| 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 |
Related Documents
:
|
23578519 - Impact of boron complexation by tris buffer on the initial dissolution rate of borosili... 23116319 - Molecular dynamics simulation of amorphous indomethacin. 21643199 - Adaptive aberration compensation for three-dimensional micro-fabrication of photonic cr... 22706579 - Luminescence properties of mn(2+)-doped li(2)zngeo(4) as an efficient green phosphor fo... 9006789 - Computer design and syntheses of antiulcer compounds. 2nd communication: n-substituted ... 23247069 - Tin clusters formed by fundamental units: a potential way to assemble tin nanowires. 19101939 - Chiral guanidine catalyzed enantioselective reactions. 16097829 - Comparative studies of substitution reactions of rhenium(i) dicarbonyl-nitrosyl and tri... 17426859 - Allosteric deprogramming of a trinuclear heterometallic helicate. |
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: 2013-01-11 |
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. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| 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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Reduction of Carbon-Carbon Double Bonds Using Organocatalytically Generated Diimide.
Next Document: A Linchpin Carbacyclization Approach for the Synthesis of Carbanucleosides.