Efficient synthesis and biological evaluation of demethyl geranylgeranoic acid derivatives.
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.
Wada
Akimori
A
Department of Organic Chemistry for Life Science, Kobe Pharmaceutical University, Higashinada-ku, Kobe, Japan. a-wada@kobepharma-u.ac.jp
Wang
Fei
F
Suhara
Yoshitomo
Y
Yamano
Yumiko
Y
Okitsu
Takashi
T
Nakagawa
Kimie
K
Okano
Toshio
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D008745:Methylation; D051381:Rats; D047488:Retinoid X Receptors / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014212:Tretinoin / Q000031:analogs & derivatives / Q000494:pharmacology
D004224:Diterpenes; D047488:Retinoid X Receptors; D014212:Tretinoin; C040155:geranylgeranic acid