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Rational Design of Novel Anti-microtubule Agent (9-Azido-Noscapine) from Quantitative Structure Activity Relationship (QSAR) Evaluation of Noscapinoids.
MedLine Citation:
PMID:  21972248     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
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 IC(50) 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 (R(2) = 0.942) was analyzed by values of the internal cross-validated regression coefficient (R(2) (LOO) = 0.815) for the training set and determination coefficient (R(2) (test) = 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 pIC(50) for both the compounds (5.585 M) turned out to be very close to predicted pIC(50) (5.731 and 5.710 M).
Authors:
Seneha Santoshi; Pradeep K Naik; Harish C Joshi
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of biomolecular screening     Volume:  16     ISSN:  1552-454X     ISO Abbreviation:  J Biomol Screen     Publication Date:  2011 Oct 
Date Detail:
Created Date:  2011-10-05     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9612112     Medline TA:  J Biomol Screen     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1047-58     Citation Subset:  IM    
Affiliation:
1Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Himachal Pradesh, India.
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