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Synthesis, cytotoxicity and QSAR study of N-tosyl-1,2,3,4- tetrahydroisoquinoline derivatives
Ratchanok Pingaew,Apilak Worachartcheewan,Chanin Nantasenamat,Supaluk Prachayasittikul,Somsak Ruchirawat,Virapong Prachayasittikul 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.9
1-Substituted-N-tosyl-1,2,3,4-tetrahydroisoquinolineanalogs (4a–4l) were synthesized using the modifiedPictet–Spengler reaction and evaluated for cytotoxicity. Alltetrahydroisoquinolines displayed cytotoxicity againstMOLT-3 cell lines, except for p-methoxy analog 4d. Interestingly,the o-hydroxy derivative 4k was shown to be themost potent cytotoxic againstHuCCA-1, A-549 andMOLT-3cell lines. The lowest IC50 value of 1.23 lMwas observed forMOLT-3 cells. Trimethoxy analog 4f exerted the most potentactivity against HepG2 with an IC50 of 22.70 lM, which islower than the reference drug, etoposide. QSAR studiesshowed that total symmetry index (Gu), 3D-MoRSE (Mor31vand Mor32u) and 3D Petitjean index (PJI3) were the mostimportant descriptors accounting for the observed cytotoxicities. The most potent cytotoxic compound (4k) againstMOLT-3 had the highest Gu value, correspondingly theinactive p-methoxy analog (4d) had the lowest Gu value. Onthe other hand, the highest molecular mass compound (4f)was shown to be the most potent cytotoxic against HepG2cells. The studies disclose that tetrahydroisoquinolines 4f and4k are potentially interesting lead pharmacophores thatshould be further explored. The QSAR models providedinsights into the physicochemical properties of the investigatedcompounds.