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Medicinal inorganic chemistry: New perspectives and targets for the periodic table

N. Farrell

Published 2020 in Unknown venue

ABSTRACT

Abstract Platinum-based anticancer drugs have had an unprecedented effect on cancer chemotherapy since the FDA approval of cisplatin in 1978. In this chapter I summarize recent new directions and results from my laboratory and our collaborators on polynuclear platinum complexes (PPCs), a discrete class of anticancer drugs. First, the biological activity of highly-charged substitution-inert complexes (SI-PPCs) will be reviewed with emphasis on their unique mode of DNA recognition through the phosphate clamp—distinct from canonical DNA-ligand binding through intercalation and minor-groove binding. Besides the molecular details of the DNA/RNA recognition, the PPCs are distinguished from intercalators and minor-groove binders by their very high efficiency in condensing DNA, even in cells. Second, evidence for membrane interactions, and especially those of glycosaminoglycans (GAGs), will be summarized leading to the clear confirmation that the PPC class must be considered an intrinsically dual-function agent, whose biological activity must be seen as the sum of its target interactions, with significant implications for approaches to personalized medicine for platinums. Especially, a systematic molecular approach to inhibition of tumor angiogenesis and invasion is suggested by consideration of GAGs as target for platinum agents. Finally, the role of metal ions in the function of the extracellular matrix will be discussed and molecular approaches to understanding of endogenous metal ion affinity will be illustrated using Mn2 + as an example.

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