Classification of Metal-based Drugs According to Their Mechanisms of Action

Abstract

Metal-based drugs and imaging agents are extensively used in the clinic for the treatment and diagnosis of cancers and a wide range of other diseases. The current clinical arsenal of compounds operate via a limited number of mechanisms, whereas new putative compounds explore alternative mechanisms of action, which could potentially bring new chemotherapeutic approaches into the clinic. In this review, metal-based drugs and imaging agents are characterized according to their primary mode of action and the key properties and features of each class of compounds are defined, wherever possible. A better understanding of the roles played by metal compounds at a mechanistic level will help to deliver new metal-based therapies to the clinic, by providing an alternative, targeted and rational approach, to supplement non-targeted screening of novel chemical entities for biological activity.

Figure 1.

Structures of a) clinically-approved drugs, b) drug candidates in clinical trials and c) other promising experimental compounds discusssed in the review.

Figure 2.

a) Chelate structures of commonly employed ligand systems DFO (M=Zr(IV), Ga(III)), DOTA (M = Cu(II), Ga(III), In(III), Y(III), Lu(III)), NOTA (M = Cu(II), Ga(III)), CHX-A”-DTPA (M = In(III), Lu(III)). The typical site of functionalization is indicated by R. b) Structures of clinically evaluated MRI contrast agents. c) Structure and mechanism of action of responsive MR probes: (A) Modulation of inner-sphere hydration of a Gd(III) complex by enzymatic activity, (B) redox-responsive Mn(II)/Mn(III) pair involving inner-sphere hydration modulation and T1e, (C) redox-responsive Eu(II)/Eu(III) probe with signal change arising from variation of T_1e.

Figure 3.

Summary of molecular and metal ion specific parameters that control proton relaxation of bound waters.

Figure 4.

Summary of the mechanism of action of metal-based drugs described in this review.

Scheme 1.

Schematic of the activation of an aminoferrocene-based prodrug candidate by ROS. The two mechanisms (Mechanisms 1 and 2) leading to cytotoxicity are also presented.