Pub Date : 2024-10-01DOI: 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
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 N6-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 AMPK (ΔAMPK) and its upstream regulator SIRT1 (ΔSIRT1) 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.
{"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":"https://doi.org/10.1016/j.bmcl.2024.129980","url":null,"abstract":"<p><p>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 N<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 AMPK (ΔAMPK) and its upstream regulator SIRT1 (ΔSIRT1) 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.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"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}
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, N1-(4-methoxybenzyl)-N4-(4-methoxyphenyl)-N1-(3,4,5-trimethoxyphenyl) succinimide DN4 (IC50 = 1.94 µM) showed the best proliferation activity on A498, superior to the positive control paclitaxel (IC50 = 8.81 µM) and colchicine (IC50 = 7.17 µM). Compound DN4 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 DN4 may be a promising drug candidate for the treatment of cancer.
{"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":"<p><p>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, N<sup>1</sup>-(4-methoxybenzyl)-N<sup>4</sup>-(4-methoxyphenyl)-N<sup>1</sup>-(3,4,5-trimethoxyphenyl) succinimide DN4 (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 DN4 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 DN4 may be a promising drug candidate for the treatment of cancer.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"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}
Pub Date : 2024-09-26DOI: 10.1016/j.bmcl.2024.129979
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-NH2-Phe)], and 17 [Tyr6(L-3,5-DiF-Phe)] as top candidates. Cyclic peptide 12 exhibited the highest inhibition (IC50 = 4.45 ± 1.36 µM). MST analysis showed cyclic peptides 12 and 13 bound LAG-3 with KD 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 in vitro results, cyclic peptide 12 failed to inhibit tumor growth in vivo, underscoring the importance of dual immunotherapies targeting several immune checkpoints to achieve anti-tumor efficacy.
{"title":"Design and Biophysical Characterization of Second-Generation cyclic peptide LAG-3 inhibitors for cancer immunotherapy","authors":"","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":null,"pages":null},"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}
Pub Date : 2024-09-25DOI: 10.1016/j.bmcl.2024.129977
Genbin Shi, Gary X Shaw, Xinhua Ji
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 (HPnA, n = 2, 3, or 4), among which HP4A exhibited the highest binding affinity (Kd = 0.47 ± 0.04 μM). Further development was carried out based on high-resolution structures of HPPK in complex with HP4A. 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 (Kd = 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.
{"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":"https://doi.org/10.1016/j.bmcl.2024.129977","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"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}
Pub Date : 2024-09-25DOI: 10.1016/j.bmcl.2024.129975
Arylalkylamine N-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.
{"title":"AANAT kinetics of CoASH-targeted electrophiles of tryptamine and related analogs","authors":"","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":null,"pages":null},"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}
Pub Date : 2024-09-25DOI: 10.1016/j.bmcl.2024.129974
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 in vitro 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 36 exhibited the most potent anti-ferroptosis activity with an EC50 value of 0.58 ± 0.02 µM. Remarkably, compound 36 also demonstrated superior stability in both microsomal (human and mouse) and mouse plasma assays. These findings indicated ferroptosis inhibitor 36 as a promising hit for further developing potential therapeutic drug candidates in cardiovascular diseases.
{"title":"Synthesis and biological evaluation of ferrostatin-based diamide derivatives as new ferroptosis inhibitors","authors":"","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":null,"pages":null},"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}
Pub Date : 2024-09-25DOI: 10.1016/j.bmcl.2024.129976
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":"","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":null,"pages":null},"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}
Pub Date : 2024-09-22DOI: 10.1016/j.bmcl.2024.129973
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。
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Pub Date : 2024-09-21DOI: 10.1016/j.bmcl.2024.129972
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":"","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":null,"pages":null},"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.2024.129970
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":"","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":null,"pages":null},"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}
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