Discovery of dihydrofuranoallocolchicinoids - Highly potent antimitotic agents with low acute toxicity

Ekaterina S Shchegravina; Elena V Svirshchevskaya; Sebastien Combes; Diane Allegro; Pascale Barbier; Benoit Gigant; Paloma F Varela; Andrei E Gavryushin; Daria A Kobanova; Andrey E Shchekotikhin; Alexey Yu Fedorov

doi:10.1016/j.ejmech.2020.112724

Discovery of dihydrofuranoallocolchicinoids - Highly potent antimitotic agents with low acute toxicity

Eur J Med Chem. 2020 Dec 1:207:112724. doi: 10.1016/j.ejmech.2020.112724. Epub 2020 Aug 13.

Affiliations

¹ Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation.
² Department of Immunology, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, GSP-7, Miklukho-Maklaya Street 16/10, 117997, Moscow, Russian Federation.
³ CRCM, CNRS UMR7258, Laboratory of Integrative Structural and Chemical Biology (ISCB), NSERM, U1068, Institut Paoli-Calmettes, Aix-Marseille Université, UM105, F-13009, Marseille, France.
⁴ Institute of NeuroPhysiopathology (INP), CNRS UMR 7051, Aix-Marseille University, 27 Boulevard Jean Moulin, 13385, Marseille Cedex 5, France.
⁵ Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198, Gif-sur-Yvette, France.
⁶ Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation; Nanoscape AG, Am Klopferspitz 19, 82152, Planegg, Germany.
⁷ Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation; Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, 119021, Moscow, Russian Federation.
⁸ Department of Organic Chemistry, Nizhny Novgorod State University, Gagarina Av. 23, Nizhny Novgorod, 603950, Russian Federation. Electronic address: afedorovnn@yandex.ru.

PMID: 32827941
DOI: 10.1016/j.ejmech.2020.112724

Abstract

Two series of heterocyclic colchicinoids bearing β-methylenedihydrofuran or 2H-pyran-2-one fragments were synthesized by the intramolecular Heck reaction. Methylenedihydrofuran compounds 9a and 9h were found to be the most cytotoxic among currently known colchicinoids, exhibiting outstanding antiproliferative activity on tumor cell lines in picomolar (0.01-2.1 nM) range of concentrations. Compound 9a potently and substoichiometrically inhibits microtubule formation in vitro, being an order of magnitude more active in this assay than colchicine. Derivatives 9a and 9h revealed relatively low acute toxicity in mice (LD₅₀ ≥ 10 mg/kg i.v.). The X-Ray structure of colchicinoid 9a bound to tubulin confirmed interaction of this compound with the colchicine binding site of tubulin.

Keywords: Antimitotics; Antiproliferative activity; Colchicine; Tubulin; X-ray structure.

MeSH terms

Animals
Antimitotic Agents / chemistry*
Antimitotic Agents / pharmacology*
Antimitotic Agents / toxicity
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / toxicity
Cell Line, Tumor
Cell Proliferation / drug effects
Colchicine / analogs & derivatives*
Colchicine / pharmacology*
Colchicine / toxicity
Crystallography, X-Ray
Drug Screening Assays, Antitumor
Furans / chemistry
Furans / pharmacology
Furans / toxicity
Humans
Mice, Inbred BALB C
Mice, Inbred C57BL
Molecular Docking Simulation
Neoplasms / drug therapy
Neoplasms / metabolism
Tubulin / metabolism
Tubulin Modulators / chemistry
Tubulin Modulators / pharmacology
Tubulin Modulators / toxicity

Substances

Antimitotic Agents
Antineoplastic Agents
Furans
Tubulin
Tubulin Modulators
Colchicine