Novel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma agents

Huagang Lu; John Rogowskyj; Wenquan Yu; Anu Venkatesh; Noshena Khan; Shigeki Nakagawa; Nicolas Goossens; Anna P. Koh; Takaaki Higashi; Ganesh Gunasekaran; Myron E. Schwarz; Spiros P. Hiotis; Xiaodong Xu; William Kinney; Yujin Hoshida; Timothy Block; Andrea Cuconati; Yanming Du

doi:10.1016/j.bmcl.2016.10.015

Novel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma agents

Huagang Lu, John Rogowskyj, Wenquan Yu, Anu Venkatesh, Noshena Khan, Shigeki Nakagawa, Nicolas Goossens, Anna P. Koh, Takaaki Higashi, Ganesh Gunasekaran, Myron E. Schwarz, Spiros P. Hiotis, Xiaodong Xu, William Kinney, Yujin Hoshida, Timothy Block, Andrea Cuconati, Yanming Du

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Based on our previous identification of a disubstituted aminothiazole termed HBF-0079 with promising selective toxicity for HCC-derived cell lines versus non-HCC liver lines, a series of tri-substituted aminothiazole derivatives were prepared and evaluated. This work resulted in the discovery of isopropyl 4-(pyrazin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate, 14, which displayed EC₅₀value of 0.11 μM and more than 450 times of selectivity, and its methyl carbonate prodrug 24 with improved solubility in organic solvents. Furthermore, 14, was shown to reduce the proliferation of several liver cancer cells derived directly from patients.

Original language	English (US)
Pages (from-to)	5819-5824
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	23
DOIs	https://doi.org/10.1016/j.bmcl.2016.10.015
State	Published - 2016
Externally published	Yes

Keywords

Hepatocellular carcinoma (HCC)
Prodrug
Substituted aminothiazole

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2016.10.015

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Lu, H., Rogowskyj, J., Yu, W., Venkatesh, A., Khan, N., Nakagawa, S., Goossens, N., Koh, A. P., Higashi, T., Gunasekaran, G., Schwarz, M. E., Hiotis, S. P., Xu, X., Kinney, W., Hoshida, Y., Block, T., Cuconati, A., & Du, Y. (2016). Novel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma agents. Bioorganic and Medicinal Chemistry Letters, 26(23), 5819-5824. https://doi.org/10.1016/j.bmcl.2016.10.015

Lu, H, Rogowskyj, J, Yu, W, Venkatesh, A, Khan, N, Nakagawa, S, Goossens, N, Koh, AP, Higashi, T, Gunasekaran, G, Schwarz, ME, Hiotis, SP, Xu, X, Kinney, W, Hoshida, Y, Block, T, Cuconati, A & Du, Y 2016, 'Novel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma agents', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 23, pp. 5819-5824. https://doi.org/10.1016/j.bmcl.2016.10.015

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title = "Novel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma agents",

abstract = "Based on our previous identification of a disubstituted aminothiazole termed HBF-0079 with promising selective toxicity for HCC-derived cell lines versus non-HCC liver lines, a series of tri-substituted aminothiazole derivatives were prepared and evaluated. This work resulted in the discovery of isopropyl 4-(pyrazin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate, 14, which displayed EC50value of 0.11 μM and more than 450 times of selectivity, and its methyl carbonate prodrug 24 with improved solubility in organic solvents. Furthermore, 14, was shown to reduce the proliferation of several liver cancer cells derived directly from patients.",

keywords = "Hepatocellular carcinoma (HCC), Prodrug, Substituted aminothiazole",

author = "Huagang Lu and John Rogowskyj and Wenquan Yu and Anu Venkatesh and Noshena Khan and Shigeki Nakagawa and Nicolas Goossens and Koh, {Anna P.} and Takaaki Higashi and Ganesh Gunasekaran and Schwarz, {Myron E.} and Hiotis, {Spiros P.} and Xiaodong Xu and William Kinney and Yujin Hoshida and Timothy Block and Andrea Cuconati and Yanming Du",

