Flavonoids as promising anticancer agents: an in silico investigation of ADMET, binding affinity by molecular docking and molecular dynamics simulations.

Cancer is one of the most concerning diseases to humankind. Various treatment strategies are being employed for its treatment, out of which use of natural products is an essential one. Flavonoids have proven to be promising anticancer targets since decades. Also, tubulin is a significant biological target for the development of anticancer agents due to its crucial role in mitosis and abundance throughout the body. In the current study, in silico ADMET parameters of 104 flavonoids were examined, followed by molecular docking with the colchicine binding site of Tubulin protein (PDB; Id 4O2B). The best conformation from each flavonoid subcategory with the best docking score (MolDock score) was further subjected to 100 ns of molecular dynamics to investigate the protein-ligand complex's stability. Different parameters such as RMSD, RMSF, rGy and SASA were calculated for the six flavonoids using molecular dynamic studies. The top most compound from all the six subcategories of flavonoids elicited best behavior in the colchicine binding site of Tubulin protein. This in silico study employing molecular docking and molecular dynamics simulation provides strong evidence for flavonoids to be excellent anti-tubulin agents for the treatment of cancer.Communicated by Ramaswamy H. Sarma.

Design, synthesis and anticancer activity of 2-arylimidazo[1,2-a]pyridinyl-3-amines.

A series of imido-heterocycle compounds were designed, synthesized, characterized, and evaluated for the anticancer potential using breast (MCF-7 and MDA-MB-231), pancreatic (PANC-1), and colon (HCT-116 and HT-29) cancer cell lines and normal cells, while normal cells showed no toxicity. Among the screened compounds, 4h exhibited the best anticancer potential with IC50 values ranging from 1 to 5.5 µM. Compound 4h caused G2/M phase arrest and apoptosis in all the cell lines except MDA-MB-231 mammosphere formation was inhibited. In-vitro enzyme assay showed selective topoisomerase IIα inhibition by compound 4h, leading to DNA damage as observed by fluorescent staining. Cell signalling studies showed decreased expression of cell cycle promoting related proteins while apoptotic proteins were upregulated. Interestingly MDA-MB-231 cells showed only cytostatic effects upon treatment with compound 4h due to defective p53 status. Toxicity study using overexpression of dominant-negative mutant p53 in MCF-7 cells (which have wild type functional p53) showed that anticancer potential of compound 4h is positively correlated with p53 expression.

E-pharmacophore guided discovery of pyrazolo[1,5-c]quinazolines as dual inhibitors of topoisomerase-I and histone deacetylase.

In the quest to ameliorate the camptothecin (CPT) downsides, we expedite to search for stable non-CPT analogues among 11 motifs of pyrazoloquinazolines reported. E-pharmacophore drug design approach helped filtering out pyrazolo[1,5-c]quinazolines as Topoisomerase I (TopoI) 'interfacial' inhibitors. Three compounds, 3c, 3e, and 3l were shown to be potent non-intercalating inhibitors of TopoI specifically and showed cancer cell-specific cytotoxicity in lung, breast and colon cancer cell lines. The compounds induced cell cycle arrest at S-phase, mitochondrial cell death pathway and modulated oxidative stress in cancer cells. Furthermore, a preliminary study was conducted to explore the feasibility of these compounds to be developed as dual TopoI-HDAC1 (histone deacetylase 1) inhibitors (4a) to combat resistance. Compound 4a was found to possess dual inhibitory capabilities in-vitro. Cytotoxic potential of 4a was found to be significantly higher than parent compound in 2D as well as 3D cancer cell models. Probable binding modes of 4a with TopoI and HDAC1 active sites were examined by molecular modelling.

Exploration of Pd-catalysed four-component tandem reaction for one-pot assembly of pyrazolo[1,5-c]quinazolines as potential EGFR inhibitors.

A series of pyrazolo[1,5-c]quinazolines as EGFR inhibitors was designed and synthesized by highly efficient and novel multicomponent route involving Pd-catalyzed tandem one-pot four-component reaction. The reaction proceeds with good functional group tolerance under a simple condition with excellent regioselectivity and high efficiency. Target compounds were screened against cancer cell lines MDA-MB-231, A549 and H1299. Of these, 9b and 10b exhibited superior anticancer activity (IC50 < 2.5 µM) to erlotinib and gefitinib. Synthetics were able to inhibit EGFR mediated kinase activity, induced ROS in cancer cells promoting mitochondrial mediated apoptosis via halting cell cycle progression at G1 phase.

Pd-Catalyzed Four-Component Sequential Reaction Delivers a Modular Fluorophore Platform for Cell Imaging.

A Pd-catalyzed cascade reaction of four versatile privileged synthons is described. The sequential reaction involves the formation of five new chemical bonds by concatenating three distinct chemical steps. One of the derivatives exhibited absorption in the visible region, fluorescence with a high quantum yield, and excellent photostability. Its application is explored in live cell imaging, which exhibited cytoplasmic and mitochondrial specific staining with no toxicity.