The activation of AMPK has emerged as a promising therapeutic approach for the treatment of metabolic diseases. AdipoRon, an agonist of the adiponectin receptor, has been identified as a compound capable of activating AMPK via the adiponectin receptor. To identify novel AdipoRon analogues with AMPK activation potential, a total of 17 analogues were designed, synthesized, and subjected to biological evaluation. Among these analogues, X-12 was discovered to exhibit potent activation of AMPK. In experimental studies, X-12 demonstrated dose-dependent improvements in glucose tolerance in normal mice. Furthermore, it significantly reduced fasting blood glucose levels and ameliorated insulin resistance in db/db diabetic mice. These findings highlight the therapeutic potential of X-12 as a novel class of AMPK activators for the treatment of metabolic diseases.
{"title":"Identification of AdipoRon analogues as novel activators of AMPK for the treatment of type 2 diabetes†","authors":"Chao Lin, Geng Sun and Yi Li","doi":"10.1039/D3MD00727H","DOIUrl":"10.1039/D3MD00727H","url":null,"abstract":"<p >The activation of AMPK has emerged as a promising therapeutic approach for the treatment of metabolic diseases. AdipoRon, an agonist of the adiponectin receptor, has been identified as a compound capable of activating AMPK <em>via</em> the adiponectin receptor. To identify novel AdipoRon analogues with AMPK activation potential, a total of 17 analogues were designed, synthesized, and subjected to biological evaluation. Among these analogues, <strong>X-12</strong> was discovered to exhibit potent activation of AMPK. In experimental studies, <strong>X-12</strong> demonstrated dose-dependent improvements in glucose tolerance in normal mice. Furthermore, it significantly reduced fasting blood glucose levels and ameliorated insulin resistance in <em>db</em>/<em>db</em> diabetic mice. These findings highlight the therapeutic potential of <strong>X-12</strong> as a novel class of AMPK activators for the treatment of metabolic diseases.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141506034","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}
Doretta Cuffaro, Tina Burkhard, Bianca Laura Bernardoni, Riccardo Di Leo, Xiaohan Zhang, Salvatore Galati, Tiziano Tuccinardi, Marco Macchia, Armando Rossello, Salvatore Santamaria, Rens de Groot and Elisa Nuti
The proteolytic activity of the enzyme ADAMTS7 was recently shown to enhance the progression of atherosclerosis, in line with human genetic findings suggesting that ADAMTS7 has a role in the pathophysiology of coronary heart disease. Targeting the active site of ADAMTS7 with a small molecule inhibitor, therefore, has therapeutic potential. Here, we report the design and synthesis of a novel hydroxamate-based arylsulfonamide that is a potent and selective ADAMTS7 inhibitor. In silico studies guided the hit optimization process aiming to improve selectivity of the previously reported (non-selective) inhibitor EDV33. Our lead compound is a p-trifluoromethyl biphenyl sulfonamide, which displayed a 12-fold selectivity for ADAMTS7 (Ki = 9 nM) over ADAMTS5 (Ki = 110 nM) and an 8-fold increase in inhibition of ADAMTS7 compared to EDV33 (Ki = 70 nM). The substitutions switched selectivity and produced a new potent ADAMTS7 inhibitor that can be taken forward for further characterisation.
