 μM), being comparable to CA-4. Furthermore, we also tested that compound 18 was a potent inducer of apoptosis in HepG-2 cells and it had cellular effects typical for microtubule interacting agents, causing accumulation of cells in the G2/M phase of the cell cycle. These studies, along with molecular docking, provided a new molecular scaffold for the further development of antitumor agents that target tubulin.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.
The n-octanol/water coefficient (log Po/w) is a key physicochemical parameter for drug discovery, design and development. Here, we present a physics-based approach that shows a strong linear correlation between the computed solvation free energy in implicit solvents and the experimental log Po/w on a cleansed data set of more than 17,500 molecules. After internal validation by five-fold cross-validation and data randomization, the predictive power of the most interesting multiple linear model, based on two GB/SA parameters solely, was tested on two different external sets of molecules. On the Martel druglike test set, the predictive power of the best model (N=706, r=0.64, MAE=1.18 and RMSE=1.40) is similar to six well established empirical methods. On the 17-drug test set, our model outperformed all compared empirical methodologies (N=17, r=0.94, MAE=0.38 and RMSE=0.52). The physical basis of our original GB/SA approach together with its predictive capacity, its computational efficiency (1 to 2 seconds per molecule) and its tridimensional molecular graphics capability lay the foundations for a promising predictor, the implicit log P method (iLOGP), to complement the portfolio of drug design tools developed and provided by SIB | Swiss Institute of Bioinformatics.
Recent era aims at developing safer partial Peroxisome proliferator-activated receptor- (PPAR- ) agonists in order to dodge the toxicity issues related to full agonists. With a view to develop non-thiazolidinediones as partial PPAR- agonists, novel analogues of oxazol-5-ones (3a-3q) were designed and virtually analyzed for their molecular and drug like properties. The newly synthesized compounds were further evaluated for their preliminary cytotoxicity in a panel of eight cancer cell lines using four concentrations at 10- fold dilutions. Sulforhodamine B (SRB) protein assay was used to estimate cell stability or growth. All the compounds demonstrated distinct effect in the extent of cytotoxicity in the breast cancer cell line MCF-7 with 3g specifically exhibiting partial PPAR- agonist activity and adipogenesis stimulating ability.
AutoDock Vina, a new program for molecular docking and virtual screening, is presented. AutoDock Vina achieves an approximately two orders of magnitude speed-up compared with the molecular docking software previously developed in our lab (AutoDock 4), while also significantly improving the accuracy of the binding mode predictions, judging by our tests on the training set used in AutoDock 4 development. Further speed-up is achieved from parallelism, by using multithreading on multicore machines. AutoDock Vina automatically calculates the grid maps and clusters the results in a way transparent to the user.
Two series of 2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-1-methyl-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitriles 5a-h and 4-(4-chlorophenyl)-2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-1-methyl-6-oxo-1,6-dihydropyrimidine-5-carbonitriles 6a-h were synthesized via a cyclocondensation reaction of the corresponding 2-hydrazinopyrimidines 3a,b with the appropriate 2-propen-1-ones 4a-h. The target compounds were screened for their antiproliferative activity against A 549 (lung), HT 29 (colon), MCF 7 and MDA-MB 231 (breast) cell lines. The two most susceptible cell lines were the colon (HT 29) and breast (MDA-MB 231). Generally, the 4-unsubstitutedphenylpyrimidine derivatives 5a-h were more active than their 4-chlorophenylpyrimidine analogs 6a-h. Compounds 5e and 5g, showed high activity against three of the cell lines. The most active compound 5c possessed IC50 = 1.76 μM against A 549 cell line.
Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting `the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP>4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.
