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

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-07 DOI:10.1016/j.bmcl.2025.130328

Daniel Okpattah , Anupam Karki , Naga V.K. Pillarsetty , Wayne W. Harding

{"title":"Synthesis and evaluation of aporphinoid 5-HT7AR ligands as inhibitors of PC3 prostate cancer cell growth","authors":"Daniel Okpattah , Anupam Karki , Naga V.K. Pillarsetty , Wayne W. Harding","doi":"10.1016/j.bmcl.2025.130328","DOIUrl":null,"url":null,"abstract":"<div><div>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).</div><div>The (<em>S</em>)-enantiomers displayed higher affinity at the 5-HT7R than the racemates and the (<em>R</em>)-enantiomer counterparts. The (<em>S</em>)-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 (<em>R</em>)-1 and (<em>R</em>)-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.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130328"},"PeriodicalIF":2.5000,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X25002379","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

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.

Abstract Image

查看原文本刊更多论文

类aporphinoid 5-HT7AR配体抑制PC3前列腺癌细胞生长的合成及评价

aporphine是一类具有多种生物活性的异喹啉类生物碱。5-HT7R是前列腺癌治疗的新兴生物学靶点。在这篇论文中，我们报道了作为5-HT7R配体的aporphine对映体的合成和评价，以及它们抑制前列腺癌细胞（特别是PC3）增殖的活性。(S)-对映体比外消旋体和(R)-对映体在5-HT7R上表现出更高的亲和力。(S)-对映体是5-HT7R的拮抗剂。外消旋体及其各自的对映体对5-HT7R受体具有选择性，优于其他5-羟色胺和多巴胺受体。在抗癌活性实验中，这些化合物显示出比选择性5-HT7R拮抗剂SB269970更强的细胞毒作用。然而，5-HT7R亲和力或5-HT7R拮抗剂活性与抗癌效力之间没有相关性，这表明其他非5-HT7R机制在化合物的抗癌作用中起作用。化合物(R)-1和(R)-4被认为是最有效的抗增殖化合物，在未来的研究中将作为先导分子用于前列腺癌的治疗开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.