{"title":"Design, synthesis and biological evaluation of arylsulfonamides as ADAMTS7 inhibitors†","authors":"Doretta Cuffaro, Tina Burkhard, Bianca Laura Bernardoni, Riccardo Di Leo, Xiaohan Zhang, Salvatore Galati, Tiziano Tuccinardi, Marco Macchia, Armando Rossello, Salvatore Santamaria, Rens de Groot and Elisa Nuti","doi":"10.1039/D4MD00149D","DOIUrl":"10.1039/D4MD00149D","url":null,"abstract":"<p >The proteolytic activity of the enzyme ADAMTS7 was recently shown to enhance the progression of atherosclerosis, in line with human genetic findings suggesting that ADAMTS7 has a role in the pathophysiology of coronary heart disease. Targeting the active site of ADAMTS7 with a small molecule inhibitor, therefore, has therapeutic potential. Here, we report the design and synthesis of a novel hydroxamate-based arylsulfonamide that is a potent and selective ADAMTS7 inhibitor. <em>In silico</em> studies guided the hit optimization process aiming to improve selectivity of the previously reported (non-selective) inhibitor EDV33. Our lead compound is a <em>p</em>-trifluoromethyl biphenyl sulfonamide, which displayed a 12-fold selectivity for ADAMTS7 (<em>K</em><small><sub>i</sub></small> = 9 nM) over ADAMTS5 (<em>K</em><small><sub>i</sub></small> = 110 nM) and an 8-fold increase in inhibition of ADAMTS7 compared to EDV33 (<em>K</em><small><sub>i</sub></small> = 70 nM). The substitutions switched selectivity and produced a new potent ADAMTS7 inhibitor that can be taken forward for further characterisation.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00149d?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141743001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zhen Wang, Juan Zhang, Conghao Gai, Jing Wang, Xiaobin Zhuo, Yan Song, Yan Zou, Peichao Zhang, Guige Hou, Qingguo Meng, Qingjie Zhao and Xiaoyun Chai
Correction for ‘Discovery of dibenzylbutane lignan LCA derivatives as potent anti-inflammatory agents’ by Zhen Wang et al., RSC Med. Chem., 2024, https://doi.org/10.1039/d4md00053f.
对 Zhen Wang 等人的文章 "Discovery of dibenzylbutane lignan LCA derivatives as potent anti-inflammatory agents "的更正,RSC Med.Chem., 2024, https://doi.org/10.1039/d4md00053f.
{"title":"Correction: Discovery of dibenzylbutane lignan LCA derivatives as potent anti-inflammatory agents","authors":"Zhen Wang, Juan Zhang, Conghao Gai, Jing Wang, Xiaobin Zhuo, Yan Song, Yan Zou, Peichao Zhang, Guige Hou, Qingguo Meng, Qingjie Zhao and Xiaoyun Chai","doi":"10.1039/D4MD90023E","DOIUrl":"10.1039/D4MD90023E","url":null,"abstract":"<p >Correction for ‘Discovery of dibenzylbutane lignan LCA derivatives as potent anti-inflammatory agents’ by Zhen Wang <em>et al.</em>, <em>RSC Med. Chem.</em>, 2024, https://doi.org/10.1039/d4md00053f.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md90023e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141529316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Many drugs target the serotonin 2A (5-HT2A) receptor, including psychedelics, antidepressants, and antipsychotics. This study investigates the 5-HT2A receptor-binding properties of a series of novel compounds with an amino-phenylmethylene-imidazolone (APMI) core structure. Two compounds (2a and 2c) demonstrated significant 5-HT2A receptor-binding affinity without agonistic activity, instead displaying antagonistic effects. Structurally, these compounds differ from previously reported phenethylamine-based antagonists. This work introduces APMIs as a novel pharmacophore for 5-HT2A receptor interaction and provides a foundation for developing new 5-HT2A receptor-targeting therapeutic agents.
{"title":"Synthesis and in vitro evaluation of novel amino-phenylmethylene-imidazolone 5-HT2A receptor antagonists†","authors":"Gregory E. Dwulet","doi":"10.1039/D4MD00262H","DOIUrl":"10.1039/D4MD00262H","url":null,"abstract":"<p >Many drugs target the serotonin 2A (5-HT<small><sub>2A</sub></small>) receptor, including psychedelics, antidepressants, and antipsychotics. This study investigates the 5-HT<small><sub>2A</sub></small> receptor-binding properties of a series of novel compounds with an amino-phenylmethylene-imidazolone (APMI) core structure. Two compounds (<strong>2a</strong> and <strong>2c</strong>) demonstrated significant 5-HT<small><sub>2A</sub></small> receptor-binding affinity without agonistic activity, instead displaying antagonistic effects. Structurally, these compounds differ from previously reported phenethylamine-based antagonists. This work introduces APMIs as a novel pharmacophore for 5-HT<small><sub>2A</sub></small> receptor interaction and provides a foundation for developing new 5-HT<small><sub>2A</sub></small> receptor-targeting therapeutic agents.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523104","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}
Avinash G. Vishakantegowda, Dasom Hwang, Prashant Chakrasali, Eunhye Jung, Joo-Youn Lee, Jin Soo Shin and Young-Sik Jung
Correction for ‘Highly potent and selective phosphatidylinositol 4-kinase IIIβ inhibitors as broad-spectrum anti-rhinoviral agents’ by Avinash G. Vishakantegowda et al., RSC Med. Chem., 2024, 15, 704–719, https://doi.org/10.1039/D3MD00630A.
