Dan Gibson

• Hebrew University of Jerusalem

Cisplatin and oxaliplatin are Pt(II) anticancer agents that are used to treat several cancers, usually in combination with other drugs. Their efficacy is diminished by dose-limiting peripheral neuropathy (PN) that affects ∼70% of patients. PN is caused by selective accumulation of the platinum drugs in the dorsal root ganglia (DRG), which overexpre...

Cisplatin [cis-diamminedichloroplatinum(II)] is a widely used chemotherapeutic agent that induces cytotoxicity primarily through DNA damage, but drug resistance severely limits its efficacy and use. Cisplatin resistance is complex and multifactorial, involving DNA repair via nucleotide excision repair (NER), and overexpression of lysine deacetylase...

The limited recapitulation of critical cancer features in 2D cultures causes poor translatability of preclinical results from in vitro assays to in vivo tumor models. This contributes to slow drug development with a low success rate. 3D cultures better recapitulate the tumor microenvironment, enabling more accurate predictions when screening drug c...

While platinum-based chemotherapeutic agents have established themselves as indispensable components of anticancer therapy, they are accompanied by a variety of side effects and the rapid occurrence of drug resistance. A promising strategy to address these challenges is the use of platinum(iv) prodrugs, which remain inert until they reach the tumor...

A multitargeting prodrug (2) that releases gemcitabine, oxaliplatin, and doxorubicin in their active form in cancer cells is a potent cytotoxic agent with nM IC50s; it is highly selective to cancer cells with mean selectivity indices to human (136) and murine (320) cancer cells. It effectively induces release of DAMPs (CALR, ATP & HMGB1) in CT26 ce...

A multitargeting prodrug (2) that releases in cancer cells gemcitabine, oxaliplatin, and doxorubicin in their active form is a potent cytotoxic agent with nM IC50s; is highly selective to cancer cells with mean selectivity indices to human (136) and murine (320) cancer cells. It effectively induces release of DAMPs (CALR, ATP & HMGB1) in CT26 cells...

For a variety of cancer types, platinum compounds are still among the best treatment options. However, their application is limited by side effects and drug resistance. Consequently, multi-targeted platinum(IV) prodrugs that target specific traits of the malignant tissue are interesting new candidates. Recently, cisPt(PhB)2 was synthesized which, u...

AuI‐carbene and PtIV−AuI‐carbene prodrugs display low to sub‐μM activity against several cancer cell lines and overcome cisplatin (cisPt) resistance. Linking a cisPt‐derived PtIV(phenylbutyrate) complex to a AuI‐phenylimidazolylidene complex 2, yielded the most potent prodrug. While in vivo tests against Lewis Lung Carcinoma showed that the prodrug...

AuI‐carbene and PtIV‐AuI‐carbene prodrugs display low to sub‐mM activity against several cancer cell lines and overcome cisplatin (cisPt) resistance. Linking a cisPt‐derived PtIV(phenylbutyrate) complex to a AuI‐phenylimidazolylidene complex 2, yielded the most potent prodrug. While in vivo tests against Lewis Lung Carcinoma showed that the prodrug...

In this work, biologically active α-lipoic acid (ALA) and its isologous 1,2-diselenolane (SeA) and cyclopentyl (CpA) analogues were investigated for their differences in redox potentials, cytotoxicity and ROS production. In addition, the corresponding Pt(IV) complexes comprising ALA (1-4), SeA (5-8) and CpA (9-12) as axial ligands were synthesized....

Front Cover. To overcome the limitations of Pt(II) drugs for cancer treatment (intrinsic or acquired resistance, severe side‐effects), the investigations on Pt(IV) complexes and their anticancer activity provide a promising strategy. Beside higher kinetic inertness and lower toxicity compared to Pt(II), Pt(IV) complexes are armed with two axial lig...

α‐Lipoic acid, known for its anti‐inflammatory and antioxidant activity, represents a promising ligand for Pt(IV) prodrugs. Three new Pt(IV) lipoate complexes were synthesized and characterized by NMR spectroscopy ( 1 H, 13 C, 195 Pt), mass spectrometry and elemental analysis. Due to the low solubility of the complex containing two axial lipoate li...

