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.

Monodemethylated geranylgeranoic acids were prepared as acyclic retinoid analogs, and evaluated their biological activities. Among the analogs, 3-demethyl derivative exhibited the highest anti-proliferative activity and apoptosis-inducing activity.Figure optionsDownload as PowerPoint slide