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

8 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
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

Keywords

Hepatocellular carcinoma (HCC)
Prodrug
Substituted aminothiazole

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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

@article{1883d49269824704a5b3fd0eaa840649,

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 = "Publisher Copyright: {\textcopyright} 2016 Elsevier Ltd",

year = "2016",

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

language = "English",

volume = "26",

pages = "5819--5824",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd.",

number = "23",

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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

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

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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U2 - 10.1016/j.bmcl.2016.10.015

DO - 10.1016/j.bmcl.2016.10.015

M3 - Article

C2 - 27793566

AN - SCOPUS:84995972553

SN - 0960-894X

VL - 26

SP - 5819

EP - 5824

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 23

ER -

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

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