Anticancer Platinum(IV) Prodrugs Containing Monoamino­phosphonate Ester as a Targeting Group Inhibit Matrix Metalloproteinases and Reverse Multidrug Resistance

A novel class of platinum­(IV) complexes comprising a monoamino­phosphonate ester moiety, which can not only act as a bone-targeting group but also inhibit matrix metalloproteinases (MMPs), were designed and synthesized. Biological assay of these compounds showed that they had potent antitumor activities against the tested cancer cell lines compared with cisplatin and oxaliplatin and indicated low cytotoxicity to human normal liver cells. Particularly, the platinum­(IV) complexes were very sensitive to cisplatin resistant cancer cell lines. The corresponding structure–activity relationships were studied and discussed. Related mechanism study revealed that the typical complex <b>11</b> caused cell cycle arrest at S phase and induced apoptosis in Bel-7404 cells via a mitochondrial-dependent apoptosis pathway. Moreover, complex <b>11</b> had potent ability to inhibit the tumor growth in the NCI-H460 xenograft model comparable to cisplatin

Combretastatin A‑4 Analogue: A Dual-Targeting and Tubulin Inhibitor Containing Antitumor Pt(IV) Moiety with a Unique Mode of Action

Three new Pt­(IV) complexes comprising a combretastatin A-4 analogue were designed and synthesized. The resulting antitumor Pt­(IV) complexes could significantly improve the antiproliferative activity and overcome the drug resistance of cisplatin in vitro. Interestingly, these novel compounds not only can carry the DNA binding Pt­(II) warhead into the cancer cells but also have a small molecule fragment that can inhibit tubulin polymerization. Among them, complex <b>13</b>, which was attached to an inhibitor of tubulin at one axial position of Pt­(IV) octahedral coordination sphere, could effectively enter cancer cells, arrest the cell cycle in HepG-2 cancer cells at G2/M phases, and induce activation of caspases triggering apoptotic signaling via the mitochondrial-dependent apoptosis pathways. Moreover, complex <b>13</b> has the ability to effectively inhibit the tumor growth in the HepG-2 xenograft model without causing significant loss of animal body weight in comparison with cisplatin