Synthesis and evaluation of aporphinoid 5-HT7AR ligands as inhibitors of PC3 prostate cancer cell growth

Aporphines are a class of Isoquinoline Alkaloids that are endowed with a range of biological activities. The 5-HT7R is an emerging biological target for prostate Cancer therapeutics. In this manuscript, we report the synthesis and evaluation of aporphine enantiomers as 5-HT7R ligands, as well as their activity in inhibiting the proliferation of prostate Cancer cells (specifically, PC3). The (S)-enantiomers displayed higher affinity at the 5-HT7R than the racemates and the (R)-enantiomer counterparts. The (S)-enantiomers were found to be antagonists at the 5-HT7R. Racemates as well as their respective enantiomers were selective for the 5-HT7R receptor over Other serotonin and dopamine receptors evaluated. In the Anticancer activity assays, the compounds showed more potent cytotoxic effects than the selective 5-HT7R antagonist control SB269970. However, no correlation was observed between the 5-HT7R affinity or 5-HT7R antagonist activity and Anticancer potency, suggesting that Other non-5-HT7R mechanisms play a role in the Anticancer effects of the compounds. Compounds (R)-1 and (R)-4 were identified as the most potent anti-proliferative compounds and will be useful as lead molecules for prostate Cancer therapeutic development in future studies.