Pub Date : 2024-09-25DOI: 10.1016/j.bmcl.2024.129976
Beata Gąsowska-Bajger, Hubert Wojtasek
Inhibition of tyrosinase by gallic acid, epigallocatechin, and epigallocatechin-3-gallate has been recently described in several publications. However, oxidation of these compounds by this enzyme was demonstrated long time ago. Gallic acid also reduced tyrosinase-generated o-quinones. We have shown that epigallocatechin and epigallocatechin-3-gallate are also rapidly oxidized by o-quinones generated from catechols by tyrosinase or by treatment with sodium periodate. Smaller changes of absorbance at 475 nm during oxidation of l-dopa in the presence of gallic acid, epigallocatechin, and epigallocatechin-3-gallate result from reduction of dopaquinone by these compounds. This reaction prevents formation of dopachrome giving an effect of inhibition, which is only apparent. The actual reaction rates measured by oxygen consumption did not decrease in the presence of these compounds. The standard spectrophotometric assay cannot therefore be used to monitor tyrosinase activity with compounds possessing strong reducing properties, particularly flavonoids, because their influence on dopachrome formation does not result from inhibition of this enzyme. Such compounds should be considered antimelanogenic or antibrowning agents.
最近有几篇文章介绍了没食子酸、表没食子儿茶素和表没食子儿茶素-3-没食子酸酯对酪氨酸酶的抑制作用。不过，这些化合物被这种酶氧化的现象很早就被证实了。没食子酸还能减少酪氨酸酶生成的邻醌。我们已经证明，表没食子儿茶素和表没食子儿茶素-3-没食子酸酯也会被酪氨酸酶或高碘酸钠处理儿茶酚生成的邻醌迅速氧化。在存在没食子酸、表没食子儿茶素和表没食子儿茶素-3-没食子酸酯的情况下，在 475 纳米波长处氧化 l 多巴时，吸光度的变化较小，这是因为这些化合物还原了多巴醌。这一反应阻止了多巴醌的形成，从而产生了明显的抑制作用。在这些化合物存在的情况下，通过耗氧量测量的实际反应速率并没有降低。因此，标准的分光光度法不能用来监测具有强还原性的化合物（尤其是类黄酮）的酪氨酸酶活性，因为它们对多巴铬形成的影响并非来自对这种酶的抑制。此类化合物应视为抗黑色素生成剂或抗褐变剂。
{"title":"Epigallocatechin and epigallocatechin-3-gallate are not inhibitors of tyrosinase","authors":"Beata Gąsowska-Bajger, Hubert Wojtasek","doi":"10.1016/j.bmcl.2024.129976","DOIUrl":"10.1016/j.bmcl.2024.129976","url":null,"abstract":"<div><div>Inhibition of tyrosinase by gallic acid, epigallocatechin, and epigallocatechin-3-gallate has been recently described in several publications. However, oxidation of these compounds by this enzyme was demonstrated long time ago. Gallic acid also reduced tyrosinase-generated <em>o</em>-quinones. We have shown that epigallocatechin and epigallocatechin-3-gallate are also rapidly oxidized by <em>o</em>-quinones generated from catechols by tyrosinase or by treatment with sodium periodate. Smaller changes of absorbance at 475 nm during oxidation of <span>l</span>-dopa in the presence of gallic acid, epigallocatechin, and epigallocatechin-3-gallate result from reduction of dopaquinone by these compounds. This reaction prevents formation of dopachrome giving an effect of inhibition, which is only apparent. The actual reaction rates measured by oxygen consumption did not decrease in the presence of these compounds. The standard spectrophotometric assay cannot therefore be used to monitor tyrosinase activity with compounds possessing strong reducing properties, particularly flavonoids, because their influence on dopachrome formation does not result from inhibition of this enzyme. Such compounds should be considered antimelanogenic or antibrowning agents.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129976"},"PeriodicalIF":2.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326377","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}
Carvacrol (CA) is a phenolic monoterpene renowned for its diverse pharmacological benefits, particularly its cardioprotective effects. Concurrently, phenolic acids have also demonstrated promise in mitigating drug-induced cardiotoxicity. Focusing on combating doxorubicin-induced cardiotoxicity (DIC), the research aims to synthesize novel cardioprotective agents by combining CA with 3-hydroxybenzoic acid (3HA). Doxorubicin, an anticancer drug, poses cardiovascular risks as its adverse effect, prompting the exploration of hybrid compounds. Various linker molecules, including alkyl and acyl with different carbon lengths, were investigated to understand their impact on bioactivity. In vitro testing on the DOX-induced H9c2 cell death model revealed the effectiveness of a CA conjugate in preserving cardiomyocyte viability. In silico analysis highlighted favorable drug-like properties and low toxicity of the conjugate. This study sheds light on molecular hybridization’s potential in developing cardioprotective agents, emphasizing CA’s pivotal role in combating DIC.
