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CarbORev‐5901: The First Carborane‐Based Inhibitor of the 5‐Lipoxygenase Pathway
Author(s) -
Kuhnert Robert,
Sárosi MenyhártBotond,
George Sven,
Lönnecke Peter,
Hofmann Bettina,
Steinhilber Dieter,
Murganic Blagoje,
Mijatovic Sanja,
MaksimovicIvanic Danijela,
HeyHawkins Evamarie
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700309
Subject(s) - chemistry , lipoxygenase , arachidonate 5 lipoxygenase , pharmacophore , enzyme , cell culture , cancer cell , carborane , arachidonic acid , biochemistry , in vivo , cancer , stereochemistry , biology , microbiology and biotechnology , genetics
The progression of cancer is accelerated by increased proliferation, angiogenesis, and inflammation. These processes are mediated by leukotrienes. Several cancer cell lines overexpress 5‐lipoxygenase, an enzyme that converts arachidonic acid into leukotrienes. An early inhibitor of the 5‐lipoxygenase pathway is Rev‐5901, which, however, lacks in in vivo efficacy, as it is rapidly metabolized. We investigated the introduction of carboranes as highly hydrophobic and metabolically stable pharmacophores into lipoxygenase inhibitors. Carboranes are icosahedral boron clusters that are remarkably stable and used to increase the metabolic stability of unstable pharmaceutics without changing their biological activity. By introduction of meta ‐carborane into Rev‐5901, the first carborane‐based inhibitor of the 5‐lipoxygenase pathway was obtained. We report the synthesis and inhibitory and cytotoxic behavior of these compounds toward several melanoma and colon cancer cell lines and their related anticancer mechanisms.