A review on the recent advances of interaction studies of anticancer metal-based drugs with therapeutic targets, DNA and RNAs.

Metal-based drugs hold promise as potent anticancer agents owing to their unique interactions with cellular targets. This review discusses recent advances in our understanding of the intricate molecular interactions of metal-based anticancer compounds with specific therapeutic targets in cancer cells. Advanced computational and experimental methodologies delineate the binding mechanisms, structural dynamics and functional outcomes of these interactions. In addition, the review sheds light on the precise modes of action of these drugs, their efficacy and the potential avenues for further optimization in cancer-treatment strategies and the development of targeted and effective metal-based therapies for combating various forms of cancer.

Synthesis and structural elucidation of a unique turn-off fluorescent sensor based on oxo-bridged tin (IV) cluster for selective detection of dopamine in biological fluids.

An oxo-bridged Sn (IV) Cluster, (TOC) was synthesized and fully characterized by FT-IR, UV-vis, 1H NMR, 119Sn NMR, Mass spectrometry and single crystal X-ray diffraction studies. The single-crystal X-ray analysis revealed that the crystal crystallizes in the monoclinic crystal system possessing the P 21/c space group and exhibited a distorted trigonal bipyramidal geometry. The TOC exhibited a unique turn-off fluorescence response for the selective detection of dopamine (DA) over other analytes. The stoichiometry between the TOC and DA was calculated using Job's plot. The value of the detection limit was found to be 1.33 µM. The Hirshfeld surface analysis was carried out on the crystal structure to investigate the H-H, Cl-H, Cl-Cl, Sn-Cl and Cl-C interaction studies in the molecule. Density Functional Theory (DFT) studies further supported the sensing mechanism, which closely agreed with the experimental results. Furthermore, the TOC chemosensor was used to detect DA in human blood plasma, and molecular docking studies validated the interaction between the chemosensor and protein. Confocal fluorescence imaging studies were carried out and validated TOC sensing ability for DA in human blood plasma.

Structural insights into interactions of new polymeric (µ-oxo) bridged Cu(II) complexes of taurine with yeast tRNA by spectroscopic and computational approaches and its application towards chemoresistant cancer lines.

RNA-targeted drugs are considered as safe treatment option for the cure of many chronic diseases preventing off-targeted delivery and acute toxic manifestations. FDA has approved many such RNA therapies in different phases of clinical trials, validating their use for the treatment of various chronic diseases. We report herein, new water-soluble (µ-oxo) bridged polymeric Cu(II) complexes of taurine (2-aminoethane sulfonic acid) complexes 1 and 2. The therapeutic potency of 1 and 2 was ascertained by studying biophysical interactions with tRNA/ct-DNA. The experimental results demonstrated that the complexes interacted avidly to nucleic acids through intercalation mode depicting a specific preference for tRNA in comparison to ct-DNA and, moreover 2 showed higher binding propensity than 1. The electrophoretic behaviour of the complexes with plasmid pBR322 DNA and tRNA were examined by gel mobility assay that revealed a concentration-dependent activity with complex 2 performing more efficient cleavage as compared to complex 1. Cytotoxicity results on cancer cell strains displayed higher cytotoxicity than complex 1 against treated cancer cells. The synthesized copper(II) taurine complexes have met the basic criteria of anticancer drug design as they are structurally well-characterized, exhibiting good solubility in water, lipophilic in nature with superior intercalating propensity towards tRNA and cytotoxic in nature.

Progress of Metal-Based Anticancer Chemotherapeutic Agents in Last two Decades and their Comprehensive Biological (DNA/RNA Binding, Cleavage and Cytotoxicity Activity) Studies.

During last two decades, there has been an enormous growth in the discovery of innovative active inorganic anticancer complexes (exerting remarkable cytotoxicity at sub micro-molar levels) derived from myriad ligand scaffolds, mainly acting on cancerous vs healthy cells by either halting or inhibiting their uncontrolled growth. The phenomenal success of cisplatin to treat numerous forms of solid malignancies has placed metal-based drugs to the forefront of treatment strategies against cancers. More than 10,000 platinum anticancer complexes have been developed during the past 40 years, but only five drugs have been approved for usage in humans while ten more complexes are currently undergoing clinical trials. Most of the compounds have failed either at R&D stages or in preclinical trails. This has led to extensive investigations by researchers of medicinal chemistry, including our group to design and prepare tailored 3d-metallo-drugs and organotin(IV) compounds from some naturally occurring bioactive compounds, such as amino-acids, peptides, chromone derivatives and NSAID's etc. that were used either alone or in cocktail combination, capable of specifically targeting DNA, lnc RNAs and proteins. Furthermore, 3d-metal ions such as copper, cobalt and zinc etc. incorporated in these ligand framework are biocompatible and induce a unique multi-modal mechanism of cytotoxic action involving angiogenesis, ROS-induced DNA damage, apoptosis by p53 mitochondrial genes and caspases etc. The results observed a positive correlation between the binding affinity of complexes with DNA (as quantified by intrinsic binding constant values) and their cytotoxic behavior. Complexes with high DNA binding propensity were typically lethal against a diverse panel of malignant cell types compared to normal cells.

