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 synthesis of PtIV prodrugs that release drugs with OH groups. We linked the OH groups of gemcitabine (Gem), paclitaxel (Tax), and estramustine (EM) to the PtIV derivative of cisplatin by a carbonate bridge. Following reduction, the axial ligands lost CO2, rapidly generating the active drugs. In contrast, succinate‐linked drugs did not readily release the free drugs. The carbonate‐bridged ctc‐[Pt(NH3)2(PhB)(Gem‐Carb)Cl2] was significantly more cytotoxic than the succinate‐bridged ctc‐[Pt(NH3)2(PhB)(Gem‐Suc)Cl2], and more potent and less toxic than gemcitabine, cisplatin, and co‐administration of cisplatin and gemcitabine.
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 prodrugs. Most Pt(IV) multiaction prodrugs have bioactive ligands possessing a carboxylate that is conjugated to the Pt(IV) because breaking the Pt(IV)−ligand bond releases the active moiety. As many drugs that act synergistically with cisplatin do not have carboxylates, a major challenge is to prepare multiaction Pt(IV) complexes with drugs that have amino groups or hydroxyl groups such that following reduction, the drugs are released in their active form. Our objective was to prepare multiaction Pt(IV) prodrugs that release bioactive molecules having amino groups. Because we cannot conjugate amino groups to the axial position of Pt(IV), we developed a novel and efficient approach for the synthesis of Pt(IV)−carbamato complexes and demonstrated that following reduction of the Pt(IV), the released carbamates undergo rapid decarboxylation, releasing the free amine, as in the case of the PARP-1 inhibitor 3aminobenzamide and the amino derivative of the HDAC inhibitor SAHA. Pt(IV)−carbamato complexes are stable in cell culture medium and are reduced by ascorbate. They are reduced slower than their carboxylato and carbonato analogues. We believe that this approach paves the way for preparing novel classes of multiaction Pt(IV) prodrugs with amino containing bioactive molecules that up to now were not accessible.
A slow hydrolyzing imidazole-based Ru(II)-arene complex [(L)Ru(II)(η(6)-p-cym)(Cl)](PF6) (1) with excellent stability in the extracellular chloride concentration shows better activity under hypoxia and strong resistance to glutathione (GSH) in vitro under hypoxic conditions. 1 arrests the cell cycle in sub G1 and G2/M phases and leads to apoptosis.
A pyridine ring containing a chelating nitrogen mustard ligand bis(2-chloroethyl)pyridylmethylamine hydrochloride (L2·HCl) was synthesized from bis(2-hydroxyethyl)pyridylmethylamine (L1) on reaction with thionyl chloride. Both the ligands upon reaction with cis-[PtCl2(DMSO)2] afforded square planar complexes cis-[PtCl2(L1)] (1) and cis-[PtCl2(L2)] (2) respectively. Both the complexes were characterized by NMR, IR, UV and elemental analysis. 2 crystallized in the P21/c space group. 2 shows greater solution stability than 1 in kinetic studies by 1H NMR. Both 1 and 2 bind the model nucleobase 9-ethylguanine (9-EtG) and form multiple mono-adducts. Existence of unusual N7,O6 chelated guanine bound 2 (2e) was traced. Binding studies of 2 with glutathione (GSH) show formation of a mono-adduct cis-[PtCl(L2)SG] (2c), which transformed within a day to give an aziridinium ion of L2 (2b) after loss of L2. In vitro cytotoxicity of ligands, complexes and the clinical anticancer drug cisplatin show that 2 is the most potent against MCF-7, A549 and MIA PaCa2 exhibiting IC50 values of 12.6 ± 0.8, 18.2 ± 1.8 and 4.2 ± 1.0 μM respectively. The in vitro cytotoxicity of 2 against MCF-7, A549 and MIA PaCa2 was also probed in hypoxia and in the presence and absence of added GSH. Even in the presence of excess GSH in hypoxia, 2 exhibits significant cytotoxicity against MIA PaCa2 and MCF-7 with IC50 of 4.4 ± 0.8 and 12.5 ± 1.1 μM respectively. Metal accumulation studies by ICP-MS display greater cellular internalization of 2, than 1 and cisplatin in MCF-7 cells. 2 arrests the cell cycle at sub G1 and G2/M phases in MCF-7 whereas cisplatin exhibits S phase arrest to be dominant with increase in concentration. Complex 2 exhibits a change in mitochondrial membrane potential, caspase activity and suggests apoptotic cell death through the intrinsic pathway. Moreover it is encouraging to find that 2 also restricts angiogenesis in chick embryo.
Oxamusplatin shows enhanced selectivity towards cancer, targets cellular DNA, disrupts the microtubule network and strongly resists sequestration by deactivating agents, glutathione, ATP7B or phosphoglycoproteins.
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