title: Synthesis, cytotoxicity and QSAR study of N-tosyl-1,2,3,4-tetrahydroisoquinoline derivatives.
abstract: 1-Substituted-N-tosyl-1,2,3,4-tetrahydroisoquinoline analogs (4a-4l) were synthesized using the modified Pictet-Spengler reaction and evaluated for cytotoxicity. All tetrahydroisoquinolines displayed cytotoxicity against MOLT-3 cell lines, except for p-methoxy analog 4d. Interestingly, the o-hydroxy derivative 4k was shown to be the most potent cytotoxic against HuCCA-1, A-549 and MOLT-3 cell lines. The lowest IC₅₀ value of 1.23 μM was observed for MOLT-3 cells. Trimethoxy analog 4f exerted the most potent activity against HepG2 with an IC₅₀ of 22.70 μM, which is lower than the reference drug, etoposide. QSAR studies showed that total symmetry index (Gu), 3D-MoRSE (Mor31v and Mor32u) and 3D Petitjean index (PJI3) were the most important descriptors accounting for the observed cytotoxicities. The most potent cytotoxic compound (4k) against MOLT-3 had the highest Gu value, correspondingly the inactive p-methoxy analog (4d) had the lowest Gu value. On the other hand, the highest molecular mass compound (4f) was shown to be the most potent cytotoxic against HepG2 cells. The studies disclose that tetrahydroisoquinolines 4f and 4k are potentially interesting lead pharmacophores that should be further explored. The QSAR models provided insights into the physicochemical properties of the investigated compounds.
authors.affiliation: Department of Chemistry, Faculty of Science, Srinakharinwirot University, Bangkok, 10110, Thailand, ratchanok@swu.ac.th.
authors.forename: Ratchanok
authors.initials: R
authors.lastname: Pingaew
authors.forename: Apilak
authors.initials: A
authors.lastname: Worachartcheewan
authors.forename: Chanin
authors.initials: C
authors.lastname: Nantasenamat
authors.forename: Supaluk
authors.initials: S
authors.lastname: Prachayasittikul
authors.forename: Somsak
authors.initials: S
authors.lastname: Ruchirawat
authors.forename: Virapong
authors.initials: V
authors.lastname: Prachayasittikul
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D015195:Drug Design; D015507:Drugs, Investigational / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006900:Hydroxylation; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D021281:Quantitative Structure-Activity Relationship; D017550:Spectroscopy, Fourier Transform Infrared; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014105:Tosyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D044005:Tetrahydroisoquinolines; D014105:Tosyl Compounds