Advances in anticancer alkaloid-derived metallo-chemotherapeutic agents in the last decade: Mechanism of action and future prospects.

Metal-based complexes have occupied a pioneering niche in the treatment of many chronic diseases, including various types of cancers. Despite the phenomenal success of cisplatin for the treatment of many solid malignancies, a limited number of metallo-drugs are in clinical use against cancer chemotherapy till date. While many other prominent platinum and non­platinum- based metallo-drugs (e.g. NAMI-A, KP1019, carboplatin, oxaliplatin, titanocene dichloride, casiopeinas® etc) have entered clinical trials, many have failed at later stages of R&D due to deleterious toxic effects, intrinsic resistance and poor pharmacokinetic response and low therapeutic efficacy. Nonetheless, research in the area of medicinal inorganic chemistry has been increasing exponentially over the years, employing novel target based drug design strategies aimed at improving pharmacological outcomes and at the same time mitigating the side-effects of these drug entities. Over the last few decades, natural products became one of the key structural motifs in the anticancer drug development. Many eminent researchers in the area of medicinal chemistry are devoted to develop new 3d-transition metal-based anticancer drugs/repurpose the existing bioactive compounds derived from myriad pharmacophores such as coumarins, flavonoids, chromones, alkaloids etc. Metal complexes of natural alkaloids and their analogs such as luotonin A, jatrorrhizine, berberine, oxoaporphine, 8-oxychinoline etc. have gained prominence in the anticancer drug development process as the naturally occurring alkaloids can be anti-proliferative, induce apoptosis and exhibit inhibition of angiogenesis with better healing effect. While some of them are inhibitors of ERK signal-regulated kinases, others show activity based on cyclooxygenases-2 (COX-2) and telomerase inhibition. However, the targets of these alkaloid complexes are still unclear, though it is well-established that they demonstrate anticancer potency by interfering with multiple pathways of tumorigenesis and tumor progression both in vitro and in vivo. Over the last decade, many significant advances have been made towards the development of natural alkaloid-based metallo-drug therapeutics for intervention in cancer chemotherapy that have been summarized below and reviewed in this article.

Mapping Clinical Documents to the Logical Observation Identifiers, Names and Codes (LOINC) Document Ontology using Electronic Health Record Systems Structured Metadata.

As Electronic Health Record (EHR) systems increase in usage, organizations struggle to maintain and categorize clinical documentation so it can be used for clinical care and research. While prior research has often employed natural language processing techniques to categorize free text documents, there are shortcomings relative to computational scalability and the lack of key metadata within notes' text. This study presents a framework that can allow institutions to map their notes to the LOINC document ontology using a Bag of Words approach. After preliminary manual value- set mapping, an automated pipeline that leverages key dimensions of metadata from structured EHR fields aligns the notes with the dimensions of the document ontology. This framework resulted in 73.4% coverage of EHR documents, while also mapping 132 million notes in less than 2 hours; an order of magnitude more efficient than NLP based methods.

New Tailored RNA-Targeted Organometallic Drug Candidates against Huh7 (Liver) and Du145 (Prostate) Cancer Cell Lines.

New organometallic drug candidates [Ph2Sn(HL)], 1, and [Ru(η6--p-cymene)(HL)Cl], 2, were designed and synthesized by in situ reaction of a Schiff base ligand (HL) and diphenyltin dichloride and [RuCl2(p-cymene)]2, respectively. The drug candidates 1 and 2 have been characterized by spectroscopic methods (Fourier-transform infrared spectroscopy, UV-vis, and 1H/13C NMR), elemental analysis, and single X-ray crystallographic studies (in case of 1). The ground-state geometry optimization of 1 and 2 was performed by density functional theory calculations. The interaction of 1 and 2 with tRNA was assessed by absorption spectroscopy, cyclic voltammetry, circular dichroism, and ethidium bromide displacement assay using fluorescence emission spectroscopy to determine their potential to act as antitumor agents. The cytotoxicity of 1 and 2 was screened against human liver carcinoma (Huh7), prostate cancer (Du145), and the normal prostate cell line (PNT 2). The results implicated a dose-dependent growth inhibition of the two cancer cells at concentrations (2.5-15 µM) of 1 and 2 with the treatment after 48 h. Interestingly, 1 revealed good selective activity toward the liver cancer cell line (Huh7). Furthermore, both the drug candidates 1 and 2 were found to be nontoxic toward the PNT 2 normal cell line. These studies lay a paradigm for rational efficacious drug design for chemotherapeutic intervention in cancers using new tailored organometallic drug entities; organotin(IV) and organoruthenium(II) have been demonstrated to be viable for the safe administration and specific targeted drug uptake by the resistant cancerous cell lines at low intracellular concentrations.

