Bioorganic & Medicinal Chemistry Letters最新文献_第8页

Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold 基于一个支架发现可逆的共价 TEAD 1 选择性抑制剂 MSC-1254 和 MSC-5046。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-05 DOI: 10.1016/j.bmcl.2024.129981

Emma Carswell , Timo Heinrich , Carl Petersson , Jakub Gunera , Sakshi Garg , Daniel Schwarz , Sarah Schlesiger , Frank Fischer , Thomas Eichhorn , Mathew Calder , Geoffrey Smith , Ellen MacDonald , Hollie Wilson , Katherine Hazel , Elisabeth Trivier , Rebecca Broome , Alexander Balsiger , Sameer Sirohi , Djordje Musil , Filipe Freire , Dirk Wienke

{"title":"Discovery of reversible and covalent TEAD 1 selective inhibitors MSC-1254 and MSC-5046 based on one scaffold","authors":"Emma Carswell , Timo Heinrich , Carl Petersson , Jakub Gunera , Sakshi Garg , Daniel Schwarz , Sarah Schlesiger , Frank Fischer , Thomas Eichhorn , Mathew Calder , Geoffrey Smith , Ellen MacDonald , Hollie Wilson , Katherine Hazel , Elisabeth Trivier , Rebecca Broome , Alexander Balsiger , Sameer Sirohi , Djordje Musil , Filipe Freire , Dirk Wienke","doi":"10.1016/j.bmcl.2024.129981","DOIUrl":"10.1016/j.bmcl.2024.129981","url":null,"abstract":"<div><div>The Transcriptional Enhanced Associated Domain (TEAD) family of transcription factors are key components of the Hippo signalling family which play a crucial role in the regulation of cell proliferation, differentiation and apoptosis. The identification of inhibitors of the TEAD transcription factors are an attractive strategy for the development of novel anticancer therapies. A HTS campaign identified hit <strong>1</strong>, which was optimised using structure-based drug design, to deliver potent TEAD1 selective inhibitors with both a reversible and covalent mode of inhibition. The preference for TEAD1 could be rationalised by steric differences observed in the lower pocket of the palmitoylation-site between subtypes, with TEAD1 having the largest available volume to accommodate substitution in this region.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 129981"},"PeriodicalIF":2.5,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379692","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

Modified (2′-deoxy)adenosines activate autophagy primarily through AMPK/ULK1-dependent pathway 修饰的（2'-脱氧）腺苷主要通过 AMPK/ULK1 依赖性途径激活自噬。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-10-01 DOI: 10.1016/j.bmcl.2024.129980

Ekaterina A. Guseva , Polina N. Kamzeeva , Sofya Y. Sokolskaya , Georgy K. Slushko , Evgeny S. Belyaev , Boris P. Myasnikov , Julia A. Golubeva , Vera A. Alferova , Petr V. Sergiev , Andrey V. Aralov

{"title":"Modified (2′-deoxy)adenosines activate autophagy primarily through AMPK/ULK1-dependent pathway","authors":"Ekaterina A. Guseva , Polina N. Kamzeeva , Sofya Y. Sokolskaya , Georgy K. Slushko , Evgeny S. Belyaev , Boris P. Myasnikov , Julia A. Golubeva , Vera A. Alferova , Petr V. Sergiev , Andrey V. Aralov","doi":"10.1016/j.bmcl.2024.129980","DOIUrl":"10.1016/j.bmcl.2024.129980","url":null,"abstract":"<div><div>Autophagy is a conserved self-digestion process, which governs regulated degradation of cellular components. Autophagy is upregulated upon energy shortage sensed by AMP-dependent protein kinase (AMPK). Autophagy activators might be contemplated as therapies for metabolic neurodegenerative diseases and obesity, as well as cancer, considering tumor-suppressive functions of autophagy. Among them, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), a nucleoside precursor of the active phosphorylated AMP analog, is the most commonly used pharmacological modulator of AMPK activity, despite its multiple reported “off-target” effects. Here, we assessed the autophagy/mitophagy activation ability of a small set of (2′-deoxy)adenosine derivatives and analogs using a fluorescent reporter assay and immunoblotting analysis. The first two leader compounds, 7,8-dihydro-8-oxo-2′-deoxyadenosine and -adenosine, are nucleoside forms of major oxidative DNA and RNA lesions. The third, a derivative of inactive <em>N</em><sup>6</sup>-methyladenosine with a metabolizable phosphate-masking group, exhibited the highest activity in the series. These compounds primarily contributed to the activation of AMPK and outperformed AICAr; however, retaining the activity in knockout cell lines for <em>AMPK (ΔAMPK)</em> and its upstream regulator <em>SIRT1 (ΔSIRT1)</em> suggests that AMPK is not a main cellular target. Overall, we confirmed the prospects of searching for autophagy activators among (2′-deoxy)adenosine derivatives and demonstrated the applicability of the phosphate-masking strategy for increasing their efficacy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129980"},"PeriodicalIF":2.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142370468","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