Modern cancer therapies are highly effective in the treatment of various malignancies, but their use is limited by the potential for cardiotoxicity. The most frequent and typical clinical manifestation of cardiotoxicity is left ventricular dysfunction, induced not only by cytotoxic conventional cancer therapy like anthracyclines, but also by new antitumor targeted therapy such as trastuzumab. The current standard for monitoring cardiac function, based on periodic assessment of left ventricular ejection fraction detects cardiotoxicity only when a functional impairment has already occurred, precluding any chance of preventing its development. A novel approach, based on the use of cardiac biomarkers has emerged in the last decade, resulting in a cost-effective diagnostic tool for early, real-time identification, assessment and monitoring of cardiotoxicity. In particular, prophylactic treatment with enalapril in patients with an early increase in troponin after chemotherapy has been shown to be very effective in preventing left ventricular dysfunction and associated cardiac events. In patients developing cancer treatment induced-cardiomyopathy, complete left ventricular ejection fraction recovery and a reduction of cardiac events may be achieved only when left ventricular dysfunction is detected early after the end of cancer treatment and treatment with angiotensin-converting enzyme inhibitors, possibly in combination with beta-blockers, is promptly initiated.
Background:
The discovery of ABT-263, a rationally designed Bcl-2/Bcl-xL inhibitor at present in Phase I clinical trials for cancer, is described. Emphasis is placed on the specific hurdles overcome throughout the discovery process that relate to the nature of the targeted protein-protein interaction (PPI).
Objective/methods:
This review draws on observations from the experience of discovering ABT-263 and discusses them within the framework of the larger issue of discovering drugs targeting PPIs. Issues discussed include the 'hot spot' paradigm, hit and lead generation, serum protein binding, structure-based design, and in particular, hydrophobicity and molecular size and their relation to pharmacokinetic/pharmacodynamic properties.
Results/conclusion:
Approaches to understanding obstacles thought of as being specifically attached to PPIs, and existing techniques to combat these obstacles, were very helpful in overcoming them. The example of ABT-263 provides evidence that the larger family of PPI targets is more tractable than may have been thought.
Two groups of coumarin-pyrazoline hybrids were synthesized. The target compounds were obtained by cyclization of the coumarin chalcones with various substituted hydrazines to produce the corresponding pyrazolines through 1,4-addition on α,β-unsaturated carbonyl system. Selected compounds were investigated for their anticancer activity toward 60 cancer cell lines according to US NCI protocol where breast cancer MCF7 and colon cancer HCT-116 were the most susceptible to the influence of compounds 7d, 8c and 9c. Encouraged by this, all final compounds were screened against colorectal cell line HCT-116. The tested compounds exhibited high potency with IC(50) ranging from 0.01 μM to 2.8 μM. Moreover, compound 9c which possessed the highest cytotoxicity proved to have weak enzyme inhibitory activity against PI3K (p110α/p85α).
Thiazolidinediones have been established as a drug class of significant importance in the treatment of Type II diabetes mellitus and have more recently displayed emergent potential as anti-cancer agents. However, their toxicity has hampered clinical development and usage in both therapeutic areas. Studies to date have implicated that the thiazolidinedione ring is responsible for the generation of reactive metabolites after metabolism. As an attempt to improve their safety profiles, we considered the bioisosteric replacement of the thiazolidinedione ring with a chemically conserved pyrrolidinedione heterocyclic system. Using pyrrolidinedione analogs of the thiazolidinedione drugs troglitazone (TGZ), rosiglitazone (RGZ), and pioglitazone (PGZ), we evaluated their PPAR(γ) activities, anti-cancer properties as well as toxicological effects. Of significance, both pyrrolidinedione analogs demonstrated reduced toxicity. Pharmacologically, they also displayed diminished PPAR(γ) binding and ap2 gene expression in a mouse pre-adipocyte cell line 3T3-L1, but enhanced anti-cancer properties based on the suppression of liver cancer cell line (Huh-7) proliferation and the expression of tumor marker, afp. Overall, this study ascertains the general contribution of the thiazolidinedione ring to their cytotoxicity and proposes the applicability of the pyrrolidinedione ring as a selective and safer choice in anti-diabetic and cancer chemotherapeutics for future drug design.
