A-ring modified betulinic acid derivatives as potent cancer preventive agents

Hsin Yi Hung; Kyoko Nakagawa-Goto; Harukuni Tokuda; Akira Iida; Nobutaka Suzuki; Ibrahim D. Bori; Keduo Qian; Kuo Hsiung Lee

doi:10.1016/j.bmcl.2013.12.041

A-ring modified betulinic acid derivatives as potent cancer preventive agents

Hsin Yi Hung
, Kyoko Nakagawa-Goto
, Harukuni Tokuda
, Akira Iida
, Nobutaka Suzuki
, Ibrahim D. Bori
, Keduo Qian
, Kuo Hsiung Lee

Institute of Clinical Pharmacy and Pharmaceutical Sciences

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

10 Citations (Scopus)

Abstract

Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1 × 10³ mol ratio/TPA and 73.4%, 35.9%, and 8.4% inhibition at 5 × 10², 1 × 10 ², and 1 × 10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.

Original language	English
Pages (from-to)	1005-1008
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2013.12.041
Publication status	Published - 2014 Feb 1

All Science Journal Classification (ASJC) codes

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

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10.1016/j.bmcl.2013.12.041

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title = "A-ring modified betulinic acid derivatives as potent cancer preventive agents",

abstract = "Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100\% inhibition at 1 × 103 mol ratio/TPA and 73.4\%, 35.9\%, and 8.4\% inhibition at 5 × 102, 1 × 10 2, and 1 × 10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.",

author = "Hung, \{Hsin Yi\} and Kyoko Nakagawa-Goto and Harukuni Tokuda and Akira Iida and Nobutaka Suzuki and Bori, \{Ibrahim D.\} and Keduo Qian and Lee, \{Kuo Hsiung\}",

note = "Funding Information: This work was supported in part by NIH Grant CA177584-01 from the National Cancer Institute and AI-33066-22 from the National Institute of Allergy and Infectious Diseases awarded to K.-H. Lee. ",

year = "2014",

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doi = "10.1016/j.bmcl.2013.12.041",

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AU - Hung, Hsin Yi

AU - Nakagawa-Goto, Kyoko

AU - Tokuda, Harukuni

AU - Iida, Akira

AU - Suzuki, Nobutaka

AU - Bori, Ibrahim D.

AU - Qian, Keduo

AU - Lee, Kuo Hsiung

N1 - Funding Information: This work was supported in part by NIH Grant CA177584-01 from the National Cancer Institute and AI-33066-22 from the National Institute of Allergy and Infectious Diseases awarded to K.-H. Lee.

PY - 2014/2/1

Y1 - 2014/2/1

N2 - Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1 × 103 mol ratio/TPA and 73.4%, 35.9%, and 8.4% inhibition at 5 × 102, 1 × 10 2, and 1 × 10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.

AB - Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1 × 103 mol ratio/TPA and 73.4%, 35.9%, and 8.4% inhibition at 5 × 102, 1 × 10 2, and 1 × 10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.

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A-ring modified betulinic acid derivatives as potent cancer preventive agents

Abstract

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