Molecular mechanisms underlying the regulation of tumour suppressor genes in lung cancer.

Tumour suppressor genes play a cardinal role in the development of a large array of human cancers, including lung cancer, which is one of the most frequently diagnosed cancers worldwide. Therefore, extensive studies have been committed to deciphering the underlying mechanisms of alterations of tumour suppressor genes in governing tumourigenesis, as well as resistance to cancer therapies. In spite of the encouraging clinical outcomes demonstrated by lung cancer patients on initial treatment, the subsequent unresponsiveness to first-line treatments manifested by virtually all the patients is inherently a contentious issue. In light of the aforementioned concerns, this review compiles the current knowledge on the molecular mechanisms of some of the tumour suppressor genes implicated in lung cancer that are either frequently mutated and/or are located on the chromosomal arms having high LOH rates (1p, 3p, 9p, 10q, 13q, and 17p). Our study identifies specific genomic loci prone to LOH, revealing a recurrent pattern in lung cancer cases. These loci, including 3p14.2 (FHIT), 9p21.3 (p16INK4a), 10q23 (PTEN), 17p13 (TP53), exhibit a higher susceptibility to LOH due to environmental factors such as exposure to DNA-damaging agents (carcinogens in cigarette smoke) and genetic factors such as chromosomal instability, genetic mutations, DNA replication errors, and genetic predisposition. Furthermore, this review summarizes the current treatment landscape and advancements for lung cancers, including the challenges and endeavours to overcome it. This review envisages inspired researchers to embark on a journey of discovery to add to the list of what was known in hopes of prompting the development of effective therapeutic strategies for lung cancer.

In Vivo Wound Healing Potential and Molecular Pathways of Amniotic Fluid and Moringa Olifera-Loaded Nanoclay Films.

Cutaneous wounds pose a significant health burden, affecting millions of individuals annually and placing strain on healthcare systems and society. Nanofilm biomaterials have emerged as promising interfaces between materials and biology, offering potential for various biomedical applications. To explore this potential, our study aimed to assess the wound healing efficacy of amniotic fluid and Moringa olifera-loaded nanoclay films by using in vivo models. Additionally, we investigated the antioxidant and antibacterial properties of these films. Using a burn wound healing model on rabbits, both infected and non-infected wounds were treated with the nanoclay films for a duration of twenty-one days on by following protocols approved by the Animal Ethics Committee. We evaluated wound contraction, proinflammatory mediators, and growth factors levels by analyzing blood samples. Histopathological changes and skin integrity were assessed through H&E staining. Statistical analysis was performed using SPSS software (version 2; Chicago, IL, USA) with significance set at p < 0.05. Our findings demonstrated a significant dose-dependent increase in wound contraction in the 2%, 4%, and 8% AMF-Me.mo treatment groups throughout the study (p < 0.001). Moreover, macroscopic analysis revealed comparable effects (p > 0.05) between the 8% AMF-Me.mo treatment group and the standard treatment. Histopathological examination confirmed the preservation of skin architecture and complete epidermal closure in both infected and non-infected wounds treated with AMF-Me.mo-loaded nanofilms. RT-PCR analysis revealed elevated concentrations of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF), along with decreased levels of tumor necrosis factor-alpha (TNF-α) in AMF-Me.mo-loaded nanofilm treatment groups. Additionally, the antimicrobial activity of AMF-Me.mo-loaded nanofilms contributed to the decontamination of the wound site, positioning them as potential candidates for effective wound healing. However, further extensive clinical trials-based studies are necessary to confirm these findings.

2-Amino Thiazole Derivatives as Prospective Aurora Kinase Inhibitors against Breast Cancer: QSAR, ADMET Prediction, Molecular Docking, and Molecular Dynamic Simulation Studies.