Itisha Chummun Phul, Andrea Gómez-Llonín and Archana Bhaw-Luximon
The use of plant extracts as a potential cure for various conditions has moved from traditional medicine to evidence-based medicine. Skin diseases have been addressed since time immemorial using plant extracts through observational and traditional knowledge and passed on through generations. With the advent of modern techniques, the molecular mechanisms of action of plant extracts/isolates are being deciphered with more precision, and more nanomedicine-based therapies are being studied to improve their therapeutic efficacy and stability. The leaves and seeds of Ginkgo biloba (G. biloba), an ancient medicinal tree species, have been used in Chinese herbal medicine for thousands of years. G. biloba extracts have been widely studied as a neuroprotective and anti-ischaemic drug for ischaemia-reperfusion injuries in the heart, lungs, brain, kidneys, and other organs. However, the use of G. biloba can be accompanied with side effects and drug interactions. Although, there is now a growing interest for its use in skincare, the mechanisms of action of the extract are not fully understood and vital aspects of G. biloba, such as its neuroprotective and angiogenic properties contributing to the treatment of inflammatory skin diseases and skin ageing, are yet to be investigated. This review critically discusses the mechanisms of action of different constituents of G. biloba extracts linked to their potential interference in the molecular mechanisms underlying the pathogenesis of inflammatory skin diseases. In addition to its ability to act on oxidative stress, G. biloba can regulate angiogenesis through its compounds such as ginkgetin or ginkgolide K, which either inhibit aberrant angiogenesis in eczema/psoriasis or increase microcirculation during skin ageing. G. biloba may also contribute to the control of pruritus in atopic dermatitis via a neuroprotective and anti-inflammatory mechanism by suppressing JAK2/STAT3 signalling pathways. This review also highlights nanomedicine strategies to decrease the side effects and enhance the efficacy of the extracts. Similar strategies have been successfully used for anticancer molecules in targeted chemotherapy and iron delivery in anaemia treatment.
使用植物提取物作为治疗各种疾病的潜在方法,已经从传统医学转变为循证医学。自古以来,人们就通过观察和传统知识,利用世代相传的植物提取物来治疗皮肤病。随着现代技术的发展,植物提取物/分离物的分子作用机制正在被更精确地破解,更多基于纳米药物的疗法正在研究之中,以提高其疗效和稳定性。银杏叶(G. biloba)是一种古老的药用树种,其叶子和种子被用于中草药已有数千年的历史。银杏叶提取物作为一种神经保护和抗缺血药物已被广泛研究,用于治疗心、肺、脑、肾和其他器官的缺血再灌注损伤。然而,使用 G. biloba 可能会产生副作用和药物相互作用。虽然现在人们对其在护肤品中的应用越来越感兴趣,但对其提取物的作用机制还不完全了解,而且其重要的方面,如有助于治疗炎症性皮肤病和皮肤老化的神经保护和血管生成特性,还有待研究。这篇综述批判性地讨论了双叶鹅掌楸萃取物不同成分的作用机制,以及它们对炎症性皮肤病发病机制的潜在干扰。除了对氧化应激有作用外,银杏叶还能通过其化合物(如银杏黄酮或银杏内酯 K)调节血管生成,从而抑制湿疹/银屑病中异常的血管生成,或在皮肤老化过程中增加微循环。银杏叶还可通过抑制 JAK2/STAT3 信号通路,以神经保护和抗炎机制控制特应性皮炎的瘙痒。本综述还重点介绍了减少副作用和提高提取物功效的纳米药物策略。类似的策略已成功用于靶向化疗中的抗癌分子和贫血治疗中的铁输送。
{"title":"From traditional medicine to nanomedicine: potential of Ginkgo biloba extracts in treating inflammatory skin diseases","authors":"Itisha Chummun Phul, Andrea Gómez-Llonín and Archana Bhaw-Luximon","doi":"10.1039/D4MD00194J","DOIUrl":"10.1039/D4MD00194J","url":null,"abstract":"<p >The use of plant extracts as a potential cure for various conditions has moved from traditional medicine to evidence-based medicine. Skin diseases have been addressed since time immemorial using plant extracts through observational and traditional knowledge and passed on through generations. With the advent of modern techniques, the molecular mechanisms of action of plant extracts/isolates are being deciphered with more precision, and more nanomedicine-based therapies are being studied to improve their therapeutic efficacy and stability. The leaves and seeds of <em>Ginkgo biloba</em> (<em>G. biloba</em>), an ancient medicinal tree species, have been used in Chinese herbal medicine for thousands of years. <em>G. biloba</em> extracts have been widely studied as a neuroprotective and anti-ischaemic drug for ischaemia-reperfusion injuries in the heart, lungs, brain, kidneys, and other organs. However, the use of <em>G. biloba</em> can be accompanied with side effects and drug interactions. Although, there is now a growing interest for its use in skincare, the mechanisms of action of the extract are not fully understood and vital aspects of <em>G. biloba</em>, such as its neuroprotective and angiogenic properties