Potent Cytotoxic Effects of Novel Retinamide Derivatives in Ovarian Cancer Cells(Medicinal Chemistry)

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概要

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• 4-(N-Hydroxyphenyl)retinamide (also known as 4-HPR or fenretinide), a synthetic amide of all-trans retinoic acid (RA), has been implicated as a promising anticancer agent associated with reducing the toxicity related to RA. However, the low plasma levels of 4-HPR in patients limited clinical trials, leading to a search for derivatives with better efficacy. In this study, we synthesized a series of 4-HPR derivatives in good yields by intrducing acetate (compound 1), propionate (2), pyruvate (3), butyrate (4), or stearate (5) to the 4-hydroxylphenyl moiety of 4-HPR. In our initial proliferation assays, we identified compound 3 as the most cytotoxic of the series against four ovarian cancer cell lines (OVCAR-3, PA-1, 2774, and SKOV-3). Dose-response curves yielded IC_<50> values of 3.75-7.75/μm for AtRA, 2.80-5.50μM for 9-cis RA, 0.65-4.05 μm for 4-HPR, and 0.25-0.75 μM for compound 3, depending on the cell type treated. Nuclear staining with 4',6-diamidino-2-phenylindole (DAPI) and DNA fragmentation assays clearly indicated that the antiproliferative effect of compound 3 was mediated by apoptosis. In contrast to natural retinoids, both 4-HPR and compound 3 activated two (RARβ and RARγ) of the three retinoic acid receptor (RAR) subtypes tested, but did not activate any of the three retinoid X receptors (RXRs), as determined by transcription assays in OVCAR-3 cells. However, like natural retinoids, 4-HPR and compound 3 actively suppressed c-Jun transcriptional activity. Thus, compound 3 not only showed more potent antiproliferative activity than any other retinoid derivatives tested, but also effectively inhibited the c-Jun activity that has been implicated in tumor promotion and invasion. These results, together with compound 3's selectivity for RAR subtypes, suggest that compound 3 could be an effective anticancer drug for ovarian cancer, with less toxicity than RA.

• 公益社団法人日本薬学会の論文
• 2003-10-01

著者

• Park Sung-soo

  Dept. Of Electronics Engineering Chungnam National University

• Bae Tae-sung

  韓国

• Bae Tae-sung

  Chebigen Inc. Sejong University

• Kim Sun-young

  Department Of Obstetrics And Gynecology Catholic University Medical College

• Park Jung-sun

  Division Of Hernato-oncology Asan Institute For Life Sciences College Of Medicine University Of Ulsa

• Park Jong-Sup

  Department of Obstetrics and Gynecology, Kangnam St.Mary's Hospital, The Catholic University of Kore

• UM Soo-Jong

  Department of Bioscience and Biotechnology

• SIN Hong-Sig

  Institute of Bioscience, Sejong University

• MAN Hye-Sook

  Chebigen Inc., Sejong University

• KWON Youn-Ja

  Department of Bioscience and Biotechnology

• KIM Eun-Joo

  Institute of Bioscience, Sejong University

• PARK Si-Ho

  Chebigen Inc., Sejong University

• RHO Young-Soy

  Department of Chemistry, Chonbuk National University

• Kim Sun-young

  Department Of Life Science Ewha Womans University

• Park Jong-sup

  Division Of Hernato-oncology Asan Institute For Life Sciences College Of Medicine University Of Ulsa

• Kwon Youn-ja

  Institute Of Bioscience Sejong University

• Kim Eun-joo

  Institute Of Bioscience Sejong University : Chebigen Inc. Sejong University

• Man Hye-sook

  Chebigen Inc. Sejong University

• Sin Hong-sig

  Department Of Chemistry Chonbuk National University

• Rho Young-soy

  Chebigen Inc. 350-b. Chungmugwan Sejong University

• Park Jong-sup

  Department Of Obstetrics & Gynecology Uijeongbu St. Mary Hospital The Catholic University Of Kor

• Han Hye-sook

  Chebigen Inc. 350-b. Chungmugwan Sejong University

• Park Si-ho

  Chebigen Inc. 350-b. Chungmugwan Sejong University

• Kim Sun-young

  Department Of Conservative Dentistry School Of Dentistry Kyung Hee University

• Kim Sun-Young

  Department of Applied Physics, Hanyang University, Ansan, Gyeonggi 426-791, Korea

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