{"title":"两种碳-14标记ARV-110的合成：前列腺癌雄激素受体PROTAC降解剂","authors":"Xiang-Sheng Dai, Bin Dong, Lei Xu, Zheng-Min Yang","doi":"10.1002/jlcr.4154","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p><i>N</i>-((1<i>R</i>,4<i>R</i>)-4-(3-Chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (ARV-110) is a proteolysis-targeting chimera (PROTAC) designed against the androgen receptor (AR), which shows great potential for treating AR-dependent diseases, such as prostate cancer. To support preclinical safety evaluations as well as studies of drug metabolism and pharmacokinetics, two versions of carbon-14-labeled ARV-110 were synthesized: <i>N</i>-((1<i>R</i>,4<i>R</i>)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-[1,3-<sup>14</sup>C2]dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (<sup>14</sup>C-ARV-110-<b>a</b>) and <i>N</i>-((1<i>R</i>,4<i>R</i>)-4-(3-chloro-4-[<i>cyano</i>-<sup>14</sup>C]cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (<sup>14</sup>C-ARV-110-<b>b</b>). The synthesis of <sup>14</sup>C-ARV-110-<b>a</b> was initiated from 1,2-dibromo-4,5-difluorobenzene and zinc cyanide-<sup>14</sup>C (Zn(<sup>14</sup>CN)₂), while <sup>14</sup>C-ARV-110-<b>b</b> was prepared from 2-chloro-4-fluoro[<i>cyano</i>-<sup>14</sup>C]benzonitrile.</p>\n </div>","PeriodicalId":16288,"journal":{"name":"Journal of labelled compounds & radiopharmaceuticals","volume":"68 9-10","pages":""},"PeriodicalIF":0.9000,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Synthesis of Two Versions of Carbon-14-Labeled ARV-110: An Androgen Receptor PROTAC Degrader for Prostate Cancer\",\"authors\":\"Xiang-Sheng Dai, Bin Dong, Lei Xu, Zheng-Min Yang\",\"doi\":\"10.1002/jlcr.4154\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p><i>N</i>-((1<i>R</i>,4<i>R</i>)-4-(3-Chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (ARV-110) is a proteolysis-targeting chimera (PROTAC) designed against the androgen receptor (AR), which shows great potential for treating AR-dependent diseases, such as prostate cancer. To support preclinical safety evaluations as well as studies of drug metabolism and pharmacokinetics, two versions of carbon-14-labeled ARV-110 were synthesized: <i>N</i>-((1<i>R</i>,4<i>R</i>)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-[1,3-<sup>14</sup>C2]dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (<sup>14</sup>C-ARV-110-<b>a</b>) and <i>N</i>-((1<i>R</i>,4<i>R</i>)-4-(3-chloro-4-[<i>cyano</i>-<sup>14</sup>C]cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (<sup>14</sup>C-ARV-110-<b>b</b>). The synthesis of <sup>14</sup>C-ARV-110-<b>a</b> was initiated from 1,2-dibromo-4,5-difluorobenzene and zinc cyanide-<sup>14</sup>C (Zn(<sup>14</sup>CN)₂), while <sup>14</sup>C-ARV-110-<b>b</b> was prepared from 2-chloro-4-fluoro[<i>cyano</i>-<sup>14</sup>C]benzonitrile.</p>\\n </div>\",\"PeriodicalId\":16288,\"journal\":{\"name\":\"Journal of labelled compounds & radiopharmaceuticals\",\"volume\":\"68 9-10\",\"pages\":\"\"},\"PeriodicalIF\":0.9000,\"publicationDate\":\"2025-07-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of labelled compounds & radiopharmaceuticals\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/jlcr.4154\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMICAL RESEARCH METHODS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of labelled compounds & radiopharmaceuticals","FirstCategoryId":"3","ListUrlMain":"https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/10.1002/jlcr.4154","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
Synthesis of Two Versions of Carbon-14-Labeled ARV-110: An Androgen Receptor PROTAC Degrader for Prostate Cancer
N-((1R,4R)-4-(3-Chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (ARV-110) is a proteolysis-targeting chimera (PROTAC) designed against the androgen receptor (AR), which shows great potential for treating AR-dependent diseases, such as prostate cancer. To support preclinical safety evaluations as well as studies of drug metabolism and pharmacokinetics, two versions of carbon-14-labeled ARV-110 were synthesized: N-((1R,4R)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-[1,3-14C2]dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (14C-ARV-110-a) and N-((1R,4R)-4-(3-chloro-4-[cyano-14C]cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide (14C-ARV-110-b). The synthesis of 14C-ARV-110-a was initiated from 1,2-dibromo-4,5-difluorobenzene and zinc cyanide-14C (Zn(14CN)₂), while 14C-ARV-110-b was prepared from 2-chloro-4-fluoro[cyano-14C]benzonitrile.
期刊介绍：
The Journal of Labelled Compounds and Radiopharmaceuticals publishes all aspects of research dealing with labeled compound preparation and applications of these compounds. This includes tracer methods used in medical, pharmacological, biological, biochemical and chemical research in vitro and in vivo.
The Journal of Labelled Compounds and Radiopharmaceuticals devotes particular attention to biomedical research, diagnostic and therapeutic applications of radiopharmaceuticals, covering all stages of development from basic metabolic research and technological development to preclinical and clinical studies based on physically and chemically well characterized molecular structures, coordination compounds and nano-particles.
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