A class of novel N-isoquinoline-3-carbonyl-l-amino acid benzylesters: Synthesis, anti-tumor evaluation and 3D QSAR analysis

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.

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► Design, evaluation, topoisomerse I inhibition and 3D QSAR of novel N-isoquinoline-3-carbonyl-l-amino acid benzylesters were investigated as the potential intercalators.
► On S180 mouse model the oral effective dose was 1 μmol/kg.
► At the dose of 1 mmol/kg the healthy mice had no neurotoxic and acute toxic response.
► The LD50 value of N-isoquinoline-3-carbonyl-l-amino acid benzylesters is more than 540 mg/kg.