Document Detail


Design, synthesis, and biological evaluation of novel C14-C3'BzN-linked macrocyclic taxoids.
MedLine Citation:
PMID:  18975909     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Novel macrocyclic paclitaxel congeners were designed to mimic the bioactive conformation of paclitaxel. Computational analysis of the "REDOR-Taxol" structure revealed that this structure could be rigidified by connecting the C14 position of the baccatin moiety and the ortho position of C3'N-benzoyl group (C3'BzN), which are ca. 7.5 A apart, with a short linker (4-6 atoms). 7-TES-14beta-allyloxybaccatin III and (3R,4S)-1-(2-alkenylbenzoyl)-beta-lactams were selected as key components, and the Ojima-Holton coupling afforded the corresponding paclitaxel-dienes. The Ru-catalyzed ring-closing metathesis (RCM) of paclitaxel-dienes gave the designed 15- and 16-membered macrocyclic taxoids. However, the RCM reaction to form the designed 14-membered macrocyclic taxoid did not proceed as planned. Instead, the attempted RCM reaction led to the occurrence of an unprecedented novel Ru-catalyzed diene-coupling process, giving the corresponding 15-membered macrocyclic taxoid (SB-T-2054). The biological activities of the novel macrocyclic taxoids were evaluated by tumor cell growth inhibition (i.e., cytotoxicity) and tubulin-polymerization assays. Those assays revealed high sensitivity of cytotoxicity to subtle conformational changes. Among the novel macrocyclic taxoids evaluated, SB-T-2054 is the most active compound, which possesses virtually the same potency as that of paclitaxel. The result may also indicate that SB-T-2054 structure is an excellent mimic of the bioactive conformation of paclitaxel. Computational analysis for the observed structure-activity relationships is also performed and discussed.
Authors:
Liang Sun; Xudong Geng; Raphaël Geney; Yuan Li; Carlos Simmerling; Zhong Li; Joseph W Lauher; Shujun Xia; Susan B Horwitz; Jean M Veith; Paula Pera; Ralph J Bernacki; Iwao Ojima
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The Journal of organic chemistry     Volume:  73     ISSN:  1520-6904     ISO Abbreviation:  J. Org. Chem.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2009-09-01     Completed Date:  2009-10-02     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  2985193R     Medline TA:  J Org Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9584-93     Citation Subset:  IM    
Affiliation:
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Phytogenic / chemical synthesis*,  pharmacology
Cell Line, Tumor
Crystallography, X-Ray
Drug Design
Drug Screening Assays, Antitumor
Humans
Indicators and Reagents
Macrocyclic Compounds / chemical synthesis*,  pharmacology
Magnetic Resonance Spectroscopy
Microscopy, Electron
Microtubules / chemistry
Models, Molecular
Molecular Conformation
Taxoids / chemical synthesis*,  pharmacology
Tubulin / chemical synthesis,  chemistry
Grant Support
ID/Acronym/Agency:
CA 73872/CA/NCI NIH HHS; CA077263/CA/NCI NIH HHS; CA083185/CA/NCI NIH HHS; CA103314/CA/NCI NIH HHS; GM42798/GM/NIGMS NIH HHS; R01 CA103314/CA/NCI NIH HHS; R01 CA103314-13A2/CA/NCI NIH HHS; R01 CA103314-14/CA/NCI NIH HHS; R01 CA103314-15/CA/NCI NIH HHS; R01 CA103314-16/CA/NCI NIH HHS; R01 CA103314-17/CA/NCI NIH HHS; R01 GM061678-08/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Phytogenic; 0/Indicators and Reagents; 0/Macrocyclic Compounds; 0/Taxoids; 0/Tubulin
Comments/Corrections

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