The synthesis and antitumor activity screening of novel 3-[2-(3,5-diaryl-4,5-dihydropyrazol-1-yl)-4-oxo-4,5-dihydro-1,3-thiazol-5-ylidene]-2,3-dihydro-1H-indol-2-ones 1-23 and 3-(3,5-diarylpyrazol-1-yl)-2,3-dihydro-1H-indol-2-ones 24-39 are performed. In vitro anticancer activity of the synthesized compounds was tested by the National Cancer Institute. Most of them displayed anticancer activity on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancers cell lines. The structure-activity relationship is discussed. The most effective anticancer compound 10 was found to be active with mean GI(50) and TGI values of 0.071 μM and 0.76 μM, respectively. It demonstrated the highest antiproliferative influence on the non-small-cell lung cancer cell line HOP-92 (GI(50) < 0.01 μM), colon cancer line HCT-116 (GI(50) = 0.018 μM), CNS cancer cell line SNB-75 (GI(50) = 0.0159 μM), ovarian cancer cell line NCI/ADR-RES (GI(50) = 0.0169 μM), and renal cancer cell line RXF 393 (GI(50) = 0.0197 μM).
A series of ureidofibrate-like derivatives was prepared and assayed for their PPAR functional activity. A calorimetric approach was used to characterize PPARγ-ligand interactions, and docking experiments and X-ray studies were performed to explain the observed potency and efficacy. R-1 and S-1 were selected to evaluate several aspects of their biological activity. In an adipogenic assay, both enantiomers increased the expression of PPARγ target genes and promoted the differentiation of 3T3-L1 fibroblasts to adipocytes. In vivo administration of these compounds to insulin resistant C57Bl/6J mice fed a high fat diet reduced visceral fat content and body weight. Examination of different metabolic parameters showed that R-1 and S-1 are insulin sensitizers. Notably, they also enhanced the expression of hepatic PPARα target genes indicating that their in vivo effects stemmed from an activation of both PPARα and γ. Finally, the capability of R-1 and S-1 to inhibit cellular proliferation in colon cancer cell lines was also evaluated.
In the present work, ten novel derivatives (3a-3j) of 5-benzylidene-2,4-thiazolidinediones were synthesized and their structures were determined by analytical and spectral (FTIR, (1)H NMR, (13)C NMR) methods. The newly synthesized compounds were evaluated for their antiproliferative activity at Tata Memorial's Advanced Center for Treatment, Research and Education in Cancer (ACTREC), India, in a panel of 7 cancer cell lines using four concentrations at 10-fold dilutions. Sulforhodamine B (SRB) protein assay was used to estimate cell stability or growth. Though the compounds showed varying degrees of cytotoxicity in the tested cell lines, most marked effect was observed by compound 3e in MCF7 (breast cancer), K562 (leukemia) and GURAV (nasopharyngeal cancer) cell lines with log(10) GI(50) values of -6.7, -6.72 and -6.73 respectively.
A series of novel oxime-containing pyrazole derivatives were synthesized by the reaction of ethyl 3-phenyl-1H-pyrazole-5-carboxylate derivatives and 2-bromo-1-phenylethanone followed by the reaction with hydroxylamine hydrochloride. The structures were determined by IR, (1)H NMR, HRMS, and X-ray analysis. A dose- and time-dependent inhibition of proliferation was observed in A549 lung cancer cell after compound treatment. Inhibition of growth was mainly attributed to the autophagy induction.
