Chiral discrimination in platinum anticancer drugs.

Abstract

In this article we review the biological activity of analogs of the antitumor drug cisplatin that contain chiral amine ligands. Interaction with DNA and formation of cross-links with adjacent purine bases are considered to be the crucial steps in the antitumor activity of this class of complexes. Because double-helical DNA has a chiral structure, interaction with enantiomeric complexes of platinum should lead to diastereomeric adducts. It has been demonstrated that DNA cross-links of platinum complexes with enantiomeric amine ligands not only can exhibit different conformational features but also can be processed differently by the cellular machinery as a consequence of these conformational differences. These results expand the general knowledge of how the stereochemistry of the platinum-DNA adduct can influence the cell response and contribute to understanding the processes that are crucial for antitumor activity. The steric requirements of the chiral ligands, in terms of configuration and flexibility, are also elucidated.

Enantiomerically Pure [1, 2‐Diamino‐1‐(4‐fluorophenyl)butane]platinum(II) Complexes: Synthesis and Antitumor Activity against MCF‐7 and MDA‐MB 231 Breast Cancer and LnCaP/FGC Prostate Cancer Cell Lines

“…Furthermore, it has been verified that DNA cross-links of platinum complexes with enantiomeric amine ligands can not only exhibit different conformational features but also be differently processed by the cellular machinery. These results expand the general knowledge about the influence of the stereochemistry on the platinum-DNA adduct can influence the cell response, and contribute to the understanding of the processes that are crucial for antitumor activity [33].…”

“…Furthermore, it has been verified that DNA cross-links of platinum complexes with enantiomeric amine ligands can not only exhibit different conformational features but also be differently processed by the cellular machinery. These results expand the general knowledge about the influence of the stereochemistry on the platinum-DNA adduct can influence the cell response, and contribute to the understanding of the processes that are crucial for antitumor activity [33].In another study, molecular modeling techniques were used to investigate the role of steric interactions between the ligands at the platinum and the DNA in influencing the bifunctional binding of two enantiomers. It was calculated that the S-configured [3-aminohexahydroazepine]dichloroplatinum(II) should bind more readily.…”

Chirality as a tool in nucleic acid recognition: Principles and relevance in biotechnology and in medicinal chemistry

“…5b) have been successfully identified. 45,46 Structure activity and enantioselectivity of these analogs have been reviewed in detail, [45][46][47] and only examples illustrating the key concepts will be given here. Chirality has in this field a well known relevance and has played an important role in the quest for new and more effective platinum drugs.…”

Carboplatin and weekly paclitaxel chemotherapy in hemodialysis patient with advanced lung cancer and severe comorbidity: effect of the drugs and their chemical intermediates

“…The hydroxyl site of platinum bind to DNA, forming a variety of intrastrand and interstrand adducts, the most abundant of which are 1,2-intrastrand cross-links between the N7 atoms of the two adjacent guanine bases [13]. The 1,2-intrastrand cross-links locally unwind and bend the double-stranded DNA toward the major groove, while the disturbance of the DNA secondary structure seems to be the ultimate reason for the inhibition of DNA replication and/or transcription, and for triggering apoptosis [14]. Carboplatin is less nephrotoxic than cisplatin.…”