N‐Aryl‐Methylimidazothiazolyl Thiazolamines: Synthesis and Evaluation for Antiproliferative Antitubulin Activity in a Sea Urchin Embryo Model and PC‐3 Cancer Cells

N‐Aryl‐Methylimidazothiazolyl Thiazolamines: Synthesis and Evaluation for Antiproliferative Antitubulin Activity in a Sea Urchin Embryo Model and PC‐3 Cancer Cells Full article

Journal

ChemistrySelect
ISSN: 2365-6549

Output data

Year: 2024, Volume: 9, Number: 39, Article number : e202403700, Pages count : DOI: 10.1002/slct.202403700

Authors

Zubarev Andrey A. ¹ , Duda Kirill A. ¹ , Kuptsova Tatiana S. ¹ , Semenova Marina N. ² , Plyutinskaya Anna D. ³ , Nemtzova Elena R. ³ , Pankratov Andrei A. ³ , Kiselyov Alex S. ⁴ , Semenov Victor V. ¹

Affiliations

1	Laboratory of Medicinal Chemistry N. D. Zelinsky Institute of Organic Chemistry Russian Academy of Sciences 47 Leninsky Prospect Moscow 119991 Russian Federation
2	Department of Physiology of Receptors & Signaling Systems N. K. Koltzov Institute of Developmental Biology, Russian Academy of Sciences 26 Vavilov Street Moscow 119334 Russian Federation
3	Department of Experimental Pharmacology and Toxicology P. Hertsen Moscow Oncology Research Institute, the Branch of the FSBI “ National Medical Research Radiology Centre”, Ministry of Health of the Russian Federation 2nd Botkinskiy pr., 3 Moscow 125284 Russian Federation
4	Myocea, Inc 9833 Pacific Heights Blvd. San Diego California 92121 USA

A series of imidazothiazoles (ITZs) were conveniently accessed via an improved four-step protocol in 55%–79% yields. The synthesized ITZs were tested in a combination of a phenotypic sea urchin embryo assay and PC-3 human adenocarcinoma cytotoxicity studies. Both experimental approaches converged on compounds that showed microtubule targeting activity and cytotoxicity similar to the control compound, combretastatin CA-4. Specifically, ITZs featuring electron-donating pharmacophores in position 4, including 4-Me-, 4-OMe-, 3-amino-4-Me-, and 3,4-ethylenedioxy-substituted benzene ring (6, 7, 28, and 34) exhibited consistent antimitotic antitubulin effect along with the pronounced inhibition of PC-3 cells growth. These compounds altered cleavage of the sea urchin eggs at 0.002–0.005 µM concentration and displayed cytotoxicity with IC50 values of 0.020–0.47 µM. Notably, the compound ITZ (25) featuring 3,4-dimethoxybenzene fragment selectively inhibited growth of malignant PC-3 cells (IC50 = 0.52 µM) while showing no effect on the sea urchin embryo development at up to 4 µM concentration. The sea urchin embryo screen also identified ITZs with systemic toxicity or solubility issues. The assay can be used to prioritize tubulin-specific molecules for advanced evaluation.

Zubarev A.A. , Duda K.A. , Kuptsova T.S. , Semenova M.N. , Plyutinskaya A.D. , Nemtzova E.R. , Pankratov A.A. , Kiselyov A.S. , Semenov V.V.
N‐Aryl‐Methylimidazothiazolyl Thiazolamines: Synthesis and Evaluation for Antiproliferative Antitubulin Activity in a Sea Urchin Embryo Model and PC‐3 Cancer Cells
ChemistrySelect. 2024. V.9. N39. e202403700 . DOI: 10.1002/slct.202403700 WOS Scopus OpenAlex

Web of science:	WOS:001339270600001
Scopus:	2-s2.0-85206620893
OpenAlex:	W4403477037

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