We would like to be able to design Pt(IV) prodrugs that can overcome resistance and minimize side effects. Unlike with the early exploration of Pt(II) anticancer agents where clear structure‐activity relationships were defined, even after more than two decades of research on Pt(IV) prodrugs, there is no roadmap that can point us to the holy grail....

Pt(IV) complexes are designed as prodrugs that are intended to overcome resistance. Pt(IV) prodrugs are activated inside cancer cells releasing cytotoxic Pt(II) drugs as well as two axial ligands that can be used to confer favorable pharmacological properties to the prodrug. The ligands can be innocent spectators, cancer targeting agents or bioacti...

The oxidation of cis‐[Pt(NH3)2(OAc)2] with H2O2 yields a mixture of two isomers: ctc‐[Pt(NH3)2(OH)2(OAc)2] and ctc‐[Pt(NH3)2(OH)(OAc)(OH)(OAc)]. Following modification with 4‐phenylbutyric (PhB) anhydride, two isomers were separated and characterized; the symmetric ctc‐[Pt(NH3)2(PhB)2(OAc)2] (1) and the nonsymmetric ctc‐[Pt(NH3)2(PhB)(OAc)(PhB)(OAc...

Recent results have confirmed that protection of transplatin from reactions on the path to cancer cells substantially increases their activity, suggesting that such complexes have greater potential than previously thought. In this study we have investigated the use of the platinum(IV) oxidation state and the tetracarboxylate coordination sphere to...

Multiaction Pt(IV) prodrugs can overcome resistance associated with the FDA approved Pt(II) drugs like cisplatin. Intracellular reduction of the octahedral Pt(IV) derivatives of cisplatin releases cisplatin and the two axial ligands. When the released axial ligands act synergistically with cisplatin to kill the cancer cells, we have multiaction pro...

PtII complexes are commonly used to treat cancer. To reduce their side effects and improve their pharmacological properties, PtIV complexes are being developed as prodrug candidates that are activated by reduction in cancer cells. Concomitantly, RuII polypyridine complexes have gained much attention as photosensitizers for use in photodynamic thera...

Metall auf Metall: In der modernen Medizin ist die Krebsbehandlung noch immer eine große Herausforderung. Hier wird ein neuer Ansatz durch die Kombination eines PtIV-Komplex als Chemotherapeutikum und eines RuII-Komplex als Agens für die Photodynamische Therapie vorgestellt. Das Konjugat wirkt auf verschiedene zelluläre Kompartimente mit unterschie...

The 2,3,4,5-tetrahydro-1H-benzo[2,3]benzofuro[6,5-b]azepine skeleton was built starting from dibenzofuran via 3-aminodibenzofuran, creating the 5-methylene-substituted azepine ring by an intramolecular Heck cyclization. Subsequent modifications led to the endocyclic 4,5-unsaturated analog, the dihydro product, and N-methyl and N-acylated derivative...

Pt(II) complexes, such as cisplatin and oxaliplatin, are in widespread use as anticancer drugs. Their use is limited by the toxic side effects and the ability of tumors to develop resistance to the drugs. A popular approach to overcome these drawbacks is to use their kinetically inert octahedral Pt(IV) derivatives that act as prodrugs. The most suc...

Most multi‐action PtIV prodrugs have bioactive ligands containing carboxylates. This is probably due to the ease of carboxylating the OH axial ligands and because following reduction, the active drug is released. A major challenge is to expand the arsenal of bioactive ligands to include those without carboxylates. We describe a general approach for...

Most multi‐action PtIV prodrugs have bioactive ligands containing carboxylates. This is probably due to the ease of carboxylating the OH axial ligands and because following reduction, the active form of the agent is released. A major challenge is to expand the arsenal of bioactive ligands to include those without carboxylates. We describe a general...

The substitution inert platinum agent [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]²⁺ (56MeSS, 5) is a potent cytotoxic metallodrug. In contrast to conventional cisplatin or oxaliplatin, the mechanism of action (MoA) of 5 is fundamentally different. However, details of the mechanism by which the 5,6-dimethyl-1,10-phenanthroline l...

A novel and highly efficient dual‐targeting platform was designed to ensure targeted in vivo delivery of dual‐action PtIV prodrugs. The dual targeting was established by liposomal encapsulation of PtIV complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain a high accumulation of t...

