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  • Song et al reported series of triazolylsalicylamide derivati

    2024-04-01

    Song et al. reported series of 1,2,3-triazolylsalicylamide derivatives and screened over kinase panel and found compound 31 as most potent which inhibited Aurora-A, specifically with IC50 of 0.37 μM. Compound 31 was about 10-fold more active for Aurora-A than for Aurora-B (IC50 = 3.58 μM reported series of 1,2,3-triazol) [64]. Srinivasa et al. synthesized novel 5H-benzo[c][1,8]naphthyridin-6-one analogues as potent Aurora kinase inhibitors. Compound 32 exhibited potent in-vitro inhibition on both Aurora-A and Aurora-B with IC50 values of 4 nM and 1 nM, respectively. X-ray crystallography data with Aurora-A (PDB code: 4JAI) gave clear view of interaction with Lys162 and carbonyl of the benzamide group. Hydrophobic region (the phenyl ring) bound to Phe275, Lue196 and Lue208 caused a partial DFG-out conformation in the protein [65]. Hui et al. prepared the compound 33 bearing an N,N-dimethylamino group showed activity against Aurora-A and Aurora-B with IC50 values of 24 nM and 53 nM, respectively. In HCT-116 cell line study, in-vitro inhibition at cellular level, compound 33 exhibited EC50 value of 57 nM. Compound 33 controlled the best lipophilicity efficiency (LipE) with 4.78 and ligand efficiency (LE) with 0.26, among the significantly active compounds. Treatment with compound 33 delayed 11302 sale process and pretentious HURP (hepatoma up-regulated protein) which was required for the mitotic spindle assembly of Aurora-A and Aurora-B [66]. Soon et al. developed potent novel benzochalcones bearing pyrazoline moieties as cancer therapeutic agents. Compound 34 was the strongest inhibitor of series screened on colon cancer cell line HCT-116 in clonogenic assays. Further biological evaluation showed that derivative 34 blocked cell cycle progression through dysregulation of cell cycle 11302 sale regulatory proteins p21 and cyclin B1 and induced apoptosis. IC50 value of derivative 34 on HCT-116 cancer cells was 2.4 μM, which was competitive. The binding mode between compound 34 and Aurora-A and Aurora-B were assessed using in-silico docking. The docking energy of the compound 34 with Aurora-B complex was better than that of the Aurora-A complex. In another research work performed by same group, chromenylchalcones series was tested for cytotoxicity with compare to flavonoids against colorectal cell line (HCT-116). Compound 35 from this series found interesting as it showed IC50 value of 93.1 nM. Compound 35 induced cell cycle arrest at the G2/M phase and apoptotic cell death [67], [68]. Harshali et al. worked on of X-ray structures and a DFG out binding mode. Through SAR study, they synthesized compound 36 and evaluated for in-vitro cell line inhibition. Compound 36 with 6-chloro pyrimidine and carboxylic acid group on phenyl moiety substituted at 4th position of pyrimidine greatly increased the efficacy. Co-crystalized structure analysis also supported this results where p-COOH group of compound formed H-bond interactions with Arg137 and Arg220 at solvent exposing region. Compound 37 having carboxamide group displayed selectivity against kinases with IC50 value of 14.1 nM in-vitro enzymatic assay & 1.2 nM in-vivo for Aurora-A, as compare to IC50 value of 10.7 nM in-vitro and 11 nM in-vivo for Aurora-B. In MDA-MB-468 breast cancer cells, compounds with water-soluble moieties at the para position inhibited the auto-phosphorylation of Aurora-A and Aurora-B substrate pHH3. A pyrimidine scaffold and amide substitution made H-bond with hinge region residues Ala213. (PDB: 3UP7, 4DEA) [69]. Gnag et al. synthesized a huge series of compounds that inhibited Aurora kinase with in-vitro and in-vivo study with good therapeutic index on the rat model. Compound 38 showed promising results in all studies. It showed IC50 value of 5.8 nM & 1.7 nM during in-vitro enzymatic assay of Aurora-A and Aurora-B, respectively. Further, it showed IC50 value of 1.2 nM on HCT-116 cell line study and it caused pHH3 inhibition of Aurora-B with spindle formation check point. Polyploidy was potently induced in a dose dependent manner, with EC50 value of 3 nM. Phenotype observed consistently with the IC50 values derived from the pHH3 assay and supported the potent Aurora-B inhibition in HCT-116 cells [70].