Bioorganic & Medicinal Chemistry Letters最新文献

Design and synthesis of imidazo[2,1-b]thiazole derivatives as potent and selective phosphatidylinositol 4-kinase IIIβ inhibitors for antiviral activity 咪唑[2,1-b]噻唑衍生物作为有效的选择性磷脂酰肌醇4-激酶IIIβ抑制剂的设计和合成

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-21 DOI: 10.1016/j.bmcl.2025.130346

Koji Ochiai, Masahiko Kinebuchi, Takekazu Kondo, Takahiro Suezawa, Morio Higuchi, Motomichi Fujita, Akinobu Yokoyama, Hitomi Matsui, Makoto Rembutsu, Yuji Ishibashi, Yuta Tanaka, Aki Yonezawa, Hirotaka Ando, Yoshiaki Kitamura, Michiaki Nagasawa, Masahiro Ueno

{"title":"Design and synthesis of imidazo[2,1-b]thiazole derivatives as potent and selective phosphatidylinositol 4-kinase IIIβ inhibitors for antiviral activity","authors":"Koji Ochiai, Masahiko Kinebuchi, Takekazu Kondo, Takahiro Suezawa, Morio Higuchi, Motomichi Fujita, Akinobu Yokoyama, Hitomi Matsui, Makoto Rembutsu, Yuji Ishibashi, Yuta Tanaka, Aki Yonezawa, Hirotaka Ando, Yoshiaki Kitamura, Michiaki Nagasawa, Masahiro Ueno","doi":"10.1016/j.bmcl.2025.130346","DOIUrl":"10.1016/j.bmcl.2025.130346","url":null,"abstract":"<div><div>The type III phosphatidylinositol 4-kinase beta (PI4KB, PI4KIIIβ) is a lipid kinase that catalyzes the phosphorylation of phosphatidylinositol at the 4-position. PI4KB is widely understood to play a critical role in supporting viral replication, and PI4KB inhibitors are under investigation as potential host-targeting antivirals. In this study, we report potent and selective imidazo[2,1-<em>b</em>]thiazole inhibitors of PI4KB with antiviral activity. Guided by ligand efficiency, optimization efforts yielded potent PI4KB inhibitors, and reducing proton donor count enhanced cellular potency (anti HRV: EC<sub>50</sub> 0.027 μM for compound <strong>29</strong>, 0.007 μM for compound <strong>30</strong>). Furthermore, compound <strong>30</strong> selectively inhibited PI4KB, with minimal off-target kinase activity, as confirmed by profiling.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130346"},"PeriodicalIF":2.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development and biological evaluation of novel SOS1 inhibitors featuring 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold 以5,8-二氢吡啶[4,3-d]嘧啶-7(6H)- 1为支架的新型SOS1抑制剂的开发和生物学评价。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-21 DOI: 10.1016/j.bmcl.2025.130344

Xiaoyu Chen , Xuepei Ma , Zixuan Yang , Mei Mao , Wenjia Niu , Chengwei Zhang , Xiaolei Meng , Mengjun Ma , Zhuoyue Li , Xiao Wang , Shanshan Du , Shumin Ma , Siqi Zhang

{"title":"Development and biological evaluation of novel SOS1 inhibitors featuring 5,8-dihydropyrido[4,3-d]pyrimidin-7(6H)-one scaffold","authors":"Xiaoyu Chen , Xuepei Ma , Zixuan Yang , Mei Mao , Wenjia Niu , Chengwei Zhang , Xiaolei Meng , Mengjun Ma , Zhuoyue Li , Xiao Wang , Shanshan Du , Shumin Ma , Siqi Zhang","doi":"10.1016/j.bmcl.2025.130344","DOIUrl":"10.1016/j.bmcl.2025.130344","url":null,"abstract":"<div><div>SOS1 plays a pivotal role in RAS activation and has emerged as a promising therapeutic target for tumors driven by KRAS mutations. In this study, we designed and synthesized a novel series of SOS1 inhibitors based on the 5,8-dihydropyrido[4,3-<em>d</em>]pyrimidin-7(6<em>H</em>)-one scaffold. Biological evaluation revealed that most compounds displayed anti-proliferative activity against K562 leukemia cells. Among these, <strong>A15f</strong> and <strong>B5a</strong> emerged as the most potent compounds comparable to BI-3406. <strong>A15f</strong> and <strong>B5a</strong> exhibited inhibitory activity against KRAS-G12C/SOS1 complex formation, with IC₅₀ value of 40.28 and 11.11 nM respectively and led to a dose-dependent decrease in pERK levels. The combination therapy of KRAS G12C inhibitor and A15f shows enhanced <em>in vitro</em> efficacy. Molecular docking revealed that these two compounds shared a conserved binding mode with SOS1, similar to the reported inhibitors. These findings provide foundation for further development of SOS1-targeted anticancer therapeutics and offer valuable insights for structural optimization of this novel class of inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130344"},"PeriodicalIF":2.5,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697225","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structure–activity relationship studies of tanzawaic acid A, an antifungal agent against Rhizopus oryzae 抗米根霉药坦桑酸A的构效关系研究。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-16 DOI: 10.1016/j.bmcl.2025.130343