Evaluation of cytotoxic activity and genotoxicity of structurally well characterized potent cobalt(II) phen-based antitumor drug entities: An in vitro and in vivo approach.

Cobalt (II) phen-based drug candidates of the formulation Co(phen)2Cl2,1, Co(phen)2L, 2 where L = 1H-pyrazole-3,5-dicarboxylic acid were synthesized and thoroughly characterized by spectroscopic methods and single X-ray crystallography. DNA binding interaction of 1 and 2 was carried out employing biophysical techniques {UV-visible, fluorescence, thermal denaturation and cyclic voltammetry} to validate their potential to act as antitumor agents. The interpretations of these biophysical studies of 1 and 2 supported the non-covalent intercalative binding mode; furthermore, a higher binding trend of 2 was observed as compared to 1, phen and 1H-pyrazole-3,5-dicarboxylic acid alone. Cleavage studies of 1 and 2 with pBR322 were assessed by gel electrophoresis and it was observed that both drug candidates cleave DNA by hydrolytic pathway involving hydroxyl radical (OH). Cytotoxic activity of 1 and 2 against human cancer cell lines [MCF-7 (breast), HeLa (cervical), MIA-PA-CA 2 (pancreatic), A-498 (kidney), Hep-G2 (hepatoma)] was evaluated by SRB assay. The obtained results showed that drug candidate 1 showed significantly low GI50 value (<10 µg/ml) against MCF-7 and HeLa cell lines. However, candidate 2 revealed excellent cytotoxicity (<10 µg/ml) against all the tested cancer cell lines. The in vivo genotoxicity of 2 was evaluated by micronucleus (MN) test and chromosomal aberration (CA) in bone marrow cells of the Wistar rats to check cobalt(II)-induced systemic toxicity. The results showed that no significant chromosomal aberrations and micronucleus formation was observed at 5 mg/kg and 10 mg/kg in presence of drug candidate 2 implicating that it could be administered safely at a low dosage. However, an elevated percentage of chromosomal aberration and micronucleated polychromatic erythrocytes (MNPCE) was observed only at higher doses (20 mg/kg and 40 mg/kg) of drug candidate 2.

Evaluation of cytotoxic potential of structurally well-characterized RNA targeted ionic non-steroidal anti-inflammatory (NSAID) Cu(ii) & Zn(ii) DACH-mefenamato drug conjugates against human cancer cell lines.

New RNA targeted ionic [Cu(DACH)2(H2O)2](mef)2, 1 and [Zn(DACH)2(H2O)2](mef)2, 2 drug conjugates were synthesized and characterized by spectroscopic techniques FT-IR, UV-vis, EPR in case of 1 and 1H and 13C NMR in case of 2, ESI-MS, thermogravimetric analysis and single-crystal X-ray structure determination in case of 1. The interaction studies of 1 & 2 with most likely drug targets like ctDNA and tRNA were performed which demonstrated that the complexes 1 and 2 exhibited strong preferential binding to tRNA as compared to ctDNA, K b = 2.52(±0.04) × 105 M-1, 7.85(±0.02) × 104 M-1, respectively. Scanning electron microscopy analyses of complex-ctDNA/tRNA condensates suggested the interaction of complexes with ctDNA/tRNA had occurred, followed by lengthening of DNA double helix and bulge region of tRNA. Cytotoxic activity of 1 and 2 against human cancer cell lines namely; MCF-7 (breast), HeLa (cervical), MIA-PA-CA 2 (pancreatic), A-498 (kidney), Hep-G2 (hepatoma) was evaluated by SRB assay. The obtained results showed that copper complex 1 was an outstanding cytotoxic agent with remarkably good GI50 value (<10 µg ml-1) against the tested cancer cell lines except for MIA-PA-CA 2, while zinc complex 2 revealed moderate cytotoxicity against all the tested cancer cell lines.