Efficient synthesis and biological evaluation of demethyl geranylgeranoic acid derivatives
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- 作者：Akimori Wada ; Fei Wang ; Yoshitomo Suhara ; Yumiko Yamano ; Takashi Okitsu ; Kimie Nakagawa ; Toshio Okano
- 关键词：Retinoid receptors ; Retinoic acid analog ; Geranylgeranoic acid ; Demethyl analog ; Coupling reaction ; Vinyl triflate
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2010
- 出版时间：15 August 2010
- 年：2010
- 卷：18
- 期：16
- 页码：5795-5806
- 全文大小：878 K
文摘
Synthetic retinoids have generated in the fields of dermatology and oncology due to their potent anti-proliferative and differentiation activities. We efficiently synthesized different demethyl geranylgeranoic acid (GGA) analogs, and evaluated their biological activities. Among the demethyl analogs synthesized, 3-demethyl derivative exhibited the highest anti-proliferative activity in HL-60 cells. In addition, a 3-demethyl derivative induced apoptosis more potently than 9Z-retinoic acid. These activities were due to the high binding affinity of 3-demethyl derivative for retinoid receptors. We found that, in a conjugated polyene system combined with a methyl substituent, the position of the methyl played an important role in the regulation of gene transcription and apoptosis-inducing activity. These results provided useful information on the structure–activity relationships of GGA derivatives that function as acyclic retinoic acid analogs. This information is likely to be useful in the development of new anti-cancer drugs.