A hybrid pharmacophore approach was used to design and synthesize isatin-benzothiazole analogs to examine their anti-breast cancer activity. The cytotoxicity of these compounds were determined using three different human breast tumor cell lines, MDA-MB231, MDA-MB468, MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Although all compounds examined were quite effective on all the cancer cell lines examined, the compounds 4-bromo-1-diethylaminomethyl-1H-indole-2,3-dione (2l) and 4-chloro-1-dimethylaminomethyl-3-(6-methyl-benzothiazol-2-ylimino)-1,3-dihydro-indol-2-one (5e) emerged as the most active compounds of this series. Importantly, the cytotoxic effect of 2l was 10-15-fold higher on cancer than non-cancer cells, suggesting that this compound can be very effective for the control of breast cancer with low side effects. Since 2l showed effective cytotoxicity on MCF7 cells and arrested the cells at G2/M at a similar concentration, these two phenomena may be closely correlated. We conclude that the isatin-linked benzothiazole analog can serve as a prototype molecule for further development of a new class of anti-breast cancer agents.
To determine apoptosis modulators of human umbilical vein endothelial cells (HUVECs), we prepared 9 novel complexes of copper (Cu) and salicylaldehyde pyrazole hydrazone (SPH) derivatives (Cu-SPHs). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay revealed that all of the SPHs and Cu-SPHs effectively inhibited cell growth. Six of the 9 Cu-SPHs induced apoptosis in HUVECs. Among the 9 Cu-SPHs, the complex of Cu and (E)-N'-(2-hydroxybenzylidene)-1-benzyl-3-phenyl-1H-pyrazole-5-carbohydrazide, named Cu-15, was one of the most effective apoptosis inducers and inhibited angiogenesis on Matrigel and HUVEC migration in vitro. We further studied the mechanism of Cu-15 action and found that the protein level of integrin beta 4 increased with 10 microM Cu-15 treatment for 12 or 24 h. Knockdown of integrin beta 4 by RNA interference significantly inhibited apoptosis induced by Cu-15 in HUVECs. Thus, high level of integrin beta 4 could promote apoptosis induced by Cu-15. Cu-15 might be a useful tool for further investigating the functions of integrin beta 4 in regulating angiogenesis and HUVEC apoptosis.
Overexpression of prosurvival proteins such as Bcl-2 and Bcl-X L has been correlated with tumorigenesis and resistance to chemotherapy, and thus, the development of antagonists of these proteins may provide a novel means for the treatment of cancer. We recently described the discovery of 1 (ABT-737), which binds Bcl-2, Bcl-X L, and Bcl-w with high affinity, shows robust antitumor activity in murine tumor xenograft models, but is not orally bioavailable. Herein, we report that targeted modifications at three key positions of 1 resulted in a 20-fold improvement in the pharmacokinetic/pharmacodynamic relationship (PK/PD) between oral exposure (AUC) and in vitro efficacy in human tumor cell lines (EC 50). The resulting compound, 2 (ABT-263), is orally efficacious in an established xenograft model of human small cell lung cancer, inducing complete tumor regressions in all animals. Compound 2 is currently in multiple phase 1 clinical trials in patients with small cell lung cancer and hematological malignancies.
The discovery of various protein/receptor targets from genomic research is expanding rapidly. Along with the automation of organic synthesis and biochemical screening, this is bringing a major change in the whole field of drug discovery research. In the traditional drug discovery process, the industry tests compounds in the thousands. With automated synthesis, the number of compounds to be tested could be in the millions. This two-dimensional expansion will lead to a major demand for resources, unless the chemical libraries are made wisely. The objective of this work is to provide both quantitative and qualitative characterization of known drugs which will help to generate "drug-like" libraries. In this work we analyzed the Comprehensive Medicinal Chemistry (CMC) database and seven different subsets belonging to different classes of drug molecules. These include some central nervous system active drugs and cardiovascular, cancer, inflammation, and infection disease states. A quantitative characterization based on computed physicochemical property profiles such as log P, molar refractivity, molecular weight, and number of atoms as well as a qualitative characterization based on the occurrence of functional groups and important substructures are developed here. For the CMC database, the qualifying range (covering more than 80% of the compounds) of the calculated log P is between -0.4 and 5.6, with an average value of 2.52. For molecular weight, the qualifying range is between 160 and 480, with an average value of 357. For molar refractivity, the qualifying range is between 40 and 130, with an average value of 97. For the total number of atoms, the qualifying range is between 20 and 70, with an average value of 48. Benzene is by far the most abundant substructure in this drug database, slightly more abundant than all the heterocyclic rings combined. Nonaromatic heterocyclic rings are twice as abundant as the aromatic heterocycles. Tertiary aliphatic amines, alcoholic OH and carboxamides are the most abundant functional groups in the drug database. The effective range of physicochemical properties presented here can be used in the design of drug-like combinatorial libraries as well as in developing a more efficient corporate medicinal chemistry library.