香芹酚（CA）是一种酚类单萜，因其多种药理作用而闻名，尤其是对心脏的保护作用。同时，酚酸在减轻药物引起的心脏毒性方面也表现出了良好的前景。这项研究以对抗多柔比星诱导的心脏毒性（DIC）为重点，旨在通过将 CA 与 3-hydroxybenzoic acid（3HA）结合，合成新型心脏保护剂。多柔比星是一种抗癌药物，其不良反应对心血管造成危害，这促使人们探索混合化合物。我们研究了各种连接分子，包括不同碳长的烷基和酰基，以了解它们对生物活性的影响。对 DOX 诱导的 H9c2 细胞死亡模型进行的体外测试表明，CA 结合物能有效保持心肌细胞的活力。硅学分析强调了该共轭物具有良好的类药物特性和低毒性。这项研究揭示了分子杂交在开发心脏保护剂方面的潜力，强调了 CA 在抗 DIC 中的关键作用。
{"title":"Carvacrol-conjugated 3-Hydroxybenzoic Acids: Design, Synthesis, cardioprotective potential against doxorubicin-induced Cardiotoxicity, and ADMET study","authors":"Rini Retnosari , Kentaro Oh-hashi , Azizah Ugusman , Satirah Zainalabidin , Jalifah Latip , Natsuhisa Oka","doi":"10.1016/j.bmcl.2024.129973","DOIUrl":"10.1016/j.bmcl.2024.129973","url":null,"abstract":"<div><div>Carvacrol (CA) is a phenolic monoterpene renowned for its diverse pharmacological benefits, particularly its cardioprotective effects. Concurrently, phenolic acids have also demonstrated promise in mitigating drug-induced cardiotoxicity. Focusing on combating doxorubicin-induced cardiotoxicity (DIC), the research aims to synthesize novel cardioprotective agents by combining CA with 3-hydroxybenzoic acid (3HA). Doxorubicin, an anticancer drug, poses cardiovascular risks as its adverse effect, prompting the exploration of hybrid compounds. Various linker molecules, including alkyl and acyl with different carbon lengths, were investigated to understand their impact on bioactivity. <em>In vitro</em> testing on the DOX-induced H9c2 cell death model revealed the effectiveness of a CA conjugate in preserving cardiomyocyte viability. <em>In silico</em> analysis highlighted favorable drug-like properties and low toxicity of the conjugate. This study sheds light on molecular hybridization’s potential in developing cardioprotective agents, emphasizing CA’s pivotal role in combating DIC.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129973"},"PeriodicalIF":2.5,"publicationDate":"2024-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142319443","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}
Pub Date : 2024-09-21DOI: 10.1016/j.bmcl.2024.129972
Yanxin Huang , Linyuan Zhu , Muhammad Zeeshan , Chenyang Jing , Hongji Li , Wen Li
In this work, two series of water-soluble derivatives were designed and synthesized based on the structure of propofol as the lead compound. Furthermore, the anesthetic activities of the synthesized compounds were evaluated in vivo against mice, and the in vitro propofol release rate from five target compounds was determined. The findings of this study have shown that series II compounds which possess the structure feature of propofol + γ-hydroxybutyric acid + α-aminoacetate or γ-aminobutyrate have higher therapeutic index than that of series I compounds which possess the structure feature of propofol + α-aminoacetate or β-aminopropionate. In addition, the rate of propofol released from series II compounds was significantly better than that of series I compounds. Among series II compounds, compound II-20 had a therapeutic index of 5.6 (propofol = 2.7), a duration time of 571 s (propofol = 57 s), and no significant toxicity was observed in vivo, which made it valuable for further development.