Kotaro Tanaka , Shiho Arima , Daiki Lee , Satoshi Ohte , Hiroshi Tomoda , Ryuji Uchida , Taichi Ohshiro , Tohru Nagamitsu

引用次数: 0

Discovery of novel benzomorpholine derivatives as potent URAT1 inhibitors with hypouricemic effects 发现新的苯并噻吩啉衍生物作为具有降尿酸作用的URAT1抑制剂。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-14 DOI: 10.1016/j.bmcl.2025.130342

Yongcheng Wang , Lei Zhang , Mengjie Shao , Xianxin Hou , Ying Yang , Yifan Yang , Fei Ye , Xuechen Li , Zhiyan Xiao

{"title":"Discovery of novel benzomorpholine derivatives as potent URAT1 inhibitors with hypouricemic effects","authors":"Yongcheng Wang , Lei Zhang , Mengjie Shao , Xianxin Hou , Ying Yang , Yifan Yang , Fei Ye , Xuechen Li , Zhiyan Xiao","doi":"10.1016/j.bmcl.2025.130342","DOIUrl":"10.1016/j.bmcl.2025.130342","url":null,"abstract":"<div><div>Urate transporter 1 (URAT1) is a clinically validated therapeutic target for hyperuricemia and gout. To obtain structurally novel URAT1 inhibitors, a series of benzomorpholine derivatives were designed by adopting a pharmacophore guided molecular hybridization strategy. Most compounds potently inhibit the human URAT1 in HEK293 cells, and the most active compound <strong>7</strong> exhibited an IC<sub>50</sub> of 0.72 μM, which was much more potent than Lesinurad and comparable to Benzbromarone. The possible interaction mode of compound <strong>7</strong> with URAT1 was revealed by molecular modeling. Cell viability assays indicated that compound <strong>7</strong> was less cytotoxic than Benzbromarone in Hep-G2 cells. The urate-lowering effects of compounds <strong>1</strong> and <strong>7</strong> were confirmed in two different hyperuricemia mouse models, and no obvious toxicity was observed in the treated mice. The results provide new chemical prototypes for urate-lowering drug discovery targeting URAT1.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130342"},"PeriodicalIF":2.5,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fluorescein diacetate (FDA) should not be used to study human carboxylesterase 2 (CES2) in complex biological systems without validation 未经验证，不应将双醋酸荧光素（FDA）用于复杂生物系统中人羧酸酯酶2 （CES2）的研究。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-11 DOI: 10.1016/j.bmcl.2025.130331

Carolyn J. Karns , Anchal Singh , Makenzie R. Walk , Emmanuel Adusah , Alyssa M. Pearson , Samuel J. Knebel , Michael W. Beck

{"title":"Fluorescein diacetate (FDA) should not be used to study human carboxylesterase 2 (CES2) in complex biological systems without validation","authors":"Carolyn J. Karns , Anchal Singh , Makenzie R. Walk , Emmanuel Adusah , Alyssa M. Pearson , Samuel J. Knebel , Michael W. Beck","doi":"10.1016/j.bmcl.2025.130331","DOIUrl":"10.1016/j.bmcl.2025.130331","url":null,"abstract":"<div><div>The utility of fluorogenic chemical tools for investigating processes in biologically complex systems depends on validating their specificity in the same system. This is particularly crucial for tools that report on enzymatic activity, especially when enzymes with similar activity are also present which is often true for serine hydrolases. One such serine hydrolase is human carboxylesterase 2 (CES2). CES2 is a key xenobiotic metabolism enzyme responsible for the hydrolysis of drugs belonging to multiple classes. Due to its importance in drug metabolism and potential as a cancer biomarker, there is a need for reliable and accessible tools to study CES2. Fluorescein DiAcetate (FDA) is a commercially available fluorogenic compound that has been employed to study CES2 activity in various systems. Studies carried out <em>in vitro</em> have shown FDA prefers hydrolysis by CES2 over closely related CES1. However, the specificity of FDA for CES2 over CES1 and other hydrolases in complex biological systems has not been rigorously evaluated. This study aimed to characterize FDA as a tool for studying CES2 in complex biological systems using computational, biochemical, and live cell imaging. Our results indicate that FDA is unsuitable for studying CES2 in systems with multiple hydrolases, like HepG2 cells, but may be used when CES2 is the predominant hydrolase, such as in overexpression models. We advise caution when using FDA to study CES2 and emphasize that rigorous validation is necessary to ensure that chemical tools used in complex biological systems specifically report on the intended molecular target in each experimental context.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130331"},"PeriodicalIF":2.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Recent advances and perspectives in therapeutics for mpox m痘治疗方法的最新进展和展望。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-11 DOI: 10.1016/j.bmcl.2025.130330

