Sydnone Cycloaddition Route to Pyrazole-Based Analogs of Combretastatin A4.
The combretastatins are an important class of tubulin-binding agents. Of this family, a number of compounds are potent tumor vascular disrupting agents (VDAs) and have shown promise in the clinic for cancer therapy. We have developed a modular synthetic route to combretastatin analogs based on a pyrazole core through highly regioselective alkyne cycloaddition reactions of sydnones. These compounds show modest to high potency against human umbilical vein endothelial cell proliferation. Moreover, evidence is presented that these novel VDAs have the same mode of action as CA4P and bind reversibly to β-tubulin, believed to be a key feature in avoiding toxicity. The most active compound from in vitro studies was taken forward to an in vivo model and instigated an increase in tumor cell necrosis.
Department of Chemistry, University of Sheffield , Dainton Building, Brook Hill, Sheffield S3 7HF, U.K.|Department of Oncology and Metabolism, The Medical School, University of Sheffield , Beech Hill Road, Sheffield S10 2RX, U.K.
Andrew W
AW
Brown
Department of Oncology and Metabolism, The Medical School, University of Sheffield , Beech Hill Road, Sheffield S10 2RX, U.K.
Matthew
M
Fisher
Department of Oncology and Metabolism, The Medical School, University of Sheffield , Beech Hill Road, Sheffield S10 2RX, U.K.
Gillian M
GM
Tozer
Department of Oncology and Metabolism, The Medical School, University of Sheffield , Beech Hill Road, Sheffield S10 2RX, U.K.
Chryso
C
Kanthou
Department of Chemistry, University of Sheffield , Dainton Building, Brook Hill, Sheffield S3 7HF, U.K.
Joseph P A
JP
Harrity
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013558:Sydnones / Q000737:chemistry*
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D011720:Pyrazoles; D013267:Stilbenes; D013558:Sydnones; C031280:pyrazole; C058728:fosbretabulin