Advancements in steroidal Pt(II) & Pt(IV) derivatives for targeted chemotherapy (2000-2023).

One of the key strategies in chemotherapy involves crosslinking the DNA strands of cancer cells to impede their replication, with platinum (Pt) coordination compounds being a prominent class and cisplatin being its major representative. Steroidal ligands tethered to DNA interactive Pt core act as drug carriers for targeted therapy. While crosslinking of nuclear or mitochondrial DNA strands using coordination complexes has been studied for years, there remains a lack of comprehensive reviews addressing the advancements made in steroidal-Pt derivatives. This review specifically focuses on advancements made in steroid-tethered structural derivatives of Pt(II) or prodrug Pt(IV) for targeted chemotherapy, synthesized between 2000 and 2023. This period was deliberately chosen due to the widespread use of computational techniques for more accurate structure-based drug-design in last two decades. This review discusses the strategy behind tethering steroidal ligands such as testosterone, estrogen, bile acids, and cholesterol to the central DNA interactive Pt core through specific linker groups. The steroidal ligands function as drug delivery vehicles of DNA interactive Pt core and bind with their respective target receptors or proteins that are often overexpressed in cancer cells, thus enabling targeted delivery of Pt moiety to interact with DNA. We discussed structural features such as the location of the linker group on the steroid, the mono, bi, and tridentate configuration of the chelating arm in coordination with Pt, and the rigidity and flexibility of the linker group. The comparative in vitro, in vivo activities, and relative binding affinities of the designed compounds against standard Pt drugs are also discussed. We also provided a critique of observed trends and shortcomings. Our review will provide insights into future molecular designing of targeted DNA crosslinkers and their structural optimization to achieve desired drug properties. From this analysis, we proposed further research directions leading to the future of targeted chemotherapy.

Arresting the biosynthesis of Lipid A to hinder Escherichia coli and Pseudomonas aeruginosa through fatty diglyceride.

Lipid A is a fragment of lipopolysaccharide (LPS) in gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa; hence inhibition of its biosynthesis is one of the plausible ways of preventing such bacteria from growth and thus preventing gastrointestinal diseases caused by Escherichia coli and pseudomonas aeruginosa. This research revolves around the development of antibiotic glyceride derivatives for the inhibition of the biosynthesis of lipid A. To target the enzymes involved in the biosynthesis of lipid A, four N,N-dimethylaminobenzoate moiety containing fatty diglyceride derivatives were synthesized through a multi-step synthetic scheme starting from glycerol. The molecular structure of the targeted molecules and synthesized intermediates in the synthetic scheme were confirmed by detailed structural analysis through 1N-NMR, mass and IR spectroscopic techniques. Antibacterial activity was evaluated against the gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). The derivatives also underwent docking analysis on the pdb's of enzymatic catalysts involved in the biosynthesis of lipid A using AutoDock Vina package. All synthesized fatty esters gave good antibacterial activity and binding energy upto -7 kcal/mol in the docking analysis. A structure-property relationship was established between alkyl chain lengths of diglycerides and their resultant binding energies. These molecules and their resultant activity can assist in further designing and retrosynthesis of molecular derivatives of drug molecules with lipid A biosynthesis as target for its inhibition.

Colorimetric chromophoric rapid detection of SARS-CoV-2 through breath analysis.

Early and rapid detection of SARS-CoV-2 in an infected person is one fundamental part of the strategy against the spread of this virus. As of now, the usual practice is to carry out polymerase chain reaction (PCR) test which provides results in 24-48 hours. Hence, there exists a crucial need for rapid and immediate screening of people suspected to be infected. Presence of volatile organic compounds (VOCs) in the exhaled breath can be one such prospect for detection of virus. In this paper, we have designed chromophoric adducts of VOC's in the exhaled breath that can be formed for colorimetric detection of SARS-CoV-2. We noted the bathochromic shift in λ (nm) of VOC molecules upon chromophore formation for colorimetric detection. If adapted, this research work will result in low cost solution to the requirement of immediate detection of SARS-CoV-2, hence cost and time of testing will be reduced, compared to PCR and antibodies tests. Also VOC's detection in early stage of infection where symptoms are not visible can be advantageous.

Docking analysis of aryl derivatives of diepoxide alkylating agents.

In this research, molecular structural manipulation of treosulfan alkylating agent and resultant changes in binding is studied to assist in designing derivatives of treosulfan for synthesis. Molecular docking has been conducted on simulated heterocyclic polyaromatic alkylating diepoxide derivatives of treosulfan with DNA nucleobases of dodecamer duplex of sequences d(CGCGAATTCGCG) and d(CGCGAATTCGCG) using Autodock vina package. Two series of simulated diepoxide molecules were designed with increasing aryl ring chain in linear and fused aryl way between the two epoxide reactive rings. Relationship between increasing no. of aryl rings (both linear and fused) between epoxide moieties on the binding energy values was evaluated. We also identified that designed molecules bind specifically to Guanine and Cytosine (GC) base pairs on DNA. Mode of interaction and resultant behavior as an alkylating agent or as minor groove binder was also found to be dependent up on the no. of aryl rings and their connectivity in the molecule. Both linearly bonded and fused aryl rings in higher number, between the epoxide rings, gave the strongest binding with the binding energy up to -8.1 and -8.7 Kcal/mol, respectively. These relationships can immensely help in designing and synthesis of derivatives of treosulfan like diepoxide based alkylating agents.

Derivatives of diisopropyl phenoxyphosphate with controlled reactivity for enhancement of Acetylcholine (ACh) neurotransmitter.

Here, new phenoxide derivatives of diisopropyl flourophosphate for reaction with Lewis basic sites on acetyl cholinesterase (AChE) were designed. Such binding interaction or reaction inhibits the hydrolysis of the acetylcholine (ACh) neurotransmitter thus enhancing its concentration. This increased neurotransmitter concentration can enhance memory and cognition thus improving symptoms of neurodegenerative diseases such as Alzheimer disease and down syndrome. For docking analysis, we particularly targeted those reception sites on AChE that interacts with the ACh. This led to structural design of derivatives of diisopropyl phenoxyphosphate with controlled reactivity stemming from para substituted phenoxide leaving group. Impact of electron donating (CH3, OCH3) and withdrawing substituents (COCH3) on para position of phenol group on rate of acyl addition elimination reaction was modeled using QM DFT technique. Difference in activation energy between electron donating and withdrawing substituents on phenoxide was noted hence making the derivatives of diisopropyl phenoxyphosphate less reactive and more selective. Docking also confirmed binding of designed derivatives with AChE. Hence novel derivatives with high binding energy and controlled reactivity were designed for retrosynthesis.

Heterochelates of metals as an effective anti - Urease agents couple with their docking studies.

The current article discusses the activities of several synthesized metal heterochelates in in-vitro as anti-ulcer agents followed by their docking study. For this purpose, two important ligands like 8-hydroxyquinoline and DL-methionine were used in synthesis of heterochelates of metal including Cr (III), Mn (II), Fe (III), Co (II), Ni (II), Cu (II), Zn (II), Cd (II) and Pb (II). It was observed that these complexes showed excellent urease inhibition activities in which thiourea was the standard having IC50 value 21.6 ± 0.12µM. The Cu (II) complex showed potent inhibitory activity (22.6 ± 0.72 µM) when compared with the standard thiourea (21.6±0.12µM) among the nine synthesized complexes while Mn (II), Fe (III), Cd (II) and Pb (II) also showed better inhibitory activities. The urease inhibitory activities of hetercochelates also tested and validated by docking analysis.

DNA physical interaction mediated b-lymphoma treatment offered by tetra benzimidazole-substituted zinc (ii) phthalocyanine derivative.

Role of heterocyclic compounds with nitrogen substitution in therapeutic frontiers is well established. The efforts made in this study are directed to dissect the biological significance of benzimidazole-substituted zinc phthalocyanine derivative. Its capacity to act as an anticancer agent against the 2 B-lymphoma cell lines (low-grade and high-grade malignancy) was found out by recording florescence using Alamar blue dye. Further cytotoxic effect at the DNA level was analyzed by performing agarose gel electrophoresis. Molecular docking studies made mechanistic details crystal clear by showing potential dual binding modes employed for interaction with DNA that include minor groove binding and intercalation between bases. This advocates this derivative as potential anticancer agent and deserves further rounds of mechanistic study for its final journey to serve as a marketed drug.

Aryl sulfonate based anticancer alkylating agents.

This research work revolves around synthesis of antineoplastic alkylating sulfonate esters with dual alkylating sites for crosslinking of the DNA strands. These molecules were evaluated as potential antineoplastic cross linking alkylating agents by reaction with the nucleoside of Guanine DNA nucleobase at both ends of the synthesized molecule. Synthesis of the alkylating molecules and the crosslinking with the guanosine nucleoside was monitored by MALDITOF mass spectroscopy. The synthesized molecule's crosslinking or adduct forming rate with the nucleoside was compared with that of 1,4 butane disulfonate (busulfan), in form of time taken for the appearance of [M+H]+. It was found that aryl sulfonate leaving group was causing higher rate of nucleophilic attack by the Lewis basic site of the nucleobase. Furthermore, the rate was also found to be a function of electron withdrawing or donating nature of the substituent on the aryl ring. Compound with strong electron withdrawing substituent on the para position of the ring reacted fastest. Hence, new alkylating agents were synthesized with optimized or desired reactivity.

5-Bromo-2-aryl benzimidazole derivatives as non-cytotoxic potential dual inhibitors of α-glucosidase and urease enzymes.

On the basis of previous report on promising α-glucosidase inhibitory activity of 5-bromo-2-aryl benzimidazole derivatives, these derivatives were further screened for urease inhibitory and cytotoxicity activity in order to get more potent and non-cytotoxic potential dual inhibitor for the patients suffering from diabetes as well as peptic ulcer. In this study, all compounds showed varying degree of potency in the range of (IC50=8.15±0.03-354.67±0.19µM) as compared to standard thiourea (IC50=21.25±0.15µM). It is worth mentioning that derivatives 7 (IC50=12.07±0.05µM), 8 (IC50=10.57±0.12µM), 11 (IC50=13.76±0.02µM), 14 (IC50=15.70±0.12µM) and 22 (IC50=8.15±0.03µM) were found to be more potent inhibitors than standard. All compounds were also evaluated for cytotoxicity towards 3T3 mouse fibroblast cell line and found to be completely non-toxic. Previously benzimidazole 1-25 were also showed α-glucosidase inhibitory potential. In silico studies were performed on the lead molecules i.e.2, 7, 8, 11, 14, and 22, in order to rationalize the binding interaction of compounds with the active site of urease enzyme.