A novel and highly efficient dual‐targeting platform was designed to ensure targeted in vivo delivery of dual‐action Pt(IV) prodrugs. The dual targeting was established by liposomal encapsulation of Pt(IV) complexes, thereby utilizing the enhanced permeability and retention (EPR) effect as the first stage of targeting to attain high accumulation of...

Dual‐ or multi‐action PtIV prodrugs represent a new generation of platinum anticancer drugs. The important property of these PtIV prodrugs is that their antitumor action combines several different mechanisms owing to the presence of biologically active axial ligands. This work describes the synthesis and some biological properties of a “triple‐acti...

Pt(IV) complexes act as prodrugs that are activated inside cancer cells releasing cytotoxic Pt(II) drugs such as cisplatin as well as two axial ligands. These ligands can be used to confer favorable pharmacological properties to the prodrug. They can be innocent spectators, targeting agents or bioactive moieties. When the ligands are bioactive moie...

A series of triple action Pt(IV) prodrugs was designed to test the hypothesis that multi-action compounds, where each bioactive moiety intervenes in several cellular processes, might be more effective than a single agent at killing cancer cells. In particular, “triple action” Pt(IV) derivatives of cisplatin, where the axial ligands are inhibitors o...

We developed a novel Pt(IV) prodrug that simultaneously releases four different bioactive moieties inside the cancer cell acting like a cluster bomb. Its cytotoxicity against 2D and 3D cancer cells is significantly better than cisplatin. It is 200-450 fold more potent than cisplatin against KRAS mutated pancreatic and colon cancers and is 40 fold m...

We developed a novel Pt(IV) prodrug that simultaneously releases four different bioactive moieties inside the cancer cell acting like a cluster bomb. Its cytotoxicity against 2D and 3D cancer cells is significantly better than cisplatin. It is 200-450 fold more potent than cisplatin against KRAS mutated pancreatic and colon cancers and is 40 fold m...

We present the anticancer properties of cis, cis, trans-[Pt(IV)(NH3)2Cl2(OA)2] [Pt(IV)diOA] (OA = octanoato), Pt(IV) derivative of cisplatin containing two OA units appended to the axial positions of a six-coordinate Pt(IV) center. Our results demonstrate that Pt(IV)diOA is a potent cytotoxic agent against many cancer cell lines (the IC50 values ar...

This report describes the synthesis, characterization and biological activity of a series of platinum(IV) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] (Pt56MeSS) with non-bioactive, lipophilic and bioactive axial ligands. In an attempt to explore the anticancer activity potential of the Pt(IV) derivatives, 2D and 3D cytotoxic s...

The discrepancy between the in vitro cytotoxic results and the in vivo performance of Pt56MeSS, prompted us to look into its interactions and those of its Pt(IV) derivatives with human serum, HSA, lipoproteins and serum supplemented cell culture medium. The Pt(II) complex, Pt56MeSS, binds non-covalently and reversibly to slow tumbling proteins in h...

Cisplatin is a widely used chemotherapeutic drug showing high efficiency in the treatment of primary tumors such as ovarian, testicular and cervical cancers. The major drawback of cisplatin is tumor resistance either acquired or intrinsic. Many mechanisms are involved in the resistance, among them is the Nrf2 pathway which regulates glutathione rel...

Side effects and acquired resistance by cancer cells limit the use of Platinum (Pt) anticancer drugs. Modification of oxaliplatin (OXA) into a lipophilic Pt(IV) complex [Pt(DACH)(OAc)(OPal)(ox)] (1), containing both lipophilic and hydrophilic axial ligands, was applied to improve performance and facilitate incorporation into polymeric nanoparticles...

In this manuscript we focus on Pt(iv) anticancer prodrugs. We explore the main working hypotheses for the design of effective Pt(iv) prodrugs and note the exceptions to the common assumptions that are prevalent in the field. Special attention was devoted to the emerging class of "dual action" Pt(iv) prodrugs, where bioactive ligands are conjugated...

Our study demonstrates that Pt(IV) derivative of cisplatin, with two axial PhB ligands, ctc-[Pt(NH3)2(PhB)2Cl2], is a very potent cytotoxic agent against many different human cancer cell lines and is up to 100 fold more potent than cisplatin, and significantly more potent than the Pt(IV) derivatives of cisplatin with either two hydroxido, two aceta...