note = "Funding Information: This project is supported by Pennsylvania Department of Health through the Commonwealth Universal Research Enhancement ( CURE ) program (PA grant, 4100059194 ). De-identified surgical HCC tissue acquisition was supported by Mount Sinai Biorepository. We also acknowledge the supports from Uehara Memorial Foundation for Shigeki Nakagawa, Japan Society for the Promotion of Science for Takaaki Higashi, FLAGS foundation, Nuovo-Soldati Cancer Research Foundation, an advanced training grant from Geneva University Hospital for Nicolas Goossens, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health DK099558, Irma T. Hirschl Trust, European Union ERC-AdG-2014 HEPCIR for Yujin Hoshida. This study was also partially supported by the Hepatitis B Foundation and the Commonwealth of Pennsylvania. The authors also thank Dr. Chunyan Han of Pharmaron for discussion of metabolite ID results. Publisher Copyright: {\textcopyright} 2016 Elsevier Ltd",

year = "2016",

doi = "10.1016/j.bmcl.2016.10.015",

language = "English (US)",

volume = "26",

pages = "5819--5824",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

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TY - JOUR

T1 - Novel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma agents

AU - Lu, Huagang

AU - Rogowskyj, John

AU - Yu, Wenquan

AU - Venkatesh, Anu

AU - Khan, Noshena

AU - Nakagawa, Shigeki

AU - Goossens, Nicolas

AU - Koh, Anna P.

AU - Higashi, Takaaki

AU - Gunasekaran, Ganesh

AU - Schwarz, Myron E.

AU - Hiotis, Spiros P.

AU - Xu, Xiaodong

AU - Kinney, William

AU - Hoshida, Yujin

AU - Block, Timothy

AU - Cuconati, Andrea

AU - Du, Yanming

N1 - Funding Information: This project is supported by Pennsylvania Department of Health through the Commonwealth Universal Research Enhancement ( CURE ) program (PA grant, 4100059194 ). De-identified surgical HCC tissue acquisition was supported by Mount Sinai Biorepository. We also acknowledge the supports from Uehara Memorial Foundation for Shigeki Nakagawa, Japan Society for the Promotion of Science for Takaaki Higashi, FLAGS foundation, Nuovo-Soldati Cancer Research Foundation, an advanced training grant from Geneva University Hospital for Nicolas Goossens, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health DK099558, Irma T. Hirschl Trust, European Union ERC-AdG-2014 HEPCIR for Yujin Hoshida. This study was also partially supported by the Hepatitis B Foundation and the Commonwealth of Pennsylvania. The authors also thank Dr. Chunyan Han of Pharmaron for discussion of metabolite ID results. Publisher Copyright: © 2016 Elsevier Ltd

PY - 2016

Y1 - 2016

N2 - Based on our previous identification of a disubstituted aminothiazole termed HBF-0079 with promising selective toxicity for HCC-derived cell lines versus non-HCC liver lines, a series of tri-substituted aminothiazole derivatives were prepared and evaluated. This work resulted in the discovery of isopropyl 4-(pyrazin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate, 14, which displayed EC50value of 0.11 μM and more than 450 times of selectivity, and its methyl carbonate prodrug 24 with improved solubility in organic solvents. Furthermore, 14, was shown to reduce the proliferation of several liver cancer cells derived directly from patients.

AB - Based on our previous identification of a disubstituted aminothiazole termed HBF-0079 with promising selective toxicity for HCC-derived cell lines versus non-HCC liver lines, a series of tri-substituted aminothiazole derivatives were prepared and evaluated. This work resulted in the discovery of isopropyl 4-(pyrazin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate, 14, which displayed EC50value of 0.11 μM and more than 450 times of selectivity, and its methyl carbonate prodrug 24 with improved solubility in organic solvents. Furthermore, 14, was shown to reduce the proliferation of several liver cancer cells derived directly from patients.

KW - Hepatocellular carcinoma (HCC)

KW - Prodrug

KW - Substituted aminothiazole

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

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ER -

Novel substituted aminothiazoles as potent and selective anti-hepatocellular carcinoma agents

Abstract

Keywords

ASJC Scopus subject areas

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