Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 30, Issue 23, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2020.127635
Keywords
Bisphosphonates; Indolylglyoxylamides; Indibulin; Microtubule destabilization; Sea urchin embryo
Categories
Funding
- Scientific Schools Development Program at Zelinsky Institute of Organic Chemistry
- Ministry of Science and Higher Education of the Russian Federation
- IDB RAS Government [0088-2019-0005]
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Indibulin (D-24851) derivatives with bisphosphonate fragment connected to the N1 atom of imidazole ring were synthesized by alkylation of (indolyl-3)methylglyoxylates with ethylenebisphosphonate. Biological evaluation of targeted compounds 4a-d using the phenotypic sea urchin embryo assay provided evidence that replacing of pchlorobenzene ring in indibulin by bisphosphonate group did not eliminate antimitotic microtubule destabilizing activity. The most active molecule, tetraacid 5a, at physiological pH formed tetrasodium salt 6a with aqueous solubility value of at least 10 mg/mL. Molecule 5a was more potent in the sea urchin embryo assay than the parent indibulin. This compound also exhibited pronounced cytotoxicity against A549 lung carcinoma and A375 melanoma cell lines.
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