The first synthesis of the antiangiogenic homoisoflavanone, cremastranone.

Org Biomol Chem

College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon, South Korea.

Published: October 2014

An antiangiogenic homoisoflavanone, cremastranone, was synthesized for the first time. This scalable synthesis, which includes selective demethylation, could be used to develop lead molecules to treat angiogenesis-induced eye diseases. Synthetic cremastranone inhibited the proliferation, migration and tube formation ability of human retinal microvascular endothelial cells, important steps in pathological angiogenesis.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4167916PMC
http://dx.doi.org/10.1039/c4ob01604aDOI Listing

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Article Synopsis
  • Cremastranone, part of the homoisoflavanone family, exhibits anti-angiogenic properties in the eyes, leading to the development of a synthetic derivative, SH-11037, for pharmacokinetic studies.
  • SH-11037 is rapidly converted to SH-11008 in mice and is cleared from the system at a rate exceeding hepatic blood flow, with little to no detection in plasma after oral dosing.
  • The hydrolysis of SH-11037 occurs quickly in mouse plasma via carboxylesterase, while the process is slower in dog and human plasma, suggesting SH-11008 may have limited systemic toxicity and potential as a topical treatment for ocular conditions.
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Neovascular eye diseases are a major cause of blindness. Excessive angiogenesis is a feature of several conditions, including wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity. Development of novel antiangiogenic small molecules for the treatment of neovascular eye disease is essential to provide new therapeutic leads for these diseases.

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Naturally occurring homoisoflavonoids containing either 5,7-dihydroxy-6-methoxy or 7-hydroxy-5,6-dimethoxy groups such as the antiangiogenic homoisoflavanone, cremastranone, were synthesized via three or four linear steps from the known 4-chromenone. This facile synthesis includes chemoselective 1,4-reduction of 4-chromenone and selective deprotection of 3-benzylidene-4-chromanone a containing C7-benzyloxy group.

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Eye diseases characterized by excessive angiogenesis such as wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity are major causes of blindness. Cremastranone is an antiangiogenic, naturally occurring homoisoflavanone with efficacy in retinal and choroidal neovascularization models and antiproliferative selectivity for endothelial cells over other cell types. We undertook a cell-based structure-activity relationship study to develop more potent cremastranone analogues, with improved antiproliferative selectivity for retinal endothelial cells.

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Natural product inhibitors of ocular angiogenesis.

Exp Eye Res

December 2014

Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States; Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address:

Natural products are characterized by high chemical diversity and biochemical specificity; therefore, they are appealing as lead compounds for drug discovery. Given the importance of angiogenesis to many pathologies, numerous natural products have been explored as potential anti-angiogenic drugs. Ocular angiogenesis underlies blinding eye diseases such as retinopathy of prematurity (ROP) in children, proliferative diabetic retinopathy (DR) in adults of working age, and age-related macular degeneration (AMD) in the elderly.

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