Novel 5-Substituted Oxindole Derivatives as Bruton's Tyrosine Kinase Inhibitors: Design, Synthesis, Docking, Molecular Dynamics Simulation, and Biological Evaluation.

Bruton's tyrosine kinase (BTK) is a non-RTK cytoplasmic kinase predominantly expressed by hemopoietic lineages, particularly B-cells. A new oxindole-based focused library was designed to identify potent compounds targeting the BTK protein as anticancer agents. This study used rational approaches like structure-based pharmacophore modeling, docking, and ADME properties to select compounds. Molecular dynamics simulations carried out at 20 ns supported the stability of compound 9g within the binding pocket. All the compounds were synthesized and subjected to biological screening on two BTK-expressing cancer cell lines, RAMOS and K562; six non-BTK cancer cell lines, A549, HCT116 (parental and p53-/-), U2OS, JURKAT, and CCRF-CEM; and two non-malignant fibroblast lines, BJ and MRC-5. This study resulted in the identification of four new compounds, 9b, 9f, 9g, and 9h, possessing free binding energies of -10.8, -11.1, -11.3, and -10.8 kcal/mol, respectively, and displaying selective cytotoxicity against BTK-high RAMOS cells. Further analysis demonstrated the antiproliferative activity of 9h in RAMOS cells through selective inhibition of pBTK (Tyr223) without affecting Lyn and Syk, upstream proteins in the BCR signaling pathway. In conclusion, we identified a promising oxindole derivative (9h) that shows specificity in modulating BTK signaling pathways.

Assessing Partial Inhibition of Ribonuclease A Activity by Curcumin through Fluorescence Spectroscopy and Theoretical Studies.

Molecular interactions and controlled expression of enzymatic activities are fundamental to all cellular functions in an organism. The active polyphenol in turmeric known as curcumin (CCM) is known to exhibit diverse pharmacological activities. Ribonucleases (RNases) are the hydrolytic enzymes that plays important role in ribonucleic acid (RNA) metabolism. Uncontrolled and unwanted cleavage of RNA by RNases may be the cause of cell death leading to disease states. The protein ribonuclease A (RNase A) in the superfamily of RNases cleaves the RNA besides its role in different diseases like autoimmune diseases, and pancreatic disorders. Interaction of CCM with RNase A have been reported along with the possible role of CCM to inhibit the RNase A enzymatic activity. The interaction strength was found to be 104 M-1 order from spectroscopic results. Quenching of RNase A fluorescence by CCM was 104 M-1 order. Non-radiative energy transfer from RNase A (donor) to CCM (acceptor) suggested a distance of 2.42 nm between the donor-acceptor pair. Circular dichroism studies revealed no structural changes in RNase A after binding. Binding-induced conformational variation in protein was observed from synchronous fluorescence studies. Agarose gel electrophoresis revealed a partial inhibition of the RNase A activity by CCM though not significant. Molecular docking and molecular dynamics studies suggested the residues of RNase A involved in the interaction with supporting the experimental finding for the partial inhibition of the enzyme activity. This study may help in designing new CCM analogues or related structures to understand their differential inhibition of the RNase A activity.