Pros and cons of bifunctional platinum(iv) antitumor prodrugs: two are (not always) better than one

Abstract

This article evaluates the efficacy and applicability of bifunctional prodrugs consisting of a six-coordinate Pt(iv) octahedral core and one or more bioactive molecules. The platinum(iv) complexes release upon reduction the corresponding cytotoxic Pt(ii) agents and the bioactive molecules, able to inhibit some biochemical mechanisms of cancer growth and/or prevent the deactivation of the Pt(ii) metabolites.

Platinum(iv) oxaliplatin–peptide conjugates targeting memHsp70+ phenotype in colorectal cancer cells

“…11 Attention in medicinal inorganic research is now being turned towards the development of metallodrugs, in particular Pt(IV) prodrugs, which contain bioactive ligands. 13 2 | J. Name., 2012, 00, [1][2][3] This journal is © The Royal Society of Chemistry 20xx…”

“…13,14 In bifunctional Pt(IV) prodrugs a bioligand is often coordinated to a Pt(IV) centre by a carboxylate functionality. These ligands generally play a role (i) in drug targeting and delivery or (ii) possess inherent anticancer properties.…”

Characterization of the mechanism of reduction of trans-diamminetetrachloroplatinum(IV) by l-cysteine and dl-homocysteine

“…Contrary to their inert behaviors toward substitution, Pt(IV) anticancer drugs can be reduced readily to their Pt(II) counterparts and they are thus often referred to as prodrugs [1,2,[4][5][6][7][8][9]. Some dominant small molecule reductants in plasma [10] such as L-cysteine, glutathione, and ascorbic acid are believed to be responsible for the reduction of Pt(IV) anticancer prodrugs [11][12][13][14][15].…”

“…Nevertheless, Pt(IV) complexes mostly have a typical octahedral configuration and their ligand substitution reactions are generally very slow. As a consequence, some properties of the Pt(IV) anticancer drugs can be tuned by choosing different ligands in the apical positions [4][5][6].…”

“…This process has involved the design and synthesis of numerous Pt(IV) compounds [2,[4][5][6][7][8][9]. Although Pt(IV) anticancer drugs usually have two ammines/amines in cis positions in their equatorial planes similar to cisplatin and other Pt(II) drugs [2,[4][5][6], some Pt(IV) complexes with two ammines/amines in trans positions in their equatorial planes also show anticancer activities [7][8][9]. Nevertheless, Pt(IV) complexes mostly have a typical octahedral configuration and their ligand substitution reactions are generally very slow.…”