The aurora kinase is a key enzyme that is implicated in tumor growth. Research revealed that small molecules that target aurora kinase have beneficial effects as anticancer agents. In the present study, in order to identify potential antibreast cancer agents with aurora kinase inhibitory activity, we employed QSARINS software to perform the quantitative structure-activity relationship (QSAR). The statistical values resulted from the study include R2 = 0.8902, CCCtr = 0.7580, Q2 LOO = 0.7875, Q2LMO = 0.7624, CCCcv = 0.7535, R2ext = 0.8735, and CCCext = 0.8783. Among the four generated models, the two best models encompass five important variables, including PSA, EstateVSA5, MoRSEP3, MATSp5, and RDFC24. The parameters including the atomic volume, atomic charges, and Sanderson's electronegativity played an important role in designing newer lead compounds. Based on the above data, we have designed six series of compounds including 1a-e, 2a-e, 3a-e, 4a-e, 5a-e, and 6a-e. All these compounds were subjected to molecular docking studies by using AutoDock v4.2.6 against the aurora kinase protein (1MQ4). Among the above 30 compounds, the 2-amino thiazole derivatives 1a, 2a, 3e, 4d, 5d, and 6d have excellent binding interactions with the active site of 1MQ4. Compound 1a had the highest docking score (-9.67) and hence was additionally subjected to molecular dynamic simulation investigations for 100 ns. The stable binding of compound 1a with 1MQ4 was verified by RMSD, RMSF, RoG, H-bond, molecular mechanics-generalized Born surface area (MM-GBSA), free binding energy calculations, and solvent-accessible surface area (SASA) analyses. Furthermore, newly designed compound 1a exhibited excellent ADMET properties. Based on the above findings, we propose that the designed compound 1a may be utilized as the best theoretical lead for future experimental research of selective inhibition of aurora kinase, therefore assisting in the creation of new antibreast cancer drugs.

Cyclohexane-1,3-dione Derivatives as Future Therapeutic Agents for NSCLC: QSAR Modeling, In Silico ADME-Tox Properties, and Structure-Based Drug Designing Approach.

The abnormal expression of the c-Met tyrosine kinase has been linked to the proliferation of several human cancer cell lines, including non-small-cell lung cancer (NSCLC). In this context, the identification of new c-Met inhibitors based on heterocyclic small molecules could pave the way for the development of a new cancer therapeutic pathway. Using multiple linear regression (MLR)-quantitative structure-activity relationship (QSAR) and artificial neural network (ANN)-QSAR modeling techniques, we look at the quantitative relationship between the biological inhibitory activity of 40 small molecules derived from cyclohexane-1,3-dione and their topological, physicochemical, and electronic properties against NSCLC cells. In this regard, screening methods based on QSAR modeling with density-functional theory (DFT) computations, in silico pharmacokinetic/pharmacodynamic (ADME-Tox) modeling, and molecular docking with molecular electrostatic potential (MEP) and molecular mechanics-generalized Born surface area (MM-GBSA) computations were used. Using physicochemical (stretch-bend, hydrogen bond acceptor, Connolly molecular area, polar surface area, total connectivity) and electronic (total energy, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels) molecular descriptors, compound 6d is identified as the optimal scaffold for drug design based on in silico screening tests. The computer-aided modeling developed in this study allowed us to design, optimize, and screen a new class of 36 small molecules based on cyclohexane-1,3-dione as potential c-Met inhibitors against NSCLC cell growth. The in silico rational drug design approach used in this study led to the identification of nine lead compounds for NSCLC therapy via c-Met protein targeting. Finally, the findings are validated using a 100 ns series of molecular dynamics simulations in an aqueous environment on c-Met free and complexed with samples of the proposed lead compounds and Foretinib drug.

Synthetic Imidazopyridine-Based Derivatives as Potential Inhibitors against Multi-Drug Resistant Bacterial Infections: A Review.

