Design, Synthesis, and Anti-Breast Cancer Potential of Imidazole-Pyridine Hybrid Molecules In Vitro and Ehrlich Ascites Carcinoma Growth Inhibitory Activity Assessment In Vivo.

Breast cancer remains a challenging medical issue and is a high priority for biomedical research despite significant advancements in cancer research and therapy. The current study aims to determine the anticancer activity of a group of imidazole-pyridine-based scaffolds against a variety of breast cancer cell lines differing in their receptor expression (estrogen receptor (ER), progesterone receptor (PR), and HER-2). A series of 10 molecules (coded 5a-5j) were synthesized through multicomponent and alkylation reactions. FTIR, MS, 1H, and 13C NMR spectral analyses confirmed the structures and purity of the synthesized molecules. Subsequently, these molecules were tested for their ability to inhibit the viability of cell lines representing carcinoma of the breast, viz., MDA-MB-468 (ER-, PR-, and HER-), BT-474 (ER+, PR+, and HER+), T-47D (ER+, PR+, and HER-), and MCF-7 (ER+, PR+, and HER-) in vitro. Among these 10 molecules, 5a, 5c, 5d, and 5e exhibited better potency, as evidenced by IC50 < 50 µM at 24 h of treatment against BT-474 and MDA-MB-468 cell lines. However, except for 5d, the IC50 value is much higher than 50 µM when tested against T47D and MCF-7 cell lines at 24h. Extended treatment for 48 h reduced the effect of these molecules, as an increase in IC50 was observed. In mice, intraperitoneal administration of 5e retarded the Ehrlich ascites carcinoma (EAC) growth without causing any organ toxicity at the doses tested. In summary, we report the synthesis scheme and key structural requirements for a new series of imidazole-pyridine molecules for in vitro inhibition of the feasibility of breast cancer cells and in vivo inhibition of EAC tumors.

Heterocyclic and non-heterocyclic arena of monocarboxylate transporter inhibitors to battle tumorigenesis.

Monocarboxylate transporters (MCTs) have gained significant attention in cancer research due to their critical role in tumour metabolism. MCTs are legends for transporting lactate molecules in cancer cells, an oncometabolite and waste product of glycolysis, acting as an indispensable factor of tumour proliferation. Targeting MCTs with inhibitors has emerged as a promising strategy to combat tumorigenesis. This article summarizes the most recent research on MCT inhibitors in preventing carcinogenesis, covering both heterocyclic and non-heterocyclic compounds. Heterocyclic and non-heterocyclic compounds such as pteridine, pyrazole, indole, flavonoids, coumarin derivatives and cyanoacetic acid derivatives have been reported as potent MCT inhibitors. We examine the molecular underpinnings of MCTs in cancer metabolism, the design and synthesis of heterocyclic and non-heterocyclic MCT inhibitors, their impact on tumour cells and the microenvironment and their potential as therapeutic agents. Moreover, we explore the challenges associated with MCT inhibitor development and propose future directions for advancing this field. This write-up aims to provide researchers, scientists and clinicians with a comprehensive understanding of the heterocyclic and non-heterocyclic MCT inhibitors and their potential in combating tumorigenesis.

Network analysis and ligand-based pharmacophore modeling for discovery of small molecule against glioblastoma multiforme.

Aim: This study uses network pharmacology to design a c-Src inhibitor followed by pharmacophore modeling to combat glioblastoma multiforme. These in silico approaches are suitable for designing and developing new molecules of interest. Materials & methods: The authors performed virtual screening, pharmacophore analysis and validation of results using various in silico tools and reliable data from different types of literature and databases. Results: The in silico pipeline the authors followed produced reliable chemical information to combat glioblastoma. The authors identified a chemical template against the c-Src protein, which was validated statistically and computationally. Conclusion: The authors have successfully identified a chemical template against c-Src, which will be developed into a promising inhibitor in future studies.

Pyrimidine derivatives as EGFR tyrosine kinase inhibitors in non-small-cell lung cancer: A comprehensive review.

EGFR-positive non-small-cell lung cancer (NSCLC) due to primary mutation (EGFR DEL19 & L858R) has been recognized as a crucial mediator of tumor progression. This led to the development and approval of EGFR tyrosine kinase inhibitors, which addresses EGFR-mediated NSCLC but fail to show potency after initial months of therapy due to acquired resistance (EGFR T790M, EGFR C797S). Extensive research allowed identification of drugs for EGFR-positive NSCLC, wherein the majority of compounds have a pyrimidine substructure offering marked therapeutic benefits compared with chemotherapy. This current review outlines the diverse pyrimidine derivatives with amino-linked and fused pyrimidine scaffolds such as furo-pyrimidine, pyrimido-pyrimidine, thieno-pyrimidine, highlighting pyrimidine EGFR TK inhibitors reported in research emphasizing structural aspects, design approaches, inhibition potential, selectivity profile toward mutant EGFR conveyed through biological evaluation studies. Furthermore, mentioning the in-silico interaction profile of synthesized compounds for evaluating the binding affinity with key amino acids. The epilogue of review focuses on the recent research that drives forward to aid in the discovery and development of substituted amino and fused scaffolds of pyrimidine that can counteract the mutations and effectively manage EGFR-positive NSCLC.

The Promising Role of Natural Exosomal Nanoparticles in Cancer Chemoimmunotherapy.

Exosomal nanoparticles are cell-derived nano-sized vesicles in the size range of 30-150nm formed by the inward infolding of the cell membrane. They are encased in a lipid bilayer membrane and contain various proteins and nucleic acids according to the characteristics of their parent cell. They are involved in intercellular communication. Their specific structural and inherent properties are helpful in therapeutics and as biomarkers in diagnostics. Since they are biomimetic, these small-sized nanoparticles pose many advantages if used as a drug carrier vehicle. In cancer, the exosomal nanoparticles have both stimulatory and inhibitory activity towards immune responses; hence, they are used in immunotherapy. They can also carry chemotherapeutic agents to the target site minimizing their targetability concerns. Chemoimmunotherapy (CIT) is a synergistic approach in which chemotherapy and immunotherapy are utilized to benefit each other. Exosomal nanoparticles (NPs) are essential in delivering CIT agents into tumor tissues. Most advanced studies in CIT take place in the stimulator of interferon genes (STING) signaling pathway, where the STING activation supported by chemotherapy-induced an increase in immune surveillance through the help of exosomal NPs. Dendritic cell(DC) derived exosomes, as well as Mesenchymal stem cells (MSC), are abundantly used in immunotherapy, and hence their support can be used in chemoimmunotherapy (CIT) for multifaceted benefits.