quotDESIGN SYNTHESIS AND EVALUATION OF 1 2 3 4 TETRAHYDRO CARBOLINE DERIVATIVES AND THEIR ANTICANCER ACTIVITYquot

Abstract

quotOBJECTIVE: To design and synthesize some substituted 1,2,3,4-Tetrahydro and#946;-carboline derivatives as lead molecules, which would inhibit haspin kinase, a newly identified anticancer target. newlineMETHODS: A library of 1,2,3,4 Tetrahydro and#946;-carboline derivatives were designed and their in silico docking ability on Haspin kinase. The highest ranked molecules were synthesized via Pictet-Spengler reaction and characterized. A preliminary in vitro cytotoxicity of the synthesized molecules was performed SRB assay. The mode of cell death induced by these molecules was evaluated by double staining followed by flow cytometry. Inhibition of cell cycle by these compounds was analyzed by Hoechst 33342 staining followed by High Content Screening. newlineRESULTS: A virtual library of 195 were designed and their in slico docking against Haspin kinase was carried out. A total of 10 molecules showed good glide score when compared to the standard molecule CHR 6494. ADME of selected molecules were predicted in silico using Quikprop program. No violation of Lipinski s rule was reported. A total of 9, cis-1,3 disubstituted 1,2,3,4 Tetrahydro and#946; -carboline derivatives were synthesized from L-Tryptophan through Pictect- spengler reaction and characterized. Among the nine compounds synthesized, three compounds showed good cytotoxicity against SW620 and HeLa cell lines and were selectively active on cancer cell lines rather than normal cell lines. Further evaluation of these molecules for cytotoxicity using MTT assay against cancer cell lines showed that one molecule showed good cytotoxic activity on all four cell lines. The studies on cell death demonstrated that compound induced a dose dependent and time dependent necroptotic effect on HeLa cells. newlineCONCLUSION: In conclusion, 9 cis-1,3 disubstituted 1,2,3,4 Tetrahydro and#946;-carboline derivatives were synthesized, characterized and their anticancer activity was reported for the first time. The compounds showed moderate to good in vitro anticancer activity. newlinequot