Substitutionally inert Pt(IV) prodrugs, combining bioactive axial ligands with Pt(IV) derivatives of antitumor Pt(II) compounds, represent a new generation of anticancer drugs. The rationale behind these prodrugs is to release, by reductive elimination inside the cancer cell, an active Pt(II) drug which binds nuclear DNA as well as bioactive ligand...

The present invention concerns Pt (IV) lipophilic derivatives for improved drug performance in cancer therapy, as well as nanocarriers comprising them.

The design of PtIV pro-drugs as anticancer agents is predicated on the assumption that they will not undergo substitution reactions before entering the cancer cell. Attempts to improve the cytotoxic properties of PtIV pro-drugs included the use of haloacetato axial ligands. Herein, we demonstrate that PtIV complexes with trifluoroacetato (TFA) or d...

In recent years, numerous studies have demonstrated the health benefits of polyphenols. A major portion of polyphenols in western diet are derived from coffee, which is one of the most consumed beverages in the world. It has been shown that many polyphenols gain their beneficial properties (e.g. cancer prevention) through the activation of the Nrf2...

The toxicity of the new derivative of transplatin, namely trans-[PtCl2(DEA)(NH3)] (DEA = diethylamine), in which only one NH3 group was replaced by a small, non-bulky DEA ligand, in the cisplatin sensitive and resistant tumor cell lines was examined. The results indicate that this very small modification of the transplatin molecule results in a con...

To identify an association between amino acids (AAs) metabolism and reproductive outcome. Prospective collection, observational study, in patients undergoing fresh, double embryo transfer (ET), in a tertiary hospital referral IVF unit. Spent day 1 and day 3 media were collected. Concentrations of taurine, aspartic acid, proline, and serine in the m...

Carbon nanotubes (CNTs) are promising drug delivery systems due to their external functionalizable surface and their hollowed cavity that can encapsulate several bioactive molecules. In this study, the chemotherapeutic drug cisplatin or an inert platinum(IV) complex were entrapped inside functionalized-multi-walled-CNTs and intravenously injected i...

Losing ligands rapidly: Pt(IV) complexes with haloacetato ligands can hydrolyze rapidly under biological conditions (pH 7 and 37 °C, see scheme) and the rate increases with increasing pH value. Possible mechanisms for this hydrolysis are examined using H2 (18) O and ESI-MS analysis.

Schneller Ligandenverlust: PtIV-Komplexe mit Halogenacetatoliganden können unter biologischen Bedingungen (pH 7 und 37 °C; siehe Schema) schnell hydrolysiert werden, wobei sich die Geschwindigkeit mit steigendem pH-Wert erhöht. Mögliche Mechanismen für diese Hydrolyse wurden unter Verwendung von H218O und durch ESI-MS-Analyse untersucht.

In order to shed light on the mechanism that underlies activity of bifunctional mononuclear Pt(II) analogs of transplatin we examined in the present work a DNA binding mode of the analog of transplatin, namely trans-[Pt(CH3NH2)2Cl2], in which NH3 groups were replaced only by a small, non-bulky methylamine ligand. This choice was made because we wer...

Facile strategies were developed for the versatile functionalization of platinum(IV) axial sites, allowing for easy accessibility to unsymmetric mono- and mixed-carboxylato, as well as symmetric di-substituted platinum(IV) complexes. The first method involves the direct oxidation and carboxylation of the platinum(II) center using an appropriate per...

This manuscript represents a critical review of selected topics relating to the cellular interactions of platinum anticancer drugs. The intent is not to provide a comprehensive summary of all the work described in the literature but to raise questions and cast doubts about selected topics regarding the approaches taken towards trying to elucidate t...

In an effort to design dinuclear Pt-II compounds that maintain the target (DNA) binding profile of the trans-oriented dinuclear bifunctional Pt-II complexes containing aliphatic linker chains but are less susceptible to metabolic decomposition, the new, long-chain dinuclear Pt-II complexes-[{trans-PtCl(dien)}(2)-mu-(CH2)(n)](2+) (n = 7,10,12, dien...

