In vitro anti-proliferative, and in silico ribonucleotide reductase and pharmacokinetics studies of heteroleptic silver(I), nickel(II) and copper(II) complexes of 4-methyl-3-thiosemicarbazones and ibuprofen

Over the past few decades multifunctional donor ligands such as thiosemicarbazones (TSCs) have gained pervasive success, in particular, for their biological applications because of their π-delocalization, configurational flexibility and versatility of donor atoms [1]. The biological activities of TSCs improve significantly on complex formation with various metal ions. The wide range of biological applications of TSCs and their metal complexes include antibacterial, antifungal, antiviral, antileukemic, anti-HIV and antitumor activities [2], [3]. Triapine (3-aminopyridine-2-carbaldehydethiosemicarbazone) is a well-known antitumor compound, which crossed many clinical trials but failed due to severe side effects [4]. It is presumed that the inhibition of DNA topoisomerase-II enzyme, which regulates DNA topology leads to the cytotoxicity activity of thiosemicarbazone-based metal complexes [5]. The platinum-based drugs such as cisplatin, carboplatin and oxaliplatin are ushered success models for healing various types of cancers, and paved way towards the interest in developing metallodrugs to fight cancer. However, their usage is in a narrow spectrum due to unusual side effects such as ototoxicity, nephrotoxicity and neurotoxicity [6], [7]. This forces the researches to develop a far-reaching search in designing nonplatinum-based metallodrugs with ameliorated pharmacological properties.

Many nonplatinum-based metal complexes have been designed with various metals and ligand combination, and evaluated for both in vitro and in vivo antitumor activities [8]. Silver, nickel and copper complexes exhibit promising activities because of their known biological roles. Silver is already in use for many medical applications such as antibacterial, antiseptic and anti-inflammatory agents, and as antibiotic coating in medical devices and in wound dressing [9], [10]. Many nickel bearing enzymes catalyze various reactions in living organisms, and play an important role in biosystems [11], [12]. Copper is a trace dietary mineral of living organisms, and plays key role as catalytic and structural centre of various enzymes involved in biological process [13]. Several classes of thiosemicarbazone-based silver, nickel and copper complexes have been designed and successfully evaluated for their anti-proliferative activity against cancerous and normal cell lines [14], [15], [16], [17].

The non-steroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of various diseases such as inflammation, pain and fever, and non-selectively inhibit cyclooxygenase (COX-1 and COX-2) metabolism, which further inhibits cancer growth. Ibuprofen (α-methyl-4-(isobutyl)phenylacetic acid), a member of phenylalkanoic acids, is a non-steroidal anti-inflammatory drug, used as analgesic, antipyretic and anti-inflammatory agent [18]. It is the first member of propionic acid derivatives to replace aspirin in 1969, due to which ibuprofen gained importance in research. In order to reduce the side effects associated with the NSAIDs, a successful strategy is the usage of d-block metal complexes of NSAIDs as a therapeutic agent. For example, nickel complexes of NSAID, ibuprofen, showed promising anti-proliferative activity against lung fibroblast (WI-26VA4) cells [19]. Thus, the interest towards NSAIDs coordinated to metal ions have been increased with designing more efficient metallodrugs, which showed significant results such as the improved pharmaceutical activity with reduced toxicity of NSAIDs, and exhibiting additional efficacy such as antitumor activity [20], [21], [22], [23].

An in-depth literature survey revealed that the long-standing reports has not been appeared till date on the heteroleptic metal complexes of NSAIDs with thiosemicarbazone, and their anti-proliferative and molecular docking studies. In accordance of these observations and in continuation of our recent report on heteroleptic metal complexes with terpyridines and NSAIDs, naproxen [24], [25], the current research has been converged in developing new heteroleptic metal complexes of thiosemicarbazones and ibuprofen, as the anti-proliferative activity of ibuprofen complexes was found to be inadequate in literature. The in vitro anti-proliferative activity of the complexes was tested against one normal cell line (MCF-10a) and three cancerous (estrogen positive (MCF-7), estrogen negative (MDA-MB-231) and pancreatic (PANC-1)) cell lines by MTT reduction assay. Interest is extended in exploring the mode of interaction of metal complexes with ribonucleotide reductase enzyme (RNR), and to screen the complexes for drug-likeness and ADMET properties by in silico molecular docking and pharmacokinetics studies, respectively.

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