- Bioreductively Activatable Prodrug Conjugates of Combretastatin A-1 and Combretastatin A-4 as Anticancer Agents Targeted toward Tumor-Associated Hypoxia
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The natural products combretastatin A-1 (CA1) and combretastatin A-4 (CA4) function as potent inhibitors of tubulin polymerization and as selective vascular disrupting agents (VDAs) in tumors. Bioreductively activatable prodrug conjugates (BAPCs) can enha
- Chaplin, David J.,Davis, Peter,Devkota, Laxman,Gerberich, Jeni L.,Hamel, Ernest,Kuch, Bunnarack,Macdonough, Matthew T.,Mason, Ralph P.,Mondal, Deboprosad,Pinney, Kevin G.,Ramirez, Alejandro J.,Shi, Zhe,Strecker, Tracy E.,Trawick, Mary Lynn,Wang, Yifan,Winn, Blake A.
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- Synthesis and biological evaluation of combretastatin analogs as cell cycle inhibitors of the G1 to S transition in Saccharomyces cerevisiae
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A series of Z and E combretastatin A-4 analogs bearing different substituents (OH, F, NO2, NH2, B(OH)2) in the 3′ position were synthesized. These derivatives and Z and E combretastatin A-1 were analysed by monitoring their ability to inhibit cell growth in Saccharomyces cerevisiae. Combretastatin A-1 (2a), A-4 (2b) and compound 2c were found to inhibit yeast growth. Moreover, combretatstatin A-4 (2b) and compound 2c induced a G1 arrest by affecting the synthesis of Clb5 protein, the principal S-phase cyclin. The G1 arrest is coincident with the activation of the stress activated kinase Snf1.
- Coccetti, Paola,Montano, Giuseppe,Lombardo, Alessandro,Tripodi, Farida,Orsini, Fulvia,Pagliarin, Roberto
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scheme or table
p. 2780 - 2784
(2010/08/19)
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- Development of synthetic methodology suitable for the radiosynthesis of combretastatin A-1 (CA1) and its corresponding prodrug CA1P
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Synthetic methodology has been established suitable for the preparation of combretastatin A-1 (CA1) and its corresponding phosphate prodrug salt (CA1P) in high specific activity radiolabeled form. Judicious selection of appropriate phenolic protecting groups to distinguish positions on the A-ring from the B-ring of the stilbenoid was paramount for the success of this project. Methylation of the C-4' phenolic moiety by removal of the tert- butyldimethylsilyl protecting group in the presence of methyl iodide was accomplished in excellent yield without significant Z to E isomerization. This step (carried out with 12C-methyl iodide as proof of concept in this study) represents the process in which a 14C radioisotope could be incorporated in an actual radiosynthesis. CA1 is a natural product isolated from the African bush willow tree (Combretum caffrum) that has important medicinal value due, in part, to its ability to inhibit tubulin assembly. As a prodrug, CA1P (OXi4503) is in human clinical trials as a vascular disrupting agent.
- Shirali, Anupama,Sriram, Madhavi,Hall, John J.,Nguyen, Benson L.,Guddneppanavar, Rajsekhar,Hadimani, Mallinath B.,Ackley, J. Freeland,Siles, Rogelio,Jelinek, Christopher J.,Arthasery, Phyllis,Brown, Rodney C.,Murrell, Victor Leon,McMordie, Austin,Sharma, Suman,Chaplin, David J.,Pinney, Kevin G.
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scheme or table
p. 414 - 421
(2009/12/05)
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- Synthesis of combretastatins A-1 and B-1
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Combretastatins A-1 and B-1 have been synthesized by coupling MOM-protected p-iodomethoxycatechol with 3,4,5-trimethoxyphenylacetylene in a Sonogashira reaction.
- Odlo, Kristin,Klaveness, Jo,Rongved, P?l,Hansen, Trond Vidar
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p. 1101 - 1103
(2007/10/03)
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- Direct biooxidation of arenes to corresponding catechols with E. coli JM109 (pDTG602). Application to synthesis of combretastatins A-1 and B-1
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Convergent syntheses of combretastatins A-1 and B-1 were accomplished via coupling of biocatalytically generated p-bromomethoxycatechol with trimethoxyphenylacetylene.
- Bui, Vu P,Hudlicky, Tomas,Hansen, Trond V,Stenstrom, Yngve
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p. 2839 - 2841
(2007/10/03)
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- Synthesis of biologically active polyphenolic glycosides (combretastatin and resveratrol series)
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(E)-3-(β-D-Glucopyranosyloxy)-4',5-dihydroxystilbene (resveratrol 3-β-D-glucoside, piceid), (Z)-2',3'-dihydroxy-3,4,4',5-tetramethoxystilbene (combretastatin A-1), (Z)-3'-hydroxy-3,4,4', 5-tetramethoxystilbene (combretastatin A-4), (Z)-2'-hydroxy-3,4,4',5-tetramethoxystilbene (combretastatin iso-A-4), α,β-dihydro-2',3'-dihydroxy-3,4,4',5-tetramethoxystilbene (combretastatin B-1), the corresponding glucosides, and related compounds have been synthesized via Wittig reactions followed by,glucosylation under phase-transfer catalysis. Most of the compounds synthesized have been tested with respect to biological activity (cytostatic, cytotoxic, antimitotic, neurotoxic, antiplatelet aggregation activity).
- Orsini, Fulvia,Pelizzoni, Francesca,Bellini, Barbara,Miglierini, Giuliana
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