In contrast to the Pt(IV) derivatives of cisplatin, Pt(IV) derivatives of oxaliplatin do not show the expected correlation between the electrochemical reduction potentials and rates of reduction by ascorbate. This is probably due to the lower ability of the amine and carboxylato ligands to form a bridge with the reducing agents to facilitate electr...

Before the active form of a Pt drug reaches its major pharmacological target in the cell nucleus, the Pt complex has to accumulate in cells, and during its transportation into cells and inside cells, it reacts with various biomolecules. Satraplatin is the first orally administered Pt drug under active clinical investigation. The major metabolite of...

cis-Amminedichlorido(cyclohexylamine)platinum(II) (JM118) is an antitumor Pt(II) analogue of cisplatin exhibiting considerably higher activity than cisplatin in human tumor cells. JM118 is also the major metabolite of the first orally administered Pt(IV) drug satraplatin. In an effort to design improved platinum antitumor agents, it is important to...

Reaction of methyl benzoylphosphonochloridate (3) with a secondary or primary series of amines yielded methyl benzoylphosphonamidates, 4a-e. The latter compounds reacted with hydroxylamine to yield a-hydroxyiminobenzylphosphonamidates (5a-e), largely as (E)-isomers. The structure of methyl (E)-a-hydroxyimino-benzyl-1-pyrrolidinylphosphinate (5b) wa...

Reduction of anticancer prodrugs such as ctc-[PtCl(2)(CH(3)CO(2))(2)(NH(3))(Am)] can yield three products in addition to the expected cis-[PtCl(2)(NH(3))(Am)]. A possible explanation is that reduction proceeds by several pathways where in addition to the loss of two axial ligands, one axial (acetato) and one equatorial (chlorido) ligand, or two equ...

Although 40 years have passed since the discovery of the anticancer activity of cisplatin, the mechanism of action of the drug is unclear. There are several working hypotheses that guide the researchers in this field. Unexpected results that we obtained cannot be reconciled with some of those assumptions. Our main intention is to call upon research...

Cisplatin is an anticancer drug whose efficacy is limited because tumors develop resistance to the drug. Resistant cells often have elevated levels of cellular glutathione (GSH), believed to be the major cellular target of cisplatin that inactivates the drug by binding to it irreversibly, forming [Pt(SG)(2)] adducts. We show by [(1)H,(15)N] HSQC th...

Cisplatin, cis-[Pt(NH(3))(2)Cl(2)], is an effective anticancer agent in wide clinical use whose efficacy is affected by cellular interactions with sulfur-containing nucleophiles. These interactions can potentially enhance the efficacy of the drug by mediating its delivery to nuclear DNA or inactivate the drug by binding to it irreversibly or by lab...

Carboplatin (CPT), today the most important platinum(II) anticancer drug, manifests an extreme kinetic inertness, in vitro, at physiological pH; the actual mechanisms for its activation inside cells are still poorly understood. We show here that horse heart cytochrome c reacts with CPT, leading to the formation of stable platinum/protein adducts. T...

Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were in...

Pt(IV) complexes must be reduced to kill cancer cells. While reduction rates correlate with reduction potentials, we wanted to check if the rates of reduction depend on the cell line used. The reduction of cis,trans,cis-[PtCl2(OCOCH3)2(NH3)2] by extracts of three cell lines was measured, and the rates follow the order A2780cisR > A2780 > HT-29. The...

A new tetrafunctional dinuclear platinum complex trans,trans-[{PtCl2(NH3)}2(piperazine)] with sterically rigid linking group was designed, synthesized and characterized. In this novel molecule, the DNA-binding features of two classes of the platinum compounds with proven antitumor activity are combined, namely trans oriented bifunctional mononuclea...

A series of complexes of the general formula trans-[PtCl2(Am)(pip-pip)] x HCl where pip-pip is 4-piperidinopiperidine and Am is NH3, methylamine (MA), dimethylamine (DMA), n-propylamine (NPA), isopropylamine (IPA), n-butylamine (NBA), or cyclohexylamine (CHA) were prepared and characterized, and their cytotoxic properties against ovarian and colon...

