title: Quantitative Structure-Cytotoxicity Relationship of Oleoylamides.
abstract: Eighteen oleoylamides were subjected to quantitative structure-activity relationship analysis based on their cytotoxicity, tumor selectivity and anti-HIV activity, in order to assess their biological activities. Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and five human oral normal cells (gingival fibroblast, periodontal ligament fibroblast, pulp cell, oral keratinocyte, primary gingival epithelial cells) was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor-selectivity (TS) was evaluated by the ratio of the mean 50% cytotoxic concentration (CC50) against normal human oral cells to that against OSCC cell lines. Potency-selectivity expression (PSE) was determined by the ratio of TS to CC50 against OSCC. Anti-HIV activity was evaluated by the ratio of CC50 to the concentration leading to 50% cytoprotection from HIV infection (EC50). Physicochemical, structural and quantum-chemical parameters were calculated based on the conformations optimized by the LowModeMD method. Among 18 derivatives, compounds 8: with a catechol group) and 18: with a (2-pyridyl)amino group) had the highest TS. On the other hand, doxorubicin and 5-fluorouracil (5-FU) were more highly cytotoxic to normal epithelial cells, displaying unexpectedly lower TS and PSE values. None of the compounds had anti-HIV activity. Among 330 chemical descriptors, 75, 73 and 19 descriptors significantly correlated to the cytotoxicity to normal and tumor cells, and TS, respectively. Multivariate statistics with chemical descriptors for molecular polarization and hydrophobicity may be useful for the evaluation of cytotoxicity and TS of oleoylamides.
authors.affiliation: Division of Pharmacology, Meikai University School of Dentistry, Sakado, Saitama, Japan sakagami@dent.meikai.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakagami
authors.affiliation: Department of Clinical Pharmaceutics, Meiji Pharmaceutical University, Kiyose, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uesawa
authors.affiliation: Division of Basic Chemistry, Meikai University School of Dentistry, Sakado, Saitama, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Ishihara
authors.affiliation: Department of Clinical Pharmaceutics, Meiji Pharmaceutical University, Kiyose, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Kagaya
authors.affiliation: Department of Microbiology, St. Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: Taisei
authors.initials: T
authors.lastname: Kanamoto
authors.affiliation: Department of Microbiology, St. Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: Shigemi
authors.initials: S
authors.lastname: Terakubo
authors.affiliation: Department of Microbiology, St. Marianna University School of Medicine, Kanagawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakashima
authors.affiliation: Laboratory of Bioorganic Chemistry, Department of Pharmaceutical and Health Sciences, Faculty of Pharmaceutical Sciences, Josai University, Sakado, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Takao
authors.affiliation: Laboratory of Bioorganic Chemistry, Department of Pharmaceutical and Health Sciences, Faculty of Pharmaceutical Sciences, Josai University, Sakado, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sugita
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D009829:Oleic Acids / Q000138:chemical synthesis / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D009829:Oleic Acids; C029407:oleylamide
keywords: Oleoylamides; QSAR analysis; anti-HIV activity; cytotoxicity; tumor selectivity