Design, synthesis and antitumor activity of novel 4-oxobutanamide derivatives 新型 4-氧代丁酰胺衍生物的设计、合成和抗肿瘤活性。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-26 DOI: 10.1016/j.bmcl.2024.129978

Caiju Wu , Jingliang He , Hanxue Li , Siyi Zhang , Siqi Wang , Xue Dong , Lili Yan , Ruiying Wang , Jiayin Chen , Zhiyu Liu , Luyao Zhang , Zirui Jiang , Xiaoshuo Wang , Yifei Gu , Jing Ji

{"title":"Design, synthesis and antitumor activity of novel 4-oxobutanamide derivatives","authors":"Caiju Wu , Jingliang He , Hanxue Li , Siyi Zhang , Siqi Wang , Xue Dong , Lili Yan , Ruiying Wang , Jiayin Chen , Zhiyu Liu , Luyao Zhang , Zirui Jiang , Xiaoshuo Wang , Yifei Gu , Jing Ji","doi":"10.1016/j.bmcl.2024.129978","DOIUrl":"10.1016/j.bmcl.2024.129978","url":null,"abstract":"<div><div>To find highly effective and low-toxicity antitumor drugs to overcome the challenge of cancer, we designed and synthesized a series of novel 4-oxobutanamide derivatives using the principle of molecular hybridization and tested the antiproliferative ability of the title compounds against human cervical carcinoma cells (HeLa), human breast carcinoma cells (MDA-MB-231) and human kidney carcinoma cells (A498). Among them, <em>N</em><sup>1</sup>-(4-methoxybenzyl)-<em>N</em><sup>4</sup>-(4-methoxyphenyl)-<em>N</em><sup>1</sup>-(3,4,5-trimethoxyphenyl) succinimide <strong>DN4</strong> (IC<sub>50</sub> = 1.94 µM) showed the best proliferation activity on A498, superior to the positive control paclitaxel (IC<sub>50</sub> = 8.81 µM) and colchicine (IC<sub>50</sub> = 7.17 µM). Compound <strong>DN4</strong> not only inhibited the proliferation, adhesion and invasion of A498, but also inhibited angiogenesis and tumor growth in a dose-dependent manner in the xenograft model of A498 cells. In addition, we also predicted the physicochemical properties and toxicity (ADMET) of these derivatives, and the results suggested that these derivatives may have the absorption, distribution, metabolism, excretion, and toxicity properties of drug candidates. Thus, compound <strong>DN4</strong> may be a promising drug candidate for the treatment of cancer.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129978"},"PeriodicalIF":2.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338110","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

Design and Biophysical Characterization of Second-Generation cyclic peptide LAG-3 inhibitors for cancer immunotherapy 用于癌症免疫疗法的第二代环肽 LAG-3 抑制剂的设计与生物物理特性分析

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-26 DOI: 10.1016/j.bmcl.2024.129979

Laura Calvo-Barreiro , Longfei Zhang , Yasir Ali , Ashfaq Ur Rehman , Moustafa Gabr

{"title":"Design and Biophysical Characterization of Second-Generation cyclic peptide LAG-3 inhibitors for cancer immunotherapy","authors":"Laura Calvo-Barreiro , Longfei Zhang , Yasir Ali , Ashfaq Ur Rehman , Moustafa Gabr","doi":"10.1016/j.bmcl.2024.129979","DOIUrl":"10.1016/j.bmcl.2024.129979","url":null,"abstract":"<div><div>Lymphocyte activation gene 3 (LAG-3) is an inhibitory immune checkpoint crucial for suppressing the immune response against cancer. Blocking LAG-3 interactions enables T cells to recover their cytotoxic capabilities and diminishes the immunosuppressive effects of regulatory T cells. A cyclic peptide (Cys-Val-Pro-Met-Thr-Tyr-Arg-Ala-Cys, disulfide bridge: 1–9) was recently reported as a LAG-3 inhibitor. Based on this peptide, we designed 19 derivatives by substituting tyrosine residue to maximize LAG-3 inhibition. Screening via TR-FRET assay identified 8 outperforming derivatives, with cyclic peptides 12 [Tyr6(L-3-CN-Phe)], 13 [Tyr6(L-4-NH<sub>2</sub>-Phe)], and 17 [Tyr6(L-3,5-DiF-Phe)] as top candidates. Cyclic peptide 12 exhibited the highest inhibition (IC<sub>50</sub> = 4.45 ± 1.36 µM). MST analysis showed cyclic peptides 12 and 13 bound LAG-3 with <em>K</em><sub>D</sub> values of 2.66 ± 2.06 µM and 1.81 ± 1.42 µM, respectively, surpassing the original peptide (9.94 ± 4.13 µM). Docking simulations revealed that cyclic peptide 12 exhibited significantly enhanced binding, with a docking score of −7.236 kcal/mol, outperforming the original peptide (−5.236 kcal/mol) and cyclic peptide 5 (L-4-CN-Phe) (−5.131 kcal/mol). A per-residue decomposition of the interaction energy indicated that the 3-cyano group in cyclic peptide 12 contributes to a more favorable conformation, yielding an interaction energy of −9.22 kcal/mol with Phe443 of MHC-II, compared to −6.03 kcal/mol and −5.619 kcal/mol for cyclic peptides 0 and 5, respectively. Despite promising <em>in vitro</em> results, cyclic peptide 12 failed to inhibit tumor growth <em>in vivo</em>, underscoring the importance of dual immunotherapies targeting several immune checkpoints to achieve anti-tumor efficacy.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129979"},"PeriodicalIF":2.5,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326379","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

Bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydroptein pyrophosphokinase: Toward cell permeability 6-hydroxymethyl-7,8-dihydroptein pyrophosphokinase 的双底物抑制剂：细胞渗透性。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-25 DOI: 10.1016/j.bmcl.2024.129977

Genbin Shi , Gary X. Shaw , Xinhua Ji

{"title":"Bisubstrate inhibitors of 6-hydroxymethyl-7,8-dihydroptein pyrophosphokinase: Toward cell permeability","authors":"Genbin Shi , Gary X. Shaw , Xinhua Ji","doi":"10.1016/j.bmcl.2024.129977","DOIUrl":"10.1016/j.bmcl.2024.129977","url":null,"abstract":"<div><div>6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) is a key enzyme in the folate biosynthesis pathway. It catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP). HPPK is essential for microorganisms but is absent in mammals. Yet, it is not the target of any existing antibiotics. Hence, this enzyme is an attractive target for developing novel antimicrobial agents. A wealth of structural and mechanistic information has provided solid basis for structure-based design of HPPK inhibitors. Our bisubstrate inhibitors were initially created by linking 6-hydroxymethylpterin to adenosine through 2, 3, or 4 phosphate groups (HP<sub>n</sub>A, n = 2, 3, or 4), among which HP<sub>4</sub>A exhibited the highest binding affinity (K<sub>d</sub> = 0.47 ± 0.04 μM). Further development was carried out based on high-resolution structures of HPPK in complex with HP<sub>4</sub>A. Replacing the phosphate bridge with a piperidine linked thioether eliminated multiple negative charges of the bridge. Substituting the pterin moiety with 7,7-dimethyl-7,8-dihydropterin improved the binding affinity. Arming the piperidine ring with a carboxyl group and oxidizing the thioether further enhanced the potency, resulting in a druglike inhibitor of HPPK (K<sub>d</sub> = 0.047 ± 0.007 μM). None of these inhibitors, however, exhibits bacterial cell permeability. It is most likely due to the lack of active folate transporters in bacteria. Replacing the pterin moiety with a 7-deazagaunine moiety, we have obtained a novel bisubstrate inhibitor (HP-101) showing observable cell permeability toward a Gram-positive bacterium. Here, we report the in vitro activity of HP-101 and its structure in complex with HPPK, providing a framework for structure-based further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129977"},"PeriodicalIF":2.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338109","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 biological evaluation of ferrostatin-based diamide derivatives as new ferroptosis inhibitors 铁锈素类二酰胺衍生物的合成和生物学评价，作为新的铁锈素抑制剂。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-25 DOI: 10.1016/j.bmcl.2024.129974

Lei-Yin Zheng , Nai-Yu Zhang , Hui Zheng , Kai-Ming Wang , Juan Zhang , Ning Meng , Cheng-Shi Jiang