本研究以丙泊酚为先导化合物，根据其结构设计并合成了两个系列的水溶性衍生物。此外，还对合成化合物对小鼠的体内麻醉活性进行了评价，并测定了五个目标化合物的体外异丙酚释放率。研究结果表明，具有异丙酚+γ-羟丁酸+α-氨基乙酸或γ-氨基丁酸结构特征的系列 II 化合物比具有异丙酚+α-氨基乙酸或β-氨基丙酸结构特征的系列 I 化合物具有更高的治疗指数。此外，系列 II 化合物释放异丙酚的速率明显优于系列 I 化合物。在系列 II 化合物中，化合物 II-20 的治疗指数为 5.6（异丙酚 = 2.7），持续时间为 571 秒（异丙酚 = 57 秒），且在体内未观察到明显毒性，因此具有进一步开发的价值。
{"title":"Design, synthesis, and activity evaluation of water-soluble propofol derivatives as anesthetic drugs","authors":"Yanxin Huang , Linyuan Zhu , Muhammad Zeeshan , Chenyang Jing , Hongji Li , Wen Li","doi":"10.1016/j.bmcl.2024.129972","DOIUrl":"10.1016/j.bmcl.2024.129972","url":null,"abstract":"<div><div>In this work, two series of water-soluble derivatives were designed and synthesized based on the structure of propofol as the lead compound. Furthermore, the anesthetic activities of the synthesized compounds were evaluated in vivo against mice, and the in vitro propofol release rate from five target compounds was determined. The findings of this study have shown that series II compounds which possess the structure feature of propofol + γ-hydroxybutyric acid + α-aminoacetate or γ-aminobutyrate have higher therapeutic index than that of series I compounds which possess the structure feature of propofol + α-aminoacetate or β-aminopropionate. In addition, the rate of propofol released from series II compounds was significantly better than that of series I compounds. Among series II compounds, compound <strong>II-20</strong> had a therapeutic index of 5.6 (propofol = 2.7), a duration time of 571 s (propofol = 57 s), and no significant toxicity was observed in vivo, which made it valuable for further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129972"},"PeriodicalIF":2.5,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277736","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}
Pub Date : 2024-09-19DOI: 10.1016/j.bmcl.2024.129971
Debasis Das, Lingzhi Xie, Dandan Qiao, Jianhe Jia, Jian Hong
Hepatocellular carcinoma (HCC) is considered as one of the leading causes of death in liver disease patients. Several signal transduction pathways are involved in HCC pathogenesis. Multikinase inhibitors (MKIs) show beneficial effects for HCC and the FDA approved a few MKIs including sorafenib, lenvatinib for HCC treatments. Here, a novel series of phenylacetamide derivatives were designed, synthesized and evaluated as multikinase inhibitors. Several compounds showed nanomolar IC50 values against FLT1, FLT3, FLT4, KDR, PDGFRα, PDGFRβ. The compounds were tested against human hepatocellular carcinoma (HCC), human colon adenocarcinoma and human gastric carcinoma cell lines. With favorable pharmacokinetics profiles, compound 12 and compound 14 were selected for in vivo efficacy studies in Hep3B mice models and demonstrated efficacious than sorafenib.
