New captothecin-linked platinum anticancer agents

Presently, platinum-based coordination complexes are among the most widely used antitumor agents in the clinic .The effectiveness of cisplatin lies in its ability to covalently bind DNA, leading to important changes in the helical structure. In spite of the efficacy of platinum-based treatment regimens, long-term cure is difficult to obtain. The major drawbacks include a) severe and sometimes life-threatening toxic side effects; b) activation of drug resistance mechanisms by tumor cells; c) inadequate intratumor concentration of the drug and tumor microenvironmental interactions; d) relatively poor pharmacokinetic profiles and e) increased DNA repair capacity. As part of our program aimed to advance DNA as a drug target, we were interested in devising novel platinum containing dual compounds that interacted in an effective way with DNA and in addition accomplished the requirements of solubility in the body fluids and improved cellular uptake. In this context, a promising approach seemed to be the conjugation of platinum to analogues of the natural antitumor compound camptothecin (CPT). In this poster we report the design, modeling, synthesis and biological activity evaluation of new hybrid agents formed by CPT derivatives and diaminedichloro-platinum (II) complex. The compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The derivatives were active in all the tested cell lines, and the most active one was able to overcome cisplatin resistance in the osteosarcoma U2OS/Pt cell line. Platinum-containing camptothecins produced Platinum-DNA adducts and topoisomerase I-mediated DNA damage with cleavage pattern and persistence similar to SN38, the active principle of irinotecan. The results support the interpretation that the diaminedichloro-platinum (II) complex conjugated to a functionalized camptothecin resulted in a new class of effective antitumor compounds.