Literature data on compounds both well- and poorly-absorbed in humans were used to build a statistical pattern recognition model of passive intestinal absorption. Robust outlier detection was utilized to analyze the well-absorbed compounds, some of which were intermingled with the poorly-absorbed compounds in the model space. Outliers were identified as being actively transported. The descriptors chosen for inclusion in the model were PSA and AlogP98, based on consideration of the physical processes involved in membrane permeability and the interrelationships and redundancies between available descriptors. These descriptors are quite straightforward for a medicinal chemist to interpret, enhancing the utility of the model. Molecular weight, while often used in passive absorption models, was shown to be superfluous, as it is already a component of both PSA and AlogP98. Extensive validation of the model on hundreds of known orally delivered drugs, "drug-like" molecules, and Pharmacopeia, Inc. compounds, which had been assayed for Caco-2 cell permeability, demonstrated a good rate of successful predictions (74-92%, depending on the dataset and exact criterion used).
A simple pharmacophore point filter has been developed that discriminates between drug-like and nondrug-like chemical matter. It is based on the observation that nondrugs are often underfunctionalized. Therefore, a minimum count of well-defined pharmacophore points is required to pass the filter. The application of the filter results in 66-69% of subsets of the MDDR database to be classified as drug-like. Furthermore, 61-68% of subsets of the CMC database are classified as drug-like. In contrast, only 36% of the ACD are found to be drug-like. While these results are not quite as good as those obtained with recently described neural net approaches, the method used here has clear advantages. In contrast to a neural net approach and also in contrast to decision tree methods described recently, the pharmacophore filter has been developed by using "chemical wisdom" that is unbiased from fitting the structural content of specific drug databases to prediction models. Similar to decision tree methods, the pharmacophore point filter provides a detailed structural reason for the classification of each molecule as drug or nondrug. The pharmacophore point filter results are compared to neural net filter results. A statistically significant overlap between compounds recognized as drug-like validates both approaches. The pharmacophore point filter complements neural net approaches as well as property profiling approaches used as drug-likeness filters in compound library analysis and design.
Oral bioavailability measurements in rats for over 1100 drug candidates studied at SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline) have allowed us to analyze the relative importance of molecular properties considered to influence that drug property. Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of molecular weight. That on average both the number of rotatable bonds and polar surface area or hydrogen bond count tend to increase with molecular weight may in part explain the success of the molecular weight parameter in predicting oral bioavailability. The commonly applied molecular weight cutoff at 500 does not itself significantly separate compounds with poor oral bioavailability from those with acceptable values in this extensive data set. Our observations suggest that compounds which meet only the two criteria of (1) 10 or fewer rotatable bonds and (2) polar surface area equal to or less than 140 A(2) (or 12 or fewer H-bond donors and acceptors) will have a high probability of good oral bioavailability in the rat. Data sets for the artificial membrane permeation rate and for clearance in the rat were also examined. Reduced polar surface area correlates better with increased permeation rate than does lipophilicity (C log P), and increased rotatable bond count has a negative effect on the permeation rate. A threshold permeation rate is a prerequisite of oral bioavailability. The rotatable bond count does not correlate with the data examined here for the in vivo clearance rate in the rat.