Study Of Multitargeting Antitumor Platinum(?) Prodrugs

As one of the most effective anticancer drugs available for treating a large variety of solid tumors,cisplatin has been widely used either as a single therapeutic modality or in combination with other cytotoxic agents or radio-therapy.Despite its great success,the undesirable side effects and drug resistance limit the application of cisplatin and its platinum?II?analogues.The physicochemical properties of platinum???agents differ significantly from those of their platinum?II?counterparts.platinum???agents posses two additional axial ligands,which offer a unique approach for drug design to modify the pharmacokinetic effects of the prodrugs.To overcome the drawbacks of platinum?II?drugs,we have been designed and synthesized a series of promising platinum???anticancer agents by introduction of functionalized groups to the axial positions of the platinum???complexes.The tumor progression is always accompanied by chronic inflammation.We introduced nonsteroidal anti-inflammatory drug indomethacin into the axial position of platinum???complexes and obtained a series of novel platinum???complexes.On the basis of this,we synthesized a tumor targeting prodrug II-11 by tethering a biotin motiety,which could be highly accumulated in cancer cells more than normal ones and could be reduced by ascorbic acid.In vitro assays revealed that II-11exhibited significantly selective inhibition to the tested cancer cell lines and sensitivity to cisplatin resistant SGC7901/CDDP cancer cells.Owing to its distinctive formulation bearing indomethacin,II-11 showed unique synergy to inhibit cyclooxygenases.Moreover,II-11 reduced the invasiveness of the highly aggressive PC-3 cells and disrupted capillary-like tube formation as well.Despite the benefits that are prominent in the treatment of breast cancer,the application of tamoxifen suffers from drug resistance,which is the main problem of antiestrogen therapy.With the goal of creating novel antineoplastic drugs that exhibit a therapeutic effect selectively more potent toward estrogen receptor?ER?positive breast cancer and reverse tamoxifen resistance of breast cancer,we designed platinum???conjugates in which the selective ER modulator tamoxifen was covalently linked to platinum???species.Dual-action platinum???complexes not only exhibited potent cytotoxicity against the ER positive and negative breast cancer cells,but also reversed the tamoxifen resistance of TamR-MCF-7 cancer cells.These complexes all displayed decent ER binding affinity,and the typical complex III-3could enter cells via estrogen receptor-mediate pathway.Besides,III-3 could selectively accumulated in ER positive breast cancer cells.Preliminary mechanism studies show that this kind of complexes could induce apoptosis of MCF-7 cells by activating mitochondrial-related apoptosis pathway.Histone deaceylases?HDACs?have attracted increased attention for the critical role in the regulation of gene expression owing to governing the acetylation state of lysine residues,and the overexpression of HDACs transforms the function and expression of tumor-related proteins.SAA was chosen as a bioactive ligand?HDACs and PARP-1 dual inhibitor?to conjugate with platinum???complexes,the resulting compounds were expected to simultaneously target genomic DNA,HDACs and PARP-1.It is pleasing to find that the platinum???derivatives exhibited significant ameliorative antitumor activity and the typical complex SAA1 showed much potent cytotoxicity toward cisplatin-resistant SGC7901/CDDP cells.The biological results indicates that the mechanism comprises inhibitory effect towards HDACs and PARP-1.In addition,the cell cycle of cancer cells was successfully blocked in the G2/M phase and the activation of the p53 pathway was involved in SAA1-induced cancer cell death.We synthesized a novel platinum???anticancer prodrug V-30 by introducing7-hydroxycoumarin to the axial position of cis,cis,trans-[Pt?NH₃?₂Cl₂?OH?₂]derived from cisplatin.V-30 showed superior cytotoxicity to cisplatin against all tested cancer cell lines and reduced toxicity to HUVEC cells,but did not reversed the cisplatin resistance of SGC7901/CDDP cancer cells.In addition,cellular uptake of V-30 was significantly higher than that of cisplatin and exhibit strong fluorescence after reduction,showing a promising theranostic effect.The results showed that the mechanism of V-30 inducing HCT-116 apoptosis was different from that of cisplatin,which could induce cell cycle blocked in G0/G1 phase,and the activation of mitochondrial-related pathway and Ras/Raf/MEK/ERK pathway were involved in cell apoptosis.In vivo assay showed that V-30 showed no obvious advantage compared to cisplatin and oxaliplatin,but less toxicity.