contributing to the treatment of inflammatory skin diseases and skin ageing, are yet to be investigated. This review critically discusses the mechanisms of action of different constituents of <em>G. biloba</em> extracts linked to their potential interference in the molecular mechanisms underlying the pathogenesis of inflammatory skin diseases. In addition to its ability to act on oxidative stress, <em>G. biloba</em> can regulate angiogenesis through its compounds such as ginkgetin or ginkgolide K, which either inhibit aberrant angiogenesis in eczema/psoriasis or increase microcirculation during skin ageing. <em>G. biloba</em> may also contribute to the control of pruritus in atopic dermatitis <em>via</em> a neuroprotective and anti-inflammatory mechanism by suppressing JAK2/STAT3 signalling pathways. This review also highlights nanomedicine strategies to decrease the side effects and enhance the efficacy of the extracts. Similar strategies have been successfully used for anticancer molecules in targeted chemotherapy and iron delivery in anaemia treatment.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141546768","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}
Jos J. A. G. Kamps, Dong Zhang, Timothy D. W. Claridge and Christopher J. Schofield
Rhodanines have been characterised as ‘difficult to progress’ compounds for medicinal use, though one rhodanine is used for diabetes mellitus treatment and others are in clinical development. Rhodanines can undergo hydrolysis to enethiols which are inhibitors of metallo-enzymes, such as metallo β-lactamases. We report that in DMSO, rhodanine derived enethiols undergo dimerisations to give 1,3-dithiolanes and mixed disulfides. The results highlight the potential of rhodanines and enethiols to give multiple products. They suggest that where possible DMSO should be avoided as a storage solvent for rhodanines/enethiols and highlight the need for further research on biologically relevant enethiols/mixed disulfides.
{"title":"Rhodanine derived enethiols react to give 1,3-dithiolanes and mixed disulfides†","authors":"Jos J. A. G. Kamps, Dong Zhang, Timothy D. W. Claridge and Christopher J. Schofield","doi":"10.1039/D4MD00157E","DOIUrl":"10.1039/D4MD00157E","url":null,"abstract":"<p >Rhodanines have been characterised as ‘difficult to progress’ compounds for medicinal use, though one rhodanine is used for diabetes mellitus treatment and others are in clinical development. Rhodanines can undergo hydrolysis to enethiols which are inhibitors of metallo-enzymes, such as metallo β-lactamases. We report that in DMSO, rhodanine derived enethiols undergo dimerisations to give 1,3-dithiolanes and mixed disulfides. The results highlight the potential of rhodanines and enethiols to give multiple products. They suggest that where possible DMSO should be avoided as a storage solvent for rhodanines/enethiols and highlight the need for further research on biologically relevant enethiols/mixed disulfides.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.rsc.org/en/content/articlepdf/2024/md/d4md00157e?page=search","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141255358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yonghui Sun, Xiao Liu, Qiyu He, Naizhen Zhang, Wei Yan, Xucheng Lv and Yanjie Wang
Maternal embryonic leucine zipper kinase (MELK) is a novel target for the treatment of various kinds of B-cell malignancies. However, the toxicity of inhibitors of MELK has led to clinical failures in cancer treatments. Moreover, inactivation of MELK catalytic domain is insufficient for achieving cancer cell apoptosis. To further confirm the role of MELK in Burkitt lymphoma treatment, we describe herein a structure-guided design of PROTACs targeting MELK. Through design, computer-assisted optimization and SAR studies, we developed the first-in-class MELK-targeting PROTAC MGP-39, which promoted a rapid and potent degradation of MELK in RAMOS cells. Additionally, the newly designed MELK degrader induced significant cell cycle arrest and apoptosis in cancer cells. Notably, compared to MELK inhibitors, MGP-39 has better anti-cancer activity and lower toxicity, indicating the practical role of PROTACs in avoiding the side effects of traditional inhibitors. More importantly, our results show that the use of a PROTAC can be adopted as a general and effective strategy for targeted cancer therapy.