{"title":"Discovery of novel, orally bioavailable phenylacetamide derivatives as multikinase inhibitors and in vivo efficacy study in hepatocellular carcinoma animal models","authors":"Debasis Das, Lingzhi Xie, Dandan Qiao, Jianhe Jia, Jian Hong","doi":"10.1016/j.bmcl.2024.129971","DOIUrl":"10.1016/j.bmcl.2024.129971","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is considered as one of the leading causes of death in liver disease patients. Several signal transduction pathways are involved in HCC pathogenesis. Multikinase inhibitors (MKIs) show beneficial effects for HCC and the FDA approved a few MKIs including sorafenib, lenvatinib for HCC treatments. Here, a novel series of phenylacetamide derivatives were designed, synthesized and evaluated as multikinase inhibitors. Several compounds showed nanomolar IC<sub>50</sub> values against FLT1, FLT3, FLT4, KDR, PDGFRα, PDGFRβ. The compounds were tested against human hepatocellular carcinoma (HCC), human colon adenocarcinoma and human gastric carcinoma cell lines. With favorable pharmacokinetics profiles, compound <strong>12</strong> and compound <strong>14</strong> were selected for <em>in vivo</em> efficacy studies in Hep3B mice models and demonstrated efficacious than sorafenib.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129971"},"PeriodicalIF":2.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277737","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}
Pub Date : 2024-09-19DOI: 10.1016/j.bmcl.2024.129970
József Levente Petró , Péter Bana , Nikolett Linke , Judit Eszter Szabó , Krisztina Katalin Szalai , Ildikó Kálomista , Csaba Gábor Vass , Gábor Hornyánszky , István Greiner , János Éles
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has a crucial role in cell death and inflammation. A promising approach to develop novel inhibitors of RIPK1 mediated necroptosis is to mix the different binding modes of the known RIPK1 inhibitors into one molecule. Herein we report the synthesis and biological evaluation of novel mixed type inhibitors. Using Eclitasertib as a starting point, and applying our previous, published knowledge regarding cyclic malonamides, we successfully identified a library of active compounds. The active enantiomer of the most balanced and promising compound was subjected to pharmacokinetics and in vivo hypothermia study in mice.
{"title":"Harnessing dual-mode RIPK1 ligands for cross-species anti-necroptosis inhibitor compounds","authors":"József Levente Petró , Péter Bana , Nikolett Linke , Judit Eszter Szabó , Krisztina Katalin Szalai , Ildikó Kálomista , Csaba Gábor Vass , Gábor Hornyánszky , István Greiner , János Éles","doi":"10.1016/j.bmcl.2024.129970","DOIUrl":"10.1016/j.bmcl.2024.129970","url":null,"abstract":"<div><div>Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has a crucial role in cell death and inflammation. A promising approach to develop novel inhibitors of RIPK1 mediated necroptosis is to mix the different binding modes of the known RIPK1 inhibitors into one molecule. Herein we report the synthesis and biological evaluation of novel mixed type inhibitors. Using Eclitasertib as a starting point, and applying our previous, published knowledge regarding cyclic malonamides, we successfully identified a library of active compounds. The active enantiomer of the most balanced and promising compound was subjected to pharmacokinetics and <em>in vivo</em> hypothermia study in mice.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129970"},"PeriodicalIF":2.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277738","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}
Pub Date : 2024-09-18DOI: 10.1016/j.bmcl.2024.129969
Dung Tien Nguyen , Thuong Hanh Ngo , Mai Thanh Tran , Hao Thi Thanh Nguyen , Hien Thanh Ho , Dat Van Nguyen , Tinh Thi Nguyen , Khang Duc Ly , Thao Thi Nguyen , Tam Thi Vuong , Hung-Vu Tran
While artemisinin and its derivatives, including 11-azaartemisinin-based compounds, have shown promising anticancer activity, the integration of halogens into aromatic structures can amplify drug potency, metabolic stability, and selectivity. Herein, we present the synthesis of new novel 11-azaartemisinin derivatives bearing halogenated aromatic moieties connected via 1,2,3‐triazole bridges and evaluate their anticancer activities against three human tumor cell lines: epidermoid carcinoma (KB), hepatocellular carcinoma (HepG2), and human lung adenocarcinoma (A549). Among the synthesized compounds, six of them (8c-h) displayed good to excellent antiproliferative activity in the low micromolar range across all three human cancer cell lines. In general, the m-bromide (8c) and m-iodide (8d) compounds exhibited superior anticancer activities compared to their o- and p-analogs, as well as the m-chloride and m-fluoride compounds. The most promising m-Br compound (8c) displayed 50 % inhibition of KB, HepG2, and A549 cell growth at concentrations of 7.7, 42.5, and 15.5 μM, respectively. Notably, the m-Br compound (8c) exhibited approximately 32-, 6-, and 16-fold lower activity in normal cells (Hek293) compared to KB, HepG2, and A549 tumor cells, respectively, indicating a significant tumor-selectivity.
