Jyoti Kode

Improving In Vivo Tumor Accumulation and Efficacy of Platinum Antitumor Agents by Electronic Tuning of the Kinetic Lability

AbstractThe impact of kinetic lability or reactivity on in vitro cytotoxicity, stability in plasma, in vivo tumor and tissue accumulation, and antitumor efficacy of functional platinum(II) (Pt) anticancer agents containing a O˄O β‐diketonate leaving ligand remain largely unexplored. To investigate this, we synthesized Pt complexes [(NH3)2Pt(L1‐H)]NO3 and [(DACH)Pt(L1‐H)]NO3 (L1=4,4,4‐trifluoro‐1‐ferrocenylbutane‐1,3‐dione, DACH=1R,2R‐cyclohexane‐1,2‐diamine) containing an electron deficient [L1‐H]– O˄O leaving ligand and [(NH3)2Pt(L2‐H)]NO3 and [(DACH)Pt(L2‐H)]NO3 (L2=1‐ferrocenylbutane‐1,3‐dione) containing an electron‐rich [L2‐H]– O˄O leaving ligand. While all four complexes have comparable lipophilicity, the presence of the electron‐withdrawing CF3 group was found to dramatically enhance the reactivity of these complexes toward nucleophilic biomolecules. In vitro cellular assays revealed that the more reactive complexes have higher cellular uptake and higher anticancer potency as compared to their less reactive analogs. But the scenario is opposite in vivo, where the less reactive complex showed improved tissue and tumor accumulation and better anticancer efficacy in mice bearing ovarian xenograft when compared to its more reactive analog. Finally, in addition to demonstrating the profound but contrasting impact of kinetic lability on in vitro and in vivo antitumor potencies, we also described the impact of kinetic lability on the mechanism of action of this class of promising antitumor agents.

A Rationally Designed Bimetallic Platinum (II)‐Ferrocene Antitumor Agent Induces Non‐Apoptotic Cell Death and Exerts in Vivo Efficacy

AbstractDespite phenomenal clinical success, the efficacy of platinum anticancer drugs is often compromised due to inherent and acquired drug resistant phenotypes in cancers. To circumvent this issue, we designed two heterobimetallic platinum (II)‐ferrocene hybrids that display multi‐pronged anticancer action. In cancer cells, our best compound, 2, platinates DNA, produces reactive oxygen species, and has nucleus, mitochondria, and endoplasmic reticulum as potential targets. The multi‐modal mechanism of action of these hybrid agents lead to non‐apoptotic cell death induction which enables circumventing apoptosis resistance and significant improvement in platinum cross resistance profile. Finally, in addition to describing detail mechanistic insights, we also assessed its stability in plasma and demonstrate anticancer efficacy in an in vivo A2780 xenograft model. Strikingly, compared to oxaliplatin, our compound displays better tolerability, safety profile and efficacy in vivo.