2. Academic Validation
  3. Synthesis and biological evaluation of indolylglyoxylamide bisphosphonates, antimitotic microtubule-targeting derivatives of indibulin with improved aqueous solubility

Synthesis and biological evaluation of indolylglyoxylamide bisphosphonates, antimitotic microtubule-targeting derivatives of indibulin with improved aqueous solubility

  • Bioorg Med Chem Lett. 2020 Dec 1;30(23):127635. doi: 10.1016/j.bmcl.2020.127635.
Valery K Brel 1,  Oleg I Artyushin 2,  Roman N Chuprov-Netochin 3,  Sergey V Leonov 4,  Marina N Semenova 5,  Victor V Semenov 6
Affiliations

Affiliations

  • 1 A. N. Nesmeyanov Institute of Organoelement Compounds, 28 Vavilov Street, 119991 Moscow, Russian Federation. Electronic address: v_brel@mail.ru.
  • 2 A. N. Nesmeyanov Institute of Organoelement Compounds, 28 Vavilov Street, 119991 Moscow, Russian Federation.
  • 3 Moscow Institute of Physics and Technology (State University), Institutskiy per. 9, Dolgoprudny, Moscow Region 141701, Russian Federation.
  • 4 Moscow Institute of Physics and Technology (State University), Institutskiy per. 9, Dolgoprudny, Moscow Region 141701, Russian Federation. Electronic address: leonov.sv@mipt.ru.
  • 5 N. K. Kol'tsov Institute of Developmental Biology, Russian Academy of Sciences, Vavilov Street, 26, 119334 Moscow, Russian Federation. Electronic address: ms@chemical-block.com.
  • 6 N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect, 47, 119991 Moscow, Russian Federation. Electronic address: vs@zelinsky.ru.
PMID: 33132173 DOI: 10.1016/j.bmcl.2020.127635
Abstract

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 p-chlorobenzene 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.

Keywords

Bisphosphonates; Indibulin; Indolylglyoxylamides; Microtubule destabilization; Sea urchin embryo.

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