The determination of the structures and DNA interactions and the reactions with GSH and ubiquitin of complexes of the general formula trans-[PtCl2(Am)(pip-pip)] x HCl, where pip-pip is 4-piperidinopiperidine and Am is NH3, methylamine (MA), dimethylamine (DMA), n-propylamine (NPA), isopropylamine (IPA), n-butylamine (NBA), or cyclohexylamine (CHA),...

The competitive reactions of mononucleobase cations SP-4-2-[PtCl(9-EtGua)(NH3)(quinoline)]+, 1, and trans-[PtCl(9-EtGua)(pyridine)2]+, 2, with 5′-guanosine monophosphate (5′-GMP) and N-Acetylmethionine (N-AcMet) were studied by 1H NMR Spectroscopy. The results confirmed the previously observed kinetic selectivity for sulfur over nitrogen binding. T...

In order to monitor the trans labilization of cisplatin at physiological pH we have prepared the complex cis-[PtCl(2)((13)CH(3)NH(2))(2)] and studied its interactions with excess glutathione in aqueous solution at neutral pH by two-dimensional [1H,13C] heteronuclear single-quantum correlation (HSQC) NMR spectroscopy. [1H,13C] HSQC spectroscopy is a...

trans-[PtCl2(Am)(pip-pip)] x HCl complexes, where Am = ammine, methylamine and dimethylamine, react with ubiquitin to form 1:1 covalent adducts. The platinum complexes bind exclusively to Met1 of ubiquitin forming trans-[PtCl(S-Met1-Ub)(Am)(pip-pip)] adducts. These adducts are reactive towards nucleophiles and react with deoxyguanosine (dGMP) to fo...

trans-Diaminedicholoroplatinum(II) complexes with one planar and one non-planar heterocyclic amine ligand were designed as new potential antitumor drugs. The X-ray crystallographic structures of trans-[PtCl2(4-picoline)(piperidine)] and trans-[PtCl2(4-picoline)(piperazine)].HCl revealed that the piperidine and piperazine ligands bind to the platinu...

Three isomeric complexes, trans-[PtCl2(NH3)(2-methylpiperidine)], trans-[PtCl2(NH3)(3-methylpiperidine)] and trans-[PtCl2(NH3)(4-methylpiperidine)], were prepared and their cytotoxicities against six ovarian cancer cell lines, three sensitive and three resistant to cisplatin, were measured. There were no significant differences in the cytotoxicitie...

The pharmacokinetics and metabolism of 2,2,3,3-tetramethylcyclopropanecarbonylurea (TMCU), a potent anticonvulsant compound, were studied in male Sprague-Dawley rats following i.v. (5 mg/kg), oral (20 mg/kg), and i.p. (20 mg/kg) administrations. Urine samples were analyzed by gas chromatography-mass spectrometry (GC/MS) and liquid chromatography-ma...

Umgehen der Cisplatinresistenz: Das trans-[PtCl2(NH3)(pip-pip)]+-Ion (siehe Struktur; rot Pt, blau N, grün Cl, grau C) ist eine cytotoxische Verbindung mit einem kationischen Piperidinopiperidin-Liganden. Der vom PtII-Zentrum entfernte Piperidinring ist fluktuierend und fungiert als Wasserstoffbrücken-Donor. Der Komplex bindet ohne vorherige Hydrol...

Circumventing cisplatin resistance: The trans-[PtCl2(NH3)(pip-pip)]+ ion (see structure; red Pt, blue N, green Cl, gray C) is a cytotoxic compound with a cationic piperidinopiperidine ligand. The piperidine ring that is removed from the PtII center is fluxional and acts as a hydrogen-bond donor. The complex binds calf thymus DNA directly and rapidl...

Three cannabis constituents, cannabidiol (1), Delta(8)-tetrahydrocannabinol (3), and cannabinol (5), were oxidized to their respective para-quinones 2, 4, and 6. In the 1960s, the oxidized product 4 had been assigned a para-quinone structure, which was later modified to an ortho-quinone. To distinguish between the two possible quinone structures, a...

Carboplatin is a low-molecular-weight anticancer drug that acts by binding to the nuclear DNA of cells. Thus, efficient delivery of the platinum drugs to the nucleus of the cancer cells may enhance the cytotoxicity of the drug. Efficient drug delivery to the nucleus of cancer cells requires three levels of localization: targeting to the cancerous t...