Yaru Zhang , Tingnan Ma , Tao Yuan , Lingyu Su , Dongke Yu , Lei Zhong

{"title":"Recent advances and perspectives in therapeutics for mpox","authors":"Yaru Zhang , Tingnan Ma , Tao Yuan , Lingyu Su , Dongke Yu , Lei Zhong","doi":"10.1016/j.bmcl.2025.130330","DOIUrl":"10.1016/j.bmcl.2025.130330","url":null,"abstract":"<div><div>Mpox, a viral illness caused by the monkeypox virus (MPXV), has gained global attention due to its outbreaks worldwide in recent years. MPXV infections pose significant public health threats with notable transmission risks, yet specific antiviral treatments remain limited. Current therapeutic approaches primarily rely on smallpox vaccines and a limited number of broad-spectrum antiviral agents, such as tecovirimat, lacking specific drugs against MPXV. Thus, it remains a significant clinical need to develop anti-MPXV agents for the prevention and control of mpox outbreaks. In this review, we summarized the characteristics of MPXV in terms of viral structure, genome, and replication while reporting the recent progress in the development of small molecule anti-MPXV agents. Additionally, we discussed major obstacles in anti-MPXV drug development, including insufficient understanding of virus biology, the lack of reliable disease models, and limited resources for conducting large-scale clinical evaluations, and provided insights and perspectives for anti-MPXV therapies, with the aims of accelerating the development of effective treatments and contributing to preparedness against emerging orthopoxvirus threats.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130330"},"PeriodicalIF":2.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Azolo[5′,1′,2,3]pyrimido[5,4-e]tetrazolo[1,5-c]pyrimidines as dual-action antiglycators and α-glucosidase inhibitors 偶氮[5',1',2,3]嘧啶[5,4-e]四氮[1,5-c]嘧啶作为双作用降糖剂和α-葡萄糖苷酶抑制剂。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-10 DOI: 10.1016/j.bmcl.2025.130333

Grigoriy V. Urakov , Konstantin V. Savateev , Pavel A. Slepukhin , Vladimir L. Rusinov , Umida M. Ibragimova , Roman D. Danilov , Xenia I. Zhukova , Svetlana A. Sorokina , Violetta R. Raiberg , Roman A. Litvinov , Alexander A. Spasov , Denis A. Babkov

{"title":"Azolo[5′,1′,2,3]pyrimido[5,4-e]tetrazolo[1,5-c]pyrimidines as dual-action antiglycators and α-glucosidase inhibitors","authors":"Grigoriy V. Urakov , Konstantin V. Savateev , Pavel A. Slepukhin , Vladimir L. Rusinov , Umida M. Ibragimova , Roman D. Danilov , Xenia I. Zhukova , Svetlana A. Sorokina , Violetta R. Raiberg , Roman A. Litvinov , Alexander A. Spasov , Denis A. Babkov","doi":"10.1016/j.bmcl.2025.130333","DOIUrl":"10.1016/j.bmcl.2025.130333","url":null,"abstract":"<div><div>The novel chemotype, azolo[5′,1′:2,3]pyrimido[5,4-<em>e</em>]tetrazolo[1,5-<em>c</em>]pyrimidines <strong>12</strong>, with promising dual action antiglycating and α-glucosidase inhibiting activities was developed basen on reaction of 6-(tetrazol-5-yl)-7-aminoazolo[1,5-<em>a</em>]pyrimidines <strong>3</strong> with (het)aroyl chlorides. The conditions for this process were optimized to achieve high yields of heterocycles <strong>12</strong> upon mild conditions whereas azido-tetrazole tautomerism was revealed for these products <strong>12</strong> and it was shown that the equilibrium is shifted towards azide tautomer. The obtained azolo[5′,1′:2,3]pyrimido[5,4-<em>e</em>]tetrazolo[1,5-<em>c</em>]pyrimidines <strong>12</strong> inhibited the glycation reaction in the BSA-glucose assay more strongly than pyridoxamine as a reference compound, which is promising in terms of preventing AGEs assosiated pathologies such as long-term complication of diabetes and cancer. Furthermore, some heterocycles <strong>12</strong> inhibited α-glucosidase in the mid-micromolar range - more effectively than acarbose, with an IC<sub>50</sub> 17.52 μM for the lead compound <strong>12k</strong>.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130333"},"PeriodicalIF":2.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of aldolase A inhibitors via high-throughput screening assay based on an enzymatic coupling reaction 通过基于酶偶联反应的高通量筛选试验发现醛缩酶A抑制剂