{"title":"Discovery of first-in-class PROTACs targeting maternal embryonic leucine zipper kinase (MELK) for the treatment of Burkitt lymphoma†","authors":"Yonghui Sun, Xiao Liu, Qiyu He, Naizhen Zhang, Wei Yan, Xucheng Lv and Yanjie Wang","doi":"10.1039/D4MD00252K","DOIUrl":"10.1039/D4MD00252K","url":null,"abstract":"<p >Maternal embryonic leucine zipper kinase (MELK) is a novel target for the treatment of various kinds of B-cell malignancies. However, the toxicity of inhibitors of MELK has led to clinical failures in cancer treatments. Moreover, inactivation of MELK catalytic domain is insufficient for achieving cancer cell apoptosis. To further confirm the role of MELK in Burkitt lymphoma treatment, we describe herein a structure-guided design of PROTACs targeting MELK. Through design, computer-assisted optimization and SAR studies, we developed the first-in-class MELK-targeting PROTAC <strong>MGP-39</strong>, which promoted a rapid and potent degradation of MELK in RAMOS cells. Additionally, the newly designed MELK degrader induced significant cell cycle arrest and apoptosis in cancer cells. Notably, compared to MELK inhibitors, <strong>MGP-39</strong> has better anti-cancer activity and lower toxicity, indicating the practical role of PROTACs in avoiding the side effects of traditional inhibitors. More importantly, our results show that the use of a PROTAC can be adopted as a general and effective strategy for targeted cancer therapy.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523126","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}
Yulia Volkova, Alexander Scherbakov, Yaraslau Dzichenka, Alexander Komkov, Fedor Bogdanov, Diana Salnikova, Andrey Dmitrenok, Antos Sachanka, Danila Sorokin and Igor Zavarzin
Estrogen receptor alpha (ERα) is an important target for the discovery of new therapeutic drugs against hormone-dependent breast cancer. A series of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) were synthesized and biologically evaluated as potent ERα inhibitors. Pho-STPYRs showed cytotoxicity against breast cancer cells with IC50 values of 5.9 μM and higher. Pho-STPYRs 33 and 34 [IC50 (MCF7) = 6.5 and 5.9 μM, respectively] were found to block the expression of ERα, the main driver of breast cancer growth, and modulate the ERK, cyclin D1, and CDK4 pathways. Compound 34 showed selectivity, anti-estrogenic potency and high antiproliferative efficacy in combination with the AKT inhibitor. Molecular docking was used to more accurately define the binding mode of lead compounds 33 and 34 to ERα. The selectivity analysis showed that lead compounds 33 and 34 produce no effects on cytochromes P450, including CYP7A1, CYP7B1, CYP17A1, CYP19A1, and CYP21A2. In a word, Pho-STPYRs 33 and 34 are promising ERα inhibitors for the treatment of hormone-dependent breast cancer.