{"title":"11-Azaartemisinin derivatives bearing halogenated aromatic moieties: Potent anticancer agents with high tumor selectivity","authors":"Dung Tien Nguyen , Thuong Hanh Ngo , Mai Thanh Tran , Hao Thi Thanh Nguyen , Hien Thanh Ho , Dat Van Nguyen , Tinh Thi Nguyen , Khang Duc Ly , Thao Thi Nguyen , Tam Thi Vuong , Hung-Vu Tran","doi":"10.1016/j.bmcl.2024.129969","DOIUrl":"10.1016/j.bmcl.2024.129969","url":null,"abstract":"<div><p>While artemisinin and its derivatives, including 11-azaartemisinin-based compounds, have shown promising anticancer activity, the integration of halogens into aromatic structures can amplify drug potency, metabolic stability, and selectivity. Herein, we present the synthesis of new novel 11-azaartemisinin derivatives bearing halogenated aromatic moieties connected via 1,2,3‐triazole bridges and evaluate their anticancer activities against three human tumor cell lines: epidermoid carcinoma (KB), hepatocellular carcinoma (HepG2), and human lung adenocarcinoma (A549). Among the synthesized compounds, six of them (<strong>8c-h</strong>) displayed good to excellent antiproliferative activity in the low micromolar range across all three human cancer cell lines. In general, the <em>m</em>-bromide (<strong>8c</strong>) and <em>m</em>-iodide (<strong>8d</strong>) compounds exhibited superior anticancer activities compared to their <em>o</em>- and <em>p</em>-analogs, as well as the <em>m</em>-chloride and <em>m</em>-fluoride compounds. The most promising <em>m</em>-Br compound (<strong>8c</strong>) displayed 50 % inhibition of KB, HepG2, and A549 cell growth at concentrations of 7.7, 42.5, and 15.5 μM, respectively. Notably, the <em>m</em>-Br compound (<strong>8c</strong>) exhibited approximately 32-, 6-, and 16-fold lower activity in normal cells (Hek293) compared to KB, HepG2, and A549 tumor cells, respectively, indicating a significant tumor-selectivity.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129969"},"PeriodicalIF":2.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271374","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}
Despite the recent progresses in therapeutic and diagnostic methods, there is still a significantly high rate of mortality among cancer patients. One of the main reasons for the high mortality rate in cancer patients is late diagnosis, which leads to the failure of therapeutic strategies. Therefore, investigation of cancer biology can lead to the introduction of early diagnostic markers in these patients. MicroRNAs (miRNAs) play an important role in regulation of cellular processes associated with tumor progression. Due to the high stability of miRNAs in body fluids, these factors can be considered as the non-invasive tumor markers. Deregulation of miR-382 has been widely reported in different cancers. Therefore, in this review, we investigated the role of miR-382 during tumor development. It has shown that miR-382 has mainly a tumor suppressive, which inhibits the growth of tumor cells through the regulation of signaling pathways, RNA-binding proteins, and transcription factors. Therefore, miR-382 can be suggested as a diagnostic and therapeutic marker in cancer patients.