Fused pyridines are reported to display various pharmacological activities, such as antipyretic, analgesic, antiprotozoal, antibacterial, antitumor, antifungal, anti-inflammatory, and antiapoptotic. They are widely used in the field of medicinal chemistry. Imidazopyridines (IZPs) are crucial classes of fused heterocycles that are expansively reported on in the literature. Evidence suggests that IZPs, as fused scaffolds, possess more diverse profiles than individual imidazole and pyridine moieties. Bacterial infections and antibacterial resistance are ever-growing risks in the 21st century. Only one IZP, i.e., rifaximin, is available on the market as an antibiotic. In this review, the authors highlight strategies for preparing other IZPs. A particular focus is on the antibacterial profile and structure-activity relationship (SAR) of various synthesized IZP derivatives. This research provides a foundation for the tuning of available compounds to create novel, potent antibacterial agents with fewer side effects.

QSAR and Molecular Docking Studies of Pyrimidine-Coumarin-Triazole Conjugates as Prospective Anti-Breast Cancer Agents.

Cancer is a life-threatening disease and is the second leading cause of death worldwide. Although many drugs are available for the treatment of cancer, survival outcomes are very low. Hence, rapid development of newer anticancer agents is a prime focus of the medicinal chemistry community. Since the recent past, computational methods have been extensively employed for accelerating the drug discovery process. In view of this, in the present study we performed 2D-QSAR (Quantitative Structure-Activity Relationship) analysis of a series of compounds reported with potential anticancer activity against breast cancer cell line MCF7 using QSARINS software. The best four models exhibited a r2 value of 0.99. From the generated QSAR equations, a series of pyrimidine-coumarin-triazole conjugates were designed and their MCF7 cell inhibitory activities were predicted using the QSAR equations. Furthermore, molecular docking studies were carried out for the designed compounds using AutoDock Vina against dihydrofolate reductase (DHFR), colchicine and vinblastine binding sites of tubulin, the key enzyme targets in breast cancer. The most active compounds identified through these computational studies will be useful for synthesizing and testing them as prospective novel anti-breast cancer agents.

Synthetic Strategies of Pyrimidine-Based Scaffolds as Aurora Kinase and Polo-like Kinase Inhibitors.

The past few decades have witnessed significant progress in anticancer drug discovery. Small molecules containing heterocyclic moieties have attracted considerable interest for designing new antitumor agents. Of these, the pyrimidine ring system is found in multitude of drug structures, and being the building unit of DNA and RNA makes it an attractive scaffold for the design and development of anticancer drugs. Currently, 22 pyrimidine-containing entities are approved for clinical use as anticancer drugs by the FDA. An exhaustive literature search indicates several publications and more than 59 patents from the year 2009 onwards on pyrimidine derivatives exhibiting potent antiproliferative activity. These pyrimidine derivatives exert their activity via diverse mechanisms, one of them being inhibition of protein kinases. Aurora kinase (AURK) and polo-like kinase (PLK) are protein kinases involved in the regulation of the cell cycle. Within the numerous pyrimidine-based small molecules developed as anticancer agents, this review focuses on the pyrimidine fused heterocyclic compounds modulating the AURK and PLK proteins in different phases of clinical trials as anticancer agents. This article aims to provide a comprehensive overview of synthetic strategies for the preparation of pyrimidine derivatives and their associated biological activity on AURK/PLK. It will also present an overview of the synthesis of the heterocyclic-2-aminopyrimidine, 4-aminopyrimidine and 2,4-diaminopyrimidine scaffolds, and one of the pharmacophores in AURK/PLK inhibitors is described systematically.

Thiazole-Chalcone Hybrids as Prospective Antitubercular and Antiproliferative Agents: Design, Synthesis, Biological, Molecular Docking Studies and In Silico ADME Evaluation.