A paradigm for the structure-pharmacological activity relationship of bifunctional platinum antitumor drugs is that the trans isomer of antitumor cisplatin (transplatin) is clinically ineffective. To this end, however, several new complexes of the trans structure have been identified that exhibit cytotoxicity in tumor cells that is even better than...

Replacement of the ammine group in antitumor cisplatin by a heterocyclic ligand (piperidine, piperazine, or 4-picoline) results in reduction of cytotoxicity in human ovarian cancer cells. DNA is generally believed to be a major pharmacological target of antitumor platinum complexes. Therefore, we examined conformation of oligodeoxyribonucleotide du...

The global modification of mammalian and plasmid DNAs by novel platinum compounds, cis- or trans-[PtCl(2)(NH(3))(Am)], where Am = NH(3), nonplanar heterocycle piperidine, piperazine, or aromatic planar heterocycle 4-picoline, was investigated in cell-free media using various biochemical and biophysical methods. These modifications have been compare...

Like most low molecular weight drugs, carboplatin has a short blood circulation time, which reduces tumor uptake and intracellular DNA binding. Drugs conjugated to PEG carriers benefit from prolonged blood circulation, but suffer from reduced cell permeability. In this work we attempted to develop long-circulating PEGylated carboplatin analogues wi...

As part of a systematic study of the basic principles that govern the formation and reactivity of Pt-protein adducts, we report the effect of substituting the amine ligand of cis- and trans-[PtCl(2)(NH(3))(2)] complexes with bulkier planar aromatic or nonplanar cyclic amine ligands on the binding properties of the complexes to ubiquitin and to hors...

Positively charged, water soluble cis/trans-[PtCl(2)(piperazine)(Am1)] (where Am1 = NH(3), n-butylamine, isopropylamine, 4-picoline, piperidine, and piperazine) has significant cytotoxic activity against cisplatin resistant ovarian cancer cells. The charged complexes are taken up by cancer cells much more rapidly than cisplatin and bind to cellular...

The synthesis, chemical characterization, and interaction with cells of new sterically hindered trans- and cis-diaminedichloroplatinum(II) complexes are described. The amine ligands include monofunctional piperidine (pip) and piperazine (pz). The poor solubility of trans-diaminedichloroplatinum complexes was overcome by introducing the positively c...

In this manuscript we report on the interactions of cis-DDP (cisplatin, cis-diamminedichloroplatinum(II)) and trans-DDP (transplatin, trans-diamminedichloroplatinum(II)) with two model proteins, ubiquitin (Ub) and horse heart myoglobin (Mb), and attempt to answer the question whether proteins that have methionine-Pt adducts can transfer the platinu...

In this manuscript we report on the interactions of cis-DDP (cisplatin, cis-diamminedichloroplatinum(II)) and trans-DDP (transplatin, trans-diamminedichloroplatinum(II)) with two model proteins, ubiquitin (Ub) and horse heart myoglobin (Mb), and attempt to answer the question whether proteins that have methionine-Pt adducts can transfer the platinu...

Extensive scientific efforts are directed towards finding new and improved platinum anticancer agents. A promising approach is the encapsulation of cisplatin in sterically stabilized, long circulating, PEGylated 100 nm liposomes. This liposomal cisplatin (STEALTH cisplatin, formerly known as SPI-77) shows excellent stability in plasma and has a lon...

We investigated the effect of various monofunctional platinum complexes on the thermal stability and conformation of a self-complementary 22-mer duplex oligonucleotide by means of CD and UV melting profiles. We studied several families of triamine complexes of the general formula PtA2AmCl where A2=(NH3)2 and ethylenediamine and where Am=N1-4-methyl...

cis-[Cr(phen)2(dpp)(H2O)]²⁺ (phen = 1,10-orthophenanthroline; dpp = diphenyl phosphate) is prepared in aqueous solution and is remarkably stable over a wide range of pH. The dpp ligand is bound to the Cr(III) ion in an anti, unidentate fashion.

Cisplatin is a widely used antitumor agent for the treatment of testicular and ovarian cancers. It is believed to exert its cytotoxic effect by reacting with DNA. Within one day of injection, 65-98% of the platinum in the blood plasma is protein-bound. Pt-protein adducts are believed to be the cause of the drug's side effects but, to date, nuclear...