{"title":"MicroRNA-382 as a tumor suppressor during tumor progression","authors":"Yalda Samsami , Iman Akhlaghipour , Negin Taghehchian , Mahsa Palizkaran Yazdi , Saba Farrokhi , Hamid Reza Rahimi , Meysam Moghbeli","doi":"10.1016/j.bmcl.2024.129967","DOIUrl":"10.1016/j.bmcl.2024.129967","url":null,"abstract":"<div><p>Despite the recent progresses in therapeutic and diagnostic methods, there is still a significantly high rate of mortality among cancer patients. One of the main reasons for the high mortality rate in cancer patients is late diagnosis, which leads to the failure of therapeutic strategies. Therefore, investigation of cancer biology can lead to the introduction of early diagnostic markers in these patients. MicroRNAs (miRNAs) play an important role in regulation of cellular processes associated with tumor progression. Due to the high stability of miRNAs in body fluids, these factors can be considered as the non-invasive tumor markers. Deregulation of miR-382 has been widely reported in different cancers. Therefore, in this review, we investigated the role of miR-382 during tumor development. It has shown that miR-382 has mainly a tumor suppressive, which inhibits the growth of tumor cells through the regulation of signaling pathways, RNA-binding proteins, and transcription factors. Therefore, miR-382 can be suggested as a diagnostic and therapeutic marker in cancer patients.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129967"},"PeriodicalIF":2.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242888","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}
Pub Date : 2024-09-16DOI: 10.1016/j.bmcl.2024.129960
K.T Ashitha , S. Lakshmi , S. Anjali , Ajay Krishna , Ved Prakash , Sadasivam Anbumani , S. Priya , Sasidhar B. Somappa
We report the design, synthesis, and validation of carboxamide-based pyrazole and isoxazole conjugates with a multifaceted activity against Breast Cancer Cell Line MDA-MB-231. The study established that amongst the series, N-(3,5-bis(trifluoromethyl)benzyl)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazole-5-carboxamide (5g) exhibits the highest potency in inhibiting Breast Cancer Cell Line MDA-MB-231 with an IC50 value of 15.08 ± 0.04 µM. The MDA‐MB‐231 cells, upon treatment with compound 5g, exhibited characteristic apoptotic specific activities such as nuclear fragmentation, phosphatidylserine translocation to the outer plasma membrane, release of lactate dehydrogenase (LDH), and upregulation of caspase 3 and caspase 9 activities. Also, the modulation of pro and antiapoptotic proteins in 5g treated MDA-MB-231 cells was revealed by membrane array analysis. More importantly, the combination of paclitaxel and compound 5g has exhibited improved activity by several folds via their synergistic effects.
{"title":"Design and discovery of carboxamide-based pyrazole conjugates with multifaceted potential against Triple-Negative Breast cancer MDA-MB-231 cells","authors":"K.T Ashitha , S. Lakshmi , S. Anjali , Ajay Krishna , Ved Prakash , Sadasivam Anbumani , S. Priya , Sasidhar B. Somappa","doi":"10.1016/j.bmcl.2024.129960","DOIUrl":"10.1016/j.bmcl.2024.129960","url":null,"abstract":"<div><p>We report the design, synthesis, and validation of carboxamide-based pyrazole and isoxazole conjugates with a multifaceted activity against Breast Cancer Cell Line MDA-MB-231. The study established that amongst the series, <em>N</em>-(3,5-bis(trifluoromethyl)benzyl)-3-(3,4,5-trimethoxyphenyl)-1<em>H</em>-pyrazole-5-carboxamide (<strong>5</strong><strong>g</strong>) exhibits the highest potency in inhibiting Breast Cancer Cell Line MDA-MB-231 with an IC<sub>50</sub> value of 15.08 ± 0.04 µM. The MDA‐MB‐231 cells, upon treatment with compound <strong>5</strong><strong>g</strong>, exhibited characteristic apoptotic specific activities such as nuclear fragmentation, phosphatidylserine translocation to the outer plasma membrane, release of lactate dehydrogenase (LDH), and upregulation of caspase 3 and caspase 9 activities. Also, the modulation of pro and antiapoptotic proteins in <strong>5</strong><strong>g</strong> treated MDA-MB-231 cells was revealed by membrane array analysis. More importantly, the combination of paclitaxel and compound <strong>5</strong><strong>g</strong> has exhibited improved activity by several folds via their synergistic effects.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129960"},"PeriodicalIF":2.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242894","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}
Pub Date : 2024-09-16DOI: 10.1016/j.bmcl.2024.129968
Mingwei Fu , Yuanjiang Wang , Min Ge , Chunchen Hu , Ya Xiao , Yan Ma , Shaohua Gou
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that plays an important role in cancer cells biology. However, present EZH2 inhibitors in clinic have not achieved satisfactory efficacy. Herein, a number of EZH2-targeted PROTAC compounds were designed and synthesized by selecting different linkers, using Tazemetostat as the protein of interest (POI) portion of PROTAC molecules, hoping to improve the defects of existing EZH2 inhibitors effectively. Among all the target compounds, ZJ-20 showed the best performance with an IC50 value of 5.0 nM against MINO cells, good pharmacokinetics parameters and a limited acceptable oral bioavailability. Significantly, ZJ-20 could achieve degradation of the entire PRC2 complex by targeting EZH2, which can serve as a lead compound for further study.
