Synthesis and evaluation of aporphinoid 5-HT(7A)R ligands as inhibitors of PC3 prostate cancer cell growth Journal Article
| Authors: | Okpattah, D.; Karki, A.; Pillarsetty, N. V. K.; Harding, W. W. |
| Article Title: | Synthesis and evaluation of aporphinoid 5-HT(7A)R ligands as inhibitors of PC3 prostate cancer cell growth |
| Abstract: | 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. © 2025 Elsevier Ltd |
| Keywords: | controlled study; human cell; antineoplastic agent; binding affinity; cell proliferation; gene targeting; antineoplastic activity; drug synthesis; prostate cancer; chemical structure; dopamine receptor; enantiomer; clozapine; racemic mixture; cancer; human; male; article; ic50; pc-3 [human prostate carcinoma] cell line; 5-ht7r; anti-proliferation; aporphine; pc3; 3 [2 [2 (4 methyl 1 piperidinyl)ethyl] 1 pyrrolidinesulfonyl]phenol; aporphine derivative; serotonin 7 receptor |
| Journal Title: | Bioorganic & Medicinal Chemistry Letters |
| Volume: | 128 |
| ISSN: | 0960-894X |
| Publisher: | Pergamon-Elsevier Science Ltd |
| Date Published: | 2025-12-01 |
| Start Page: | 130328 |
| Language: | English |
| DOI: | 10.1016/j.bmcl.2025.130328 |
| PROVIDER: | scopus |
| PUBMED: | 40633811 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus |
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