Metal Complexes as DNA Synthesis and/or Repair Inhibitors: Anticancer and Antimicrobial Agents

Abstract

Medicinal inorganic chemistry involving the utilization of metal-based compounds as therapeutics has become a field showing distinct promise. DNA and RNA are ideal drug targets for therapeutic intervention in the case of various diseases, such as cancer and microbial infection. Metals play a vital role in medicine, with at least 10 metals known to be essential for human life and a further 46 nonessential metals having been involved in drug therapies and diagnosis. These metal-based complexes interact with DNA in various ways, and are often delivered as prodrugs which undergo activation in vivo. Metal complexes cause DNA crosslinking, leading to the inhibition of DNA synthesis and repair. In this review, the various interactions of metal complexes with DNA nucleic acids, as well as the underlying mechanism of action, were highlighted. Furthermore, we also discussed various tools used to investigate the interaction between metal complexes and the DNA. The tools included in vitro techniques such as spectroscopy and electrophoresis, and in silico studies such as protein docking and density-functional theory that are highlighted for preclinical development.

Hydrazone bimetallic complex: synthesis, characterization, in silico and biological evaluation targeting breast and lung cancer cells’ G-quadruplex DNA

“…Each structure was assigned an appropriate bond order using the LigPrep package from Schrodinger, LLC, NY, USA (Glide 2017; LigPrep 2017). The ligands were converted to Maestro format, Schrodinger, LLC, NY, USA, and geometrically optimize the ligand and computed partial atomic charges (Ngoepe & Clayton 2021). Then, at most, 32 poses per ligand were generated with different steric features for the subsequent docking study.…”

“…Therefore, the development of cancer treatments and therapeutic strategies are urgently required. One important strategy nowadays is targeting DNA structure's stability (Ghafouri-Fard et al, 2022;Ngoepe & Clayton 2021;Couzin-Frankel, 2013) by targeting it with complexes that combine with DNA and cleave its strands and lead to variable physiological conditions (Verma et al, 2014). For example, clinically cisplatin and its analogs are known to be used as metallo-anticancer drugs, and their drawback is harming the normal tissues because cisplatin is targeting the genomic DNA (Palma et al, 2021;Cao et al, 2017).…”

“…These G-quadruplex are stabilized by alkali metal 3 cations and are located in the human chromosome's telomerase, the promoters of the oncogene, and some regions of the untranslated RNA (Cao et al, 2017;Bugaut & Balasubramanian 2012;Dinshow et al, 2007;Burge et al, 2006). Some metals when forming chemical complexes showed interesting properties such as geometric, magnetic, or catalytic (Ngoepe & Clayton 2021) which made them ideal candidates to target the structural G-quadruplex (Cao et al, 2017;Jiand & Liu 2010) leading to chromosome rigidity, inhibition of DNA synthesis, and repair, and then cancer cell death (Ghafouri-Fard et al, 2022;Palma et al, 2021;Ngoepe & Clayton 2021;Cao et al, 2017). Further, the development of small molecules that can target G-quadruplex with alternative modes such as planar molecules (Ghafouri-Fard et al, 2022;Wang et al, 2010), loop binding molecules (Suntharalingam et al, 2009) electrostatic interactions (Cao et al, 2017) direct interactions to the nucleic acids' bases or the phosphate backbone of DNA twisted ladder, and cationic metal substituted ligand with different geometries, have more attention these days (Palma et al, 2021;Cao et al, 2017;Muller & Rodriguez 2014;Jiand & Liu, 2010;Wang et al, 2010;Suntharalingam et al, 2009).…”

Synthesis and characterization of nanoscale level mono/bi-ligated metal(II) complexes

“…However, these platinum-based anticancer medications, which are clinically utilized to treat 50% of malignant tumors, have a number of drawbacks, including poor stability, significant side effects, and low absorption. 10,12,13 They were tested for DNA-binding ability and anti-tumor efficacy in order to circumvent the problems that plagued cisplatin. Also, very recently, researchers focused on the development of non-platinated metal complexes based particularly on Cu, Ru, or Os due to their improved biocompatibility and negligible toxicity, which resulted in minimal side effects.…”

Manganese Schiff Base Complexes, Crystallographic Studies, Anticancer Activities, and Molecular Docking

“…In the case of the transition metals, the partially filled "d orbitals" they possess help them to express their interesting redox chemistry via electronic properties and their abilities to act as suitable probes in anticancer agents' designs [2,5]. Additionally, the ability to go through ligand exchange reactions provides numerous opportunities for ligands to interact and coordinate with metals (ligate), to form metal complexes (coordination compounds), such as cisplatin [2,8,9]. Since the serendipitous breakthrough discovery of cisplatin's biological activity, metal-based compounds have proffered opportunities for therapeutic designs to study and treat varieties of human ailments [2,7,[10][11][12][13][14].…”