{"title":"Chemically induced degradation of PRC2 complex by EZH2-Targeted PROTACs via a Ubiquitin-Proteasome pathway","authors":"Mingwei Fu , Yuanjiang Wang , Min Ge , Chunchen Hu , Ya Xiao , Yan Ma , Shaohua Gou","doi":"10.1016/j.bmcl.2024.129968","DOIUrl":"10.1016/j.bmcl.2024.129968","url":null,"abstract":"<div><p>Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that plays an important role in cancer cells biology. However, present EZH2 inhibitors in clinic have not achieved satisfactory efficacy. Herein, a number of EZH2-targeted PROTAC compounds were designed and synthesized by selecting different linkers, using Tazemetostat as the protein of interest (POI) portion of PROTAC molecules, hoping to improve the defects of existing EZH2 inhibitors effectively. Among all the target compounds, <strong>ZJ-20</strong> showed the best performance with an IC<sub>50</sub> value of 5.0 nM against MINO cells, good pharmacokinetics parameters and a limited acceptable oral bioavailability. Significantly, <strong>ZJ-20</strong> could achieve degradation of the entire PRC2 complex by targeting EZH2, which can serve as a lead compound for further study.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129968"},"PeriodicalIF":2.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242891","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}
Pub Date : 2024-09-14DOI: 10.1016/j.bmcl.2024.129963
Rohitesh Kumar , Rhone K. Akee , Lucero Martínez-Fructuoso , Vitor F. Freire , Christopher C. Thornburg , Jason R. Evans , Brian D. Peyser , Susan Ensel , Barry R. O’Keefe , Tanja Grkovic
Two cyclic peroxides, plakortides V (1) and W (2) were purified from the organic extract of the sponge Plakinastrella sp. Their planar structures were established based on extensive NMR and MS analysis and the absolute configurations of the three stereogenic centers of the 1,2-dioxane moiety were determined to be 3R,4S,6S by comparative analysis of the 1H NMR spectral data of the R- or S-MTPA Mosher esters. Compounds 1 and 2 exhibited potent cytotoxic activity against LOX IMVI (melanoma), UO-31 (renal), and HL-60 (TB) (leukemia) cell lines in the NCI-60 cytotoxicity assay.
{"title":"Structure elucidation, absolute configuration, and biological evaluation of cyclic peroxides from the sponge Plakinastrella sp.","authors":"Rohitesh Kumar , Rhone K. Akee , Lucero Martínez-Fructuoso , Vitor F. Freire , Christopher C. Thornburg , Jason R. Evans , Brian D. Peyser , Susan Ensel , Barry R. O’Keefe , Tanja Grkovic","doi":"10.1016/j.bmcl.2024.129963","DOIUrl":"10.1016/j.bmcl.2024.129963","url":null,"abstract":"<div><p>Two cyclic peroxides, plakortides V (<strong>1</strong>) and W (<strong>2</strong>) were purified from the organic extract of the sponge <em>Plakinastrella</em> sp. Their planar structures were established based on extensive NMR and MS analysis and the absolute configurations of the three stereogenic centers of the 1,2-dioxane moiety were determined to be 3<em>R</em>,4<em>S</em>,6<em>S</em> by comparative analysis of the <sup>1</sup>H NMR spectral data of the <em>R</em>- or <em>S</em>-MTPA Mosher esters<em>.</em> Compounds <strong>1</strong> and <strong>2</strong> exhibited potent cytotoxic activity against LOX IMVI (melanoma), UO-31 (renal), and HL-60 (TB) (leukemia) cell lines in the NCI-60 cytotoxicity assay.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129963"},"PeriodicalIF":2.5,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242890","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}
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