Cytotoxic substituted indolizines as new colchicine site tubulin polymerisation inhibitors

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Abstract

A potential microtubule destabilising series of new indolizine derivatives was synthesised and tested for their anticancer activity against a panel of 60 human cancer cell lines. Compounds 11a, 11b, 15a, and 15j showed a broad spectrum of growth inhibitory activity against cancer cell lines representing leukaemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast, and prostate. Among them, compound 11a was distinguishable by its excellent cytostatic activity, showing GI ₅₀ values in the range of 10–100 nM on 43 cell lines. The less potent compounds 15a and 15j in terms of GI ₅₀ values showed a high cytotoxic effect against tested colon cancer, CNS cancer, renal cancer and melanoma cell lines and only on few cell lines from other types of cancer. In vitro assaying revealed tubulin polymerisation inhibition by all active compounds. Molecular docking showed good complementarity of active compounds with the colchicine binding site of tubulin.

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The NCI60 human tumour cell line anticancer drug screen.

Robert Shoemaker (2006)

The US National Cancer Institute (NCI) 60 human tumour cell line anticancer drug screen (NCI60) was developed in the late 1980s as an in vitro drug-discovery tool intended to supplant the use of transplantable animal tumours in anticancer drug screening. This screening model was rapidly recognized as a rich source of information about the mechanisms of growth inhibition and tumour-cell kill. Recently, its role has changed to that of a service screen supporting the cancer research community. Here I review the development, use and productivity of the screen, highlighting several outcomes that have contributed to advances in cancer chemotherapy.

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Structural basis for the regulation of tubulin by vinblastine.

Benoît Gigant, Chunguang Wang, Raimond Ravelli … (2005)

Vinblastine is one of several tubulin-targeting Vinca alkaloids that have been responsible for many chemotherapeutic successes since their introduction in the clinic as antitumour drugs. In contrast with the two other classes of small tubulin-binding molecules (Taxol and colchicine), the binding site of vinblastine is largely unknown and the molecular mechanism of this drug has remained elusive. Here we report the X-ray structure of vinblastine bound to tubulin in a complex with the RB3 protein stathmin-like domain (RB3-SLD). Vinblastine introduces a wedge at the interface of two tubulin molecules and thus interferes with tubulin assembly. Together with electron microscopical and biochemical data, the structure explains vinblastine-induced tubulin self-association into spiral aggregates at the expense of microtubule growth. It also shows that vinblastine and the amino-terminal part of RB3-SLD binding sites share a hydrophobic groove on the alpha-tubulin surface that is located at an intermolecular contact in microtubules. This is an attractive target for drugs designed to perturb microtubule dynamics by interfacial interference, for which tubulin seems ideally suited because of its propensity to self-associate.

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Anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin.

Bhabatarak Bhattacharyya, Dulal Panda, Suvroma Gupta … (2008)

In this review, an attempt has been made to throw light on the mechanism of action of colchicine and its different analogs as anti-cancer agents. Colchicine interacts with tubulin and perturbs the assembly dynamics of microtubules. Though its use has been limited because of its toxicity, colchicine can still be used as a lead compound for the generation of potent anti-cancer drugs. Colchicine binds to tubulin in a poorly reversible manner with high activation energy. The binding interaction is favored entropically. In contrast, binding of its simple analogs AC or DAAC is enthalpically favored and commences with comparatively low activation energy. Colchicine-tubulin interaction, which is normally pH dependent, has been found to be independent of pH in the presence of microtubule-associated proteins, salts or upon cleavage of carboxy termini of tubulin. Biphasic kinetics of colchicines-tubulin interaction has been explained in light of the variation in the residues around the drug-binding site on beta-tubulin. Using the crystal structure of the tubulin-DAMAcolchicine complex, a detailed discussion on the pharmacophore concept that explains the variation of affinity for different colchicine site inhibitors (CSI) has been discussed.

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Journal ID (nlm-ta): J Enzyme Inhib Med Chem

Journal ID (iso-abbrev): J Enzyme Inhib Med Chem

Title: Journal of Enzyme Inhibition and Medicinal Chemistry

Publisher: Taylor & Francis

ISSN (Print): 1475-6366

ISSN (Electronic): 1475-6374

Publication date (Electronic, pub): 4 August 2020

Publication date (Electronic, collection): 2020

Volume: 35

Issue: 1

Pages: 1581-1595

Affiliations

[a ]Department of Chemistry, Faculty of Chemistry, “Al. I. Cuza” University of Iasi , Iași, Romania

[b ]“Petru Poni” Institute of Macromolecular Chemistry of Romanian Academy , Iași, Romania

[c ]TRANSCEND Research Center, Regional Institute of Oncology , Iași, Romania

[d ]Research Department, Faculty of Chemistry, “Al. I. Cuza” University of Iasi , Iași, Romania

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Supplemental data for this article can be accessed here .

CONTACT Ramona Danac rdanac@ 123456uaic.ro Department of Chemistry, Faculty of Chemistry, “Al. I. Cuza” University of Iasi , 11 Carol I, Iași 700506, Romania

Author information

Roxana Maria Amarandi https://orcid.org/0000-0002-9937-6539

Ionel I. Mangalagiu https://orcid.org/0000-0002-4632-5076

Ramona Danac https://orcid.org/0000-0003-4370-5353

Article

Publisher ID: 1801671

DOI: 10.1080/14756366.2020.1801671

PMC ID: 7470029

PubMed ID: 32752898

SO-VID: cb4459e4-b4f4-4e8d-95cd-cf3374df8b1e

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Cytotoxic substituted indolizines as new colchicine site tubulin polymerisation inhibitors

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Neuropharmacology and Therapy

Most cited references 40

The NCI60 human tumour cell line anticancer drug screen.

Structural basis for the regulation of tubulin by vinblastine.

Anti-mitotic activity of colchicine and the structural basis for its interaction with tubulin.

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