title: A class of novel N-isoquinoline-3-carbonyl-L-amino acid benzylesters: synthesis, anti-tumor evaluation and 3D QSAR analysis.
abstract: Isoquinoline-3-carboxylic acid (2) was modified with amino acid benzylesters and 18 novel N-isoquinoline-3-carbonylamino acid benzylesters (3a-r) were provided. The IC50 values of 3a-r against the proliferation of HL-60 and Hela cells were less than 1×10(-8) M and 6×10(-7) M, respectively. On S180 mice model 100 μmol/kg of 3a-r effectively inhibited the growth of the tumors. Using MFA based Cerius2 QSAR module, two equations (r, 0.989 and 0.987) were established to correlate the structure with the in vitro and in vivo activities. The benefit of this modification was supported with both the in vitro membrane permeation test and the in vivo anti-tumor assay. The in vitro membrane permeability of N-isoquinoline-3-carbonyl-l-threonine benzylester (3n) and N-isoquinoline-3-carbonyl-l-leucine benzylester (3q) was 2.5 fold higher than that of 2, and the in vivo anti-tumor activity of 3n, q was 4.4-fold higher than that of 2.
authors.affiliation: College of Pharmaceutical Sciences, Capital Medical University, No. 10, Xitoutiao, You An Men, Beijing 100069, PR China.
authors.forename: Meiqing
authors.initials: M
authors.lastname: Zheng
authors.forename: Yifan
authors.initials: Y
authors.lastname: Yang
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Zhang
authors.forename: Jianhui
authors.initials: J
authors.lastname: Wu
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Peng
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wang
authors.forename: Shiqi
authors.initials: S
authors.lastname: Peng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004952:Esters; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism
chemical_list: D000970:Antineoplastic Agents; D004952:Esters; D007546:Isoquinolines