“DESIGN AND SYNTHESIS OF NOVEL TANKYRASE INHIBITORS FOR THE TREATMENT OF COLORECTAL CANCER

Abstract

Tankyrase (TNKS) enzymes, owing to their poly(ADP-ribose) polymerase activity, have been recognized as one of the prospective therapeutic targets for the treatment of colorectal cancer. Nevertheless, the functional penalties of tankyrase inhibition continue to be incompletely determined because of the binding approaches of tankyrase enzyme. The therapeutic effect of TNKS inhibition has been observed in selected tumor models, and TNKS inhibition may present a dependable therapeutic assistance. In course of this research work to design novel Tankyrase inhibitors, computational approach was used. Pharmacophore model was generated using 9 structurally diverse molecules using DISCOtech followed by refined with GASP module of Sybyl. Out of four refined models, model 4 containing ten features; three donor sites, three acceptor atom, one acceptor site, one donor atom and two hydrophobic region had highest fitness score and best validation results. Hence best model, model 4 was used as a query for virtual screening in NCI database and 6 compounds with Qfit value ≥97 were retrieved. 3D-QSAR was carried on thirty seven, 2-phenylquinazolin-4(3H)-one derivatives. Contour map analysis of best CoMFA and CoMSIA model suggested that by substituting hydrophobic, bulky and electronegative groups, potency of the compound could be improved. The quinazolinone ring which is bio-isostere of quinoline ring, retrieved as hit in virtual screening, was selected as acore moiety. Designed quinazolinone derivatives were docked into active site of Tankyrase structure complex and In-Silico ADMET properties were also predicted. Synthesis of top 10 quinazolinone derivatives was carried out and spectral characterization was carried out using Mass, 1H and 13C-NMR spectroscopy. Purity of compounds was checked using HPLC. Synthesized derivatives were subjected to In-vitro cytotoxicity studies. From the results, it was found that compound 100e showed most potent activity.