{"title":"Synthesis and biological evaluation of ferrostatin-based diamide derivatives as new ferroptosis inhibitors","authors":"Lei-Yin Zheng , Nai-Yu Zhang , Hui Zheng , Kai-Ming Wang , Juan Zhang , Ning Meng , Cheng-Shi Jiang","doi":"10.1016/j.bmcl.2024.129974","DOIUrl":"10.1016/j.bmcl.2024.129974","url":null,"abstract":"<div><div>Ferroptosis, a distinct type of cell death caused by iron and lipid peroxidation, has been associated with several diseases, including cardiovascular disorders. Ferrostatin-1 (Fer-1) is a known ferroptosis inhibitor, but its clinical application is limited by low efficacy and stability. In the present study, a series of Fer-1-based diamide derivatives was synthesized and evaluated to enhance ferroptosis inhibition and <em>in vitro</em> metabolic stability. The synthesized compounds were tested for their protective effects against Erastin-induced injury in human vascular endothelial cells (HUVECs). Among the derivatives, compound <strong>36</strong> exhibited the most potent anti-ferroptosis activity with an EC<sub>50</sub> value of 0.58 ± 0.02 µM. Remarkably, compound <strong>36</strong> also demonstrated superior stability in both microsomal (human and mouse) and mouse plasma assays. These findings indicated ferroptosis inhibitor <strong>36</strong> as a promising hit for further developing potential therapeutic drug candidates in cardiovascular diseases.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129974"},"PeriodicalIF":2.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142338111","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

AANAT kinetics of CoASH-targeted electrophiles of tryptamine and related analogs 以 CoASH 为靶标的色胺及相关类似物亲电体的 AANAT 动力学

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-25 DOI: 10.1016/j.bmcl.2024.129975

Nicole Wandrey , Luke Hamilton , Jake Boley , Alexis Haynes , Makenna Redinger , Mackinzi Hill , Mackenzie Hagemeister , Philip A. Cole , Michael A. Moxley , Allen A. Thomas

{"title":"AANAT kinetics of CoASH-targeted electrophiles of tryptamine and related analogs","authors":"Nicole Wandrey , Luke Hamilton , Jake Boley , Alexis Haynes , Makenna Redinger , Mackinzi Hill , Mackenzie Hagemeister , Philip A. Cole , Michael A. Moxley , Allen A. Thomas","doi":"10.1016/j.bmcl.2024.129975","DOIUrl":"10.1016/j.bmcl.2024.129975","url":null,"abstract":"<div><div>Arylalkylamine <em>N</em>-acetyltransferase (AANAT) catalyzes the rate-limiting step in melatonin synthesis and is a potential target for disorders involving melatonin overproduction, such as seasonal affective disorder. Previously described AANAT inhibitor bromoacetyltryptamine (BAT) and benzothiophenes analogs were reported to react with CoASH to form potent bisubstrate inhibitors through AANAT’s alkyltransferase function, which is secondary to its role as an acetyltransferase. We replaced the bromoacetyl group in BAT with various Michael acceptors to mitigate possible off-target activity of its bromoacetyl group. Additionally, we modified the length of the carbon linker between the Michael acceptor and indole bicycle of tryptamine to determine its effect on potency. An AANAT enzymatic assay showed a two-carbon linker present in BAT was optimal, while none of the new warheads had activity. Kinetic analysis indicated that these Michael acceptors reacted with CoASH much slower than BAT and not within the timeframe of our enzymatic assay. Additionally, we confirmed earlier reports that the acetyltransferase function of AANAT follows an ordered bi bi mechanism in which AcCoA binds before serotonin. In contrast, BAT’s alkyltransferase kinetics revealed a bi uni mechanism in which BAT binds to AANAT before CoASH. Our model combines both functions of AANAT into one kinetic mechanism.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129975"},"PeriodicalIF":2.5,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326378","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

Epigallocatechin and epigallocatechin-3-gallate are not inhibitors of tyrosinase 表没食子儿茶素和表没食子儿茶素-3-棓酸盐不是酪氨酸酶的抑制剂

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-25 DOI: 10.1016/j.bmcl.2024.129976

Beata Gąsowska-Bajger, Hubert Wojtasek

{"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}

引用次数: 0

Carvacrol-conjugated 3-Hydroxybenzoic Acids: Design, Synthesis, cardioprotective potential against doxorubicin-induced Cardiotoxicity, and ADMET study 香芹酚共轭 3-羟基苯甲酸：设计、合成、针对多柔比星诱导的心脏毒性的心脏保护潜力以及 ADMET 研究

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-22 DOI: 10.1016/j.bmcl.2024.129973

Rini Retnosari , Kentaro Oh-hashi , Azizah Ugusman , Satirah Zainalabidin , Jalifah Latip , Natsuhisa Oka

{"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}

引用次数: 0

Design, synthesis, and activity evaluation of water-soluble propofol derivatives as anesthetic drugs 作为麻醉药物的水溶性异丙酚衍生物的设计、合成和活性评估。

IF 2.5 4区医学

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-21 DOI: 10.1016/j.bmcl.2024.129972

Yanxin Huang , Linyuan Zhu , Muhammad Zeeshan , Chenyang Jing , Hongji Li , Wen Li

{"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}

引用次数: 0