The Hebrew University of Jerusalem, Israel
Platinum Anticancer Agents: from Magic Bullets to Cluster Bombs
Although Pt drugs in clinical use are Pt(II) complexes, Pt(IV) complexes have attracted a lot of attention since their chemical properties allow for great flexibility in design of novel drugs. Pt(IV) complexes are octahedral complexes that are kinetically more inert than their Pt(II) precursors and can be administered orally. Pt(IV) complexes act as prodrugs that are activated inside the cancer cells by reductive elimination resulting in the concurrent release the two axial ligands, and the Pt(II) drug. There are several recent reports on the preparation of “dual action” Pt(IV) prodrugs that are Pt(IV) derivatives of cisplatin or oxaliplatin with bioactive axial ligands. The main advantage of the “dual action” drugs is the simultaneous release of two anti-proliferative agents that act by different mechanisms of action and attack different cellular targets thereby increasing the chances of overcoming resistance to a single drug
We extended this underlying concept to “triple” and “quadruple action” Pt(IV) based prodrugs and studied their biological properties. Most of the “triple action” compounds were very potent against a variety of cancer cells but are extremely effective against KRAS mutated pancreatic cells and thyroid cancer cells. These compounds are also significantly more potent than cisplatin when screened in a 3D spheroid model. The “quadruple action” prodrug was very effective against pancreatic and colon cancer cells that are KRAS mutated.  Overall, these results open new options for using Pt(IV)-based “multi action” prodrugs as anticancer agents.
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