Rational design of novel anti-microtubule agent (9-azido-noscapine) from quantitative structure activity relationship (QSAR) evaluation of noscapinoids

Abstract

An anticough medicine, noscapine [(S)-3-((R)4-methoxy-6-methyl-5,6,7,8- tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyiso-benzofuran- 1(3H)-one], was discovered in the authors' laboratory as a novel type of tubulin-binding agent that mitigates polymerization dynamics of microtubule polymers without changing overall subunit-polymer equilibrium. To obtain systematic insight into the relationship between the structural framework of noscapine scaffold and its antitumor activity, the authors synthesized strategic derivatives (including two new ones in this article). The IC50 values of these analogs vary from 1.2 to 56.0 μM in human acute lymphoblastic leukemia cells (CEM). Geometrical optimization was performed using semiempirical quantum chemical calculations at the 3-21G* level. Structures were in agreement with nuclear magnetic resonance analysis of molecular flexibility in solution and crystal structures. A genetic function approximation algorithm of variable selection was used to generate the quantitative structure activity relationship (QSAR) model. The robustness of the QSAR model (R2 = 0.942) was analyzed by values of the internal cross-validated regression coefficient (R2LOO = 0.815) for the training set and determination coefficient (R2test = 0.817) for the test set. Validation was achieved by rational design of further novel and potent antitumor noscapinoid, 9-azido-noscapine, and reduced 9-azido-noscapine. The experimentally determined value of pIC50 for both the compounds (5.585 M) turned out to be very close to predicted pIC50 (5.731 and 5.710 M). © 2011 Society for Laboratory Automation and Screening.