Myotonic dystrophy type 1 (DM1) is caused by the aberrant expansion of CTG repeats within the DMPK gene. This study investigated the potential binding of “X-linker-Y” type molecules to the CTG/CTG motif present in CTG repeats, using heterocyclic units X and Y capable of forming complementary hydrogen bonds with nucleobases. Among the tested molecules, the heterodimer of 2-amino-1,8-naphthyridine (X) and 3-aminoisoquinoline (Y) showed significant binding to the CTG/CTG motif. NMR analysis suggested hydrogen-bonded interactions between 3-aminoisoquinoline and thymine.
{"title":"The heterodimer of 2-amino-1,8-naphthyridine and 3-aminoisoquinoline binds to the CTG/CTG triad via hydrogen bonding","authors":"Shuhei Sakurabayashi, Takeshi Yamada, Kazuhiko Nakatani","doi":"10.1016/j.bmcl.2024.129985","DOIUrl":"10.1016/j.bmcl.2024.129985","url":null,"abstract":"<div><div>Myotonic dystrophy type 1 (DM1) is caused by the aberrant expansion of CTG repeats within the DMPK gene. This study investigated the potential binding of “X-linker-Y” type molecules to the CTG/CTG motif present in CTG repeats, using heterocyclic units X and Y capable of forming complementary hydrogen bonds with nucleobases. Among the tested molecules, the heterodimer of 2-amino-1,8-naphthyridine (X) and 3-aminoisoquinoline (Y) showed significant binding to the CTG/CTG motif. NMR analysis suggested hydrogen-bonded interactions between 3-aminoisoquinoline and thymine.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 129985"},"PeriodicalIF":2.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405773","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 : 2024-10-09DOI: 10.1016/j.bmcl.2024.129982
Wei Ai , Zeping Zuo
A new set of compounds known as sulfonyl benzoyl hydrazide derivatives were synthesized and tested using cellular assays. Through systematic optimization starting from general structure S-1, compound 10e emerged as highly promising. It exhibited potent inhibitory activity with an IC50 value of 0.8 nM and possessed moderate clogP. Compounds 10e significantly inhibited solid tumor cells proliferation. Additionally, 10e induced apoptosis and arrested the cell cycle. Furthermore, in vivo studies using an HCT116 xenograft model showed substantial growth inhibition of tumors, accompanied by a favorable safety profile. These findings underscored compound 10e as a novel LSD