{"title":"Design and synthesis of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) as potent estrogen receptor alpha inhibitors: targeted treatment of hormone-dependent breast cancer cells†","authors":"Yulia Volkova, Alexander Scherbakov, Yaraslau Dzichenka, Alexander Komkov, Fedor Bogdanov, Diana Salnikova, Andrey Dmitrenok, Antos Sachanka, Danila Sorokin and Igor Zavarzin","doi":"10.1039/D4MD00153B","DOIUrl":"10.1039/D4MD00153B","url":null,"abstract":"<p >Estrogen receptor alpha (ERα) is an important target for the discovery of new therapeutic drugs against hormone-dependent breast cancer. A series of phosphoryl-substituted steroidal pyridazines (Pho-STPYRs) were synthesized and biologically evaluated as potent ERα inhibitors. Pho-STPYRs showed cytotoxicity against breast cancer cells with IC<small><sub>50</sub></small> values of 5.9 μM and higher. Pho-STPYRs <strong>33</strong> and <strong>34</strong> [IC<small><sub>50</sub></small> (MCF7) = 6.5 and 5.9 μM, respectively] were found to block the expression of ERα, the main driver of breast cancer growth, and modulate the ERK, cyclin D1, and CDK4 pathways. Compound <strong>34</strong> showed selectivity, anti-estrogenic potency and high antiproliferative efficacy in combination with the AKT inhibitor. Molecular docking was used to more accurately define the binding mode of lead compounds <strong>33</strong> and <strong>34</strong> to ERα. The selectivity analysis showed that lead compounds <strong>33</strong> and <strong>34</strong> produce no effects on cytochromes P450, including CYP7A1, CYP7B1, CYP17A1, CYP19A1, and CYP21A2. In a word, Pho-STPYRs <strong>33</strong> and <strong>34</strong> are promising ERα inhibitors for the treatment of hormone-dependent breast cancer.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141523127","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}
Kenneth Atz, David F. Nippa, Alex T. Müller, Vera Jost, Andrea Anelli, Michael Reutlinger, Christian Kramer, Rainer E. Martin, Uwe Grether, Gisbert Schneider and Georg Wuitschik
Suzuki cross-coupling reactions are considered a valuable tool for constructing carbon–carbon bonds in small molecule drug discovery. However, the synthesis of chemical matter often represents a time-consuming and labour-intensive bottleneck. We demonstrate how machine learning methods trained on high-throughput experimentation (HTE) data can be leveraged to enable fast reaction condition selection for novel coupling partners. We show that the trained models support chemists in determining suitable catalyst-solvent-base combinations for individual transformations including an evaluation of the need for HTE screening. We introduce an algorithm for designing 96-well plates optimized towards reaction yields and discuss the model performance of zero- and few-shot machine learning. The best-performing machine learning model achieved a three-category classification accuracy of 76.3% (±0.2%) and an F1-score for a binary classification of 79.1% (±0.9%). Validation on eight reactions revealed a receiver operating characteristic (ROC) curve (AUC) value of 0.82 (±0.07) for few-shot machine learning. On the other hand, zero-shot machine learning models achieved a mean ROC-AUC value of 0.63 (±0.16). This study positively advocates the application of few-shot machine learning-guided reaction condition selection for HTE campaigns in medicinal chemistry and highlights practical applications as well as challenges associated with zero-shot machine learning.
{"title":"Geometric deep learning-guided Suzuki reaction conditions assessment for applications in medicinal chemistry","authors":"Kenneth Atz, David F. Nippa, Alex T. Müller, Vera Jost, Andrea Anelli, Michael Reutlinger, Christian Kramer, Rainer E. Martin, Uwe Grether, Gisbert Schneider and Georg Wuitschik","doi":"10.1039/D4MD00196F","DOIUrl":"10.1039/D4MD00196F","url":null,"abstract":"<p >Suzuki cross-coupling reactions are considered a valuable tool for constructing carbon–carbon bonds in small molecule drug discovery. However, the synthesis of chemical matter often represents a time-consuming and labour-intensive bottleneck. We demonstrate how machine learning methods trained on high-throughput experimentation (HTE) data can be leveraged to enable fast reaction condition selection for novel coupling partners. We show that the trained models support chemists in determining suitable catalyst-solvent-base combinations for individual transformations including an evaluation of the need for HTE screening. We introduce an algorithm for designing 96-well plates optimized towards reaction yields and discuss the model performance of zero- and few-shot machine learning. The best-performing machine learning model achieved a three-category classification accuracy of 76.3% (±0.2%) and an <em>F</em><small><sub>1</sub></small>-score for a binary classification of 79.1% (±0.9%). Validation on eight reactions revealed a receiver operating characteristic (ROC) curve (AUC) value of 0.82 (±0.07) for few-shot machine learning. On the other hand, zero-shot machine learning models achieved a mean ROC-AUC value of 0.63 (±0.16). This study positively advocates the application of few-shot machine learning-guided reaction condition selection for HTE campaigns in medicinal chemistry and highlights practical applications as well as challenges associated with zero-shot machine learning.</p>","PeriodicalId":21462,"journal":{"name":"RSC medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141546769","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}