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-10 DOI: 10.1016/j.bmcl.2025.130332

Qingwen Xiong , Rongyu Qian , Qingcheng Huang , Jingqiu Liu , Chen Zhou , Cheng Luo , Dongxiang Liu , Daohai Du

{"title":"Discovery of aldolase A inhibitors via high-throughput screening assay based on an enzymatic coupling reaction","authors":"Qingwen Xiong , Rongyu Qian , Qingcheng Huang , Jingqiu Liu , Chen Zhou , Cheng Luo , Dongxiang Liu , Daohai Du","doi":"10.1016/j.bmcl.2025.130332","DOIUrl":"10.1016/j.bmcl.2025.130332","url":null,"abstract":"<div><div>Aldolase A (ALDOA) is a key enzyme in glycolysis, catalyzing the reversible conversion of fructose-1,6-diphosphate (FBP) to dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (GAP). The aberrant overexpression of ALDOA is associated with the development of various solid tumors. Here, we developed an <em>in vitro</em> enzymatic coupling reaction assay, which demonstrates high cost-efficiency and is suitable for high-throughput screening (HTS). With this assay we identified two potential ALDOA inhibitors, merbromin and ellagic acid, from our in-house compound library. Merbromin and ellagic acid exhibit significant inhibitory activities with IC<sub>50</sub> values of 8.49 ± 0.62 μM and 19.87 ± 2.03 μM, respectively. The nuclear magnetic resonance (NMR) and surface plasmon resonance (SPR) experiments further confirmed their high affinities to ALDOA, with the dissociation constants (<em>K</em><sub>d</sub>) of 0.49 ± 0.10 μM and 0.64 ± 0.10 μM, respectively. Enzyme kinetics experiment revealed that both compounds act as noncompetitive inhibitors of ALDOA. Our study showed that the enzymatic coupling reaction-based assay established here is highly effective and offers a promising approach for the development of ALDOA inhibitors.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130332"},"PeriodicalIF":2.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144613810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

4′-O-methoxyethyl-2′-deoxy-uridine and cytidine ribonucleotides improve duplex stability, nuclease resistance, and elicit efficient knockdown of Bcl-2 expression 4 ' - o -甲氧基乙基-2 ' -脱氧尿苷和胞苷核糖核苷酸改善双链稳定性，核酸酶抗性，并引发有效的Bcl-2表达下调

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-07 DOI: 10.1016/j.bmcl.2025.130329

Sumit Gangopadhyay , Gourav Das , Swrajit Nath Sharma , Atanu Ghosh , Siddharam Shivappa Bagale , Surajit Sinha , Kiran R. Gore

{"title":"4′-O-methoxyethyl-2′-deoxy-uridine and cytidine ribonucleotides improve duplex stability, nuclease resistance, and elicit efficient knockdown of Bcl-2 expression","authors":"Sumit Gangopadhyay , Gourav Das , Swrajit Nath Sharma , Atanu Ghosh , Siddharam Shivappa Bagale , Surajit Sinha , Kiran R. Gore","doi":"10.1016/j.bmcl.2025.130329","DOIUrl":"10.1016/j.bmcl.2025.130329","url":null,"abstract":"<div><div>In this study, we report the synthesis of 4′-<em>O</em>-methoxyethyl deoxyuridine and 4′-<em>O</em>-methoxyethyl deoxycytidine phosphoramidites and their incorporation into oligonucleotides. The 3′-exonuclease experiment indicated a significant increase in stability with the incorporation of 4′-<em>O</em>-MOE dU alone (<em>T</em><sub>1/2</sub> = 178 min) and in combination with phosphorothioate modification (<em>T</em><sub>1/2</sub> = 13 h) in dT<sub>10</sub>-mer. Western blot studies demonstrated that 4′-<em>O</em>-MOE-dU and 4′-<em>O</em>-MOE-dC modifications were well-tolerated when placed at both overhang regions and multiple positions within the passenger strand of anti-Bcl2 siRNAs. Moreover, overhang-modified siRNA duplexes showed no significant change in the IFNα level compared to native siRNA. Molecular modelling studies revealed that the 4′-<em>O</em>-MOE group makes multiple steric interactions with 3′-exonuclease residues, contributing to improved nuclease resistance. Additionally, this modification accommodates well within the PAZ domain, potentially influencing RNAi activity. Overall, the modified deoxynucleotides could enhance the stability and efficacy of nucleic acid drugs.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"128 ","pages":"Article 130329"},"PeriodicalIF":2.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and evaluation of aporphinoid 5-HT7AR ligands as inhibitors of PC3 prostate cancer cell growth 类aporphinoid 5-HT7AR配体抑制PC3前列腺癌细胞生长的合成及评价

IF 2.5 4区医学

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":"10.1016/j.bmcl.2025.130328","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":2.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144580502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0