Metallodrugs are unique: opportunities and challenges of discovery and development - PubMed (original) (raw)

Review

. 2020 Nov 12;11(48):12888-12917.

doi: 10.1039/d0sc04082g.

Elizabeth M Bolitho 1, Hannah E Bridgewater 1, Oliver W L Carter 1, Jane M Donnelly 1, Cinzia Imberti 1, Edward C Lant 1, Frederik Lermyte 1 2, Russell J Needham 1, Marta Palau 1, Peter J Sadler 1, Huayun Shi 1, Fang-Xin Wang 1, Wen-Ying Zhang 1, Zijin Zhang 1

Affiliations

Review

Metallodrugs are unique: opportunities and challenges of discovery and development

Elizabeth J Anthony et al. Chem Sci. 2020.

Abstract

Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure-activity relationships. We focus on early-stage in vitro drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs.

This journal is © The Royal Society of Chemistry.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1

Fig. 1. (a) Metallodrugs approved in US and/or EU countries classified by metal centre. Different formulations of the same active ingredient are not included, nor are pharmaceuticals where the metal represents only the counter ion. Imaging/diagnostic agents, food supplements, agents used as anaesthetics and in implants are also excluded. A comprehensive list of the agents included is in Table S1. Remarkably, the total number of clinically-approved metallodrugs is about half of that for kinase inhibitors, a single class of organic drugs (see https://www.ppu.mrc.ac.uk/list-clinically-approved-kinase-inhibitors). (b) Timeline describing the development of anticancer drugs cisplatin (Pt1), carboplatin (Pt2) and oxaliplatin (Pt3).

Fig. 2

Fig. 2. Structures of selected (candidate) metallodrugs. Others labelled in the text are in the ESI, Section 6.

Fig. 3

Fig. 3. Comparison of the p_K_a values of aquated species of metal-based complexes. values refer to M–OD2 complexes based on pH* (pH meter reading not corrected for the effect of deuterium on the electrode).

Fig. 4

Fig. 4. Hydrolytic activation of two types of half-sandwich complex; RM175 (Ru1), bearing a σ-donor bidentate ligand (en), for which hydrolysis is activated by reduced [Cl−] levels in cells; FY26 (Os4), bearing a strong π-acceptor ligand (azpy), for which hydrolysis is activated by GSH attack on the azo-bond.

Fig. 5

Fig. 5. Simulated isotope pattern for 8.6 kDa protein ubiquitin (black) and [ubiquitin + Pt(NH3)2] (red, shifted by 228 Da, monoisotopic mass of Pt(NH3)2, for ease of comparison). Due to the characteristic isotope pattern of Pt (inset), the isotopic distribution of the protein–metal complex is broader and shifted to higher mass compared to the apo-protein. Automated peak-picking procedures can identify such platinated species in complex mixtures (e.g. cell lysates) providing insight into the binding sites for metallodrugs on proteins.

Fig. 6

Fig. 6. Examples of the large differences in IC50 values for cisplatin reported by 3 different labs (bars a, d; b, e and c, f) for the same cell lines (MCF7, human breast cancer, and MDA-MB-231, epithelial human breast cancer). The effect of the solvent used to solubilise cisplatin is highlighted; other differences in the screening conditions including type of assay, time of treatment, and composition of culture media are listed in Table S6.

Fig. 7

Fig. 7. Cisplatin (CDDP) resistance in cancer cells. CDDP enters cells via active transport (e.g. via transporters CTR1 and OCT2) or by passive transport. Reduced influx and elevated efflux are forms of CDDP resistance. The ATPases ATP7A/B are located at the Golgi apparatus, in the trans-Golgi network, facilitating the sequestration and export of cisplatin within membrane vesicles that are released. Intracellular CDDP activation occurs by aquation (first stage shown). Activated CDDP can react with glutathione (GSH) to form platinum-GSH conjugates (Pt-SG) and leave the cell via MRP2, or interact with metallothionein (MT), contributing to CDDP tolerance. CDDP exposure generates mitochondria-dependent reactive oxygen species (ROS). CDDP enters the nucleus and forms platinum–DNA adducts. Shielding from repair, by high mobility group (HMG) protein protection, or no repair leads to apoptosis. Excision-repair and high expression of proteins such as ERCC1 and XPF, subsequently inhibit apoptosis. Augmented expression of p53 and pATM is associated G2/M arrest of the cell cycle and apoptosis, in contrast to lowered expression, linked to CDDP resistance. Created with https://www.BioRender.com.

Fig. 8

Fig. 8. Examples of cell cycle arrest by metallodrugs. Abrogation of the cell cycle enables the initiation of apoptosis to control cell proliferation. Metal complexes can inhibit cell cycle progression at different stages which vary between different cell lines, doses, and exposure times. The cell cycle checkpoints (pink) determine progression to the next stage, and cell cycle regulators include cyclins (green) and CDKs (cyclin-dependent kinases, blue). Subpopulations of cells enter a quiescent state at the G0 phase. CDDP (cisplatin, Pt1); l-OHP (oxaliplatin, Pt3); NAMI-A (Ru4); NKP1339 (Ru9); FY26 (Os4). Created with https://www.BioRender.com.

Fig. 9

Fig. 9. Relationship between circadian rhythm and chemotherapy. The rhythm of the GSH content of mouse liver (black, based on data from ref. 225) is compared to the schedule of administration of oxaliplatin (Pt3) in a typical chronomodulated chemotherapy. Patients show best tolerance at 16:00 (red). Oxaliplatin is detoxified by conjugation to glutathione, hence, tolerance is linked directly to GSH levels (note the 12 h phase-shift between the highest GSH levels in mice and best tolerance in humans due to nocturnality of mice).

Fig. 10

Fig. 10. Examples of metallodrug mapping by the indicated techniques. (a) LA-ICP-MS image of 193Ir (red) and 238U (green) in HeLa cells (overlay = yellow, scale bar 50 μm). (b) nanoSIMS image of 197Au in A2780 cells treated with AuMesoIX (Au2, scale bar: 4 μm). (c) Mitochondrial viscosity in Ir3-treated A549 cells determined by two-photon phosphorescence lifetime imaging (scale bar: 10 μm). (d) IR image of a Re–CO complex at 1925 cm−1 in MDA-MB-231 cells (scale bar 5 μm). (e) Biodistribution in a mouse of positron-emitting 89Zr-antibody conjugated to a drug via a Pt complex at different drug : antibody ratios (0, 2.6 and 5.2). (f) 3D-reconstructed image of Ir3-treated MCF7 cells, illustrating morphology of suborganelle structures (scale bars: 5 μm and 1 μm) blue: nucleus, red: dense vesicles, green: lipid droplets, white: vacuoles, yellow: mitochondria, dark red: cell membrane. Illustrations are adapted from the references given.

Fig. 11

Fig. 11. Characteristic K-L3 (2p3/2−1 → 1 s−1) and L3-M5 (3d5/2−1 → 2p3/2−1) X-ray fluorescence emissions. K-L3 for elements exploited in cryo-soft-X-ray tomography are in yellow, abundant endogenous elements in red; L3-M5 of exogenous elements are blue. Additional elements are reported in Table S11 B24 and I14 refer to beamlines at the Diamond synchrotron (www.diamond.ac.uk).

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