2. Academic Validation
  3. Synthesis and evaluation of aporphinoid 5-HT7AR ligands as inhibitors of PC3 prostate cancer cell growth

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

  • Bioorg Med Chem Lett. 2025 Dec 1:128:130328. doi: 10.1016/j.bmcl.2025.130328.
Daniel Okpattah 1,  Anupam Karki 2,  Naga V K Pillarsetty 3,  Wayne W Harding 4
Affiliations

Affiliations

  • 1 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA; Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
  • 2 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA.
  • 3 Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA; Department of Radiology, Weill Cornell Medicine, 520 East 70th Street, New York, NY 10021, USA.
  • 4 Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA; Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA. Electronic address: [email protected].
PMID: 40633811 DOI: 10.1016/j.bmcl.2025.130328
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.

Keywords

5-HT7R; Anti-proliferation; Aporphine; PC3; cancer.

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