Compounds bearing thiazole and chalcone pharmacophores have been reported to possess excellent antitubercular and anticancer activities. In view of this, we designed, synthesized and characterized a novel series of thiazole-chalcone hybrids (1-20) and further evaluated them for antitubercular and antiproliferative activities by employing standard protocols. Among the twenty compounds, chalcones 12 and 7, containing 2,4-difluorophenyl and 2,4-dichlorophenyl groups, showed potential antitubercular activity higher than the standard pyrazinamide (MIC = 25.34 µM) with MICs of 2.43 and 4.41 µM, respectively. Chalcone 20 containing heteroaryl 2-thiazolyl moiety exhibited promising antiproliferative activity against the prostate cancer cell line (DU-145), higher than the standard methotrexate (IC50 = 11 ± 1 µM) with an IC50 value of 6.86 ± 1 µM. Furthermore, cytotoxicity studies of these compounds against normal human liver cell lines (L02) revealed that the target molecules were comparatively less selective against L02. Additional computational studies using AutoDock predicted the key binding interactions responsible for the activity and the SwissADME tool computed the in silico drug likeliness properties. The lead compounds generated through this study, create a way for the optimization and development of novel drugs against tuberculosis infections and prostate cancer.

Design, Facile Synthesis and Characterization of Dichloro Substituted Chalcones and Dihydropyrazole Derivatives for Their Antifungal, Antitubercular and Antiproliferative Activities.

Infectious diseases caused by fungi and mycobacteria pose an important problem for humankind. Similarly, cancer is one of the leading causes of death globally. Therefore, there is an urgent need for the development of novel agents to combat the deadly problems of cancer, tuberculosis, and also fungal infections. Hence, in the present study, we designed, synthesized, and characterized 30 compounds including 15 chalcones (2-16) and 15 dihydropyrazoles (17-31) containing dichlorophenyl moiety and also screened these compounds for their antifungal, antitubercular, and antiproliferative activities. Among these compounds, the dihydropyrazoles showed excellent antifungal and antitubercular activities whereas the chalcones exhibited promising antiproliferative activity. Among the dihydropyrazoles, compound 31 containing 2-thienyl moiety showed promising antifungal activity (MIC 5.35 µM), whereas compounds 22 and 24 containing 2,4-difluorophenyl and 4-trifluoromethyl scaffolds revealed significant antitubercular activity with the MICs of 3.96 and 3.67 µM, respectively. Compound 16 containing 2-thienyl moiety in the chalcone series showed the highest anti-proliferative activity with an IC50 value of 17 ± 1 µM. The most active compounds identified through this study could be considered as starting points in the development of drugs with potential antifungal, antitubercular, and antiproliferative activities.

Antimicrobial, Antioxidant, and Anticancer Activities of Some Novel Isoxazole Ring Containing Chalcone and Dihydropyrazole Derivatives.

Our previous work identified isoxazole-based chalcones and their dihydropyrazole derivatives as two important five-membered heterocycles having antitubercular activity. Hence, in the present study, we biologically evaluated 30 compounds, including 15 isoxazole ring-containing chalcones (17-31) and 15 dihydropyrazoles (32-46) derived from these chalcones for their antimicrobial, antioxidant, and anticancer activities. Chalcones exhibited superior antibacterial and antioxidant activities compared to dihydropyrazoles. Among the chalcones, compound 28 showed potent antibacterial (MIC = 1 µg/mL) and antioxidant activities (IC50 = 5 ± 1 µg/mL). Dihydropyrazoles, on the contrary, demonstrated remarkable antifungal and anticancer activities. Compound 46 (IC50 = 2 ± 1 µg/mL) showed excellent antifungal activity whereas two other dihydropyrazoles 45 (IC50 = 2 ± 1 µg/mL) and 39 (IC50 = 4 ± 1 µg/mL) exhibited potential anticancer activity. The compounds were also tested for their toxicity on normal human cell lines (LO2) and were found to be nontoxic. The active compounds that have emerged out of this study are potential lead molecules for the development of novel drugs against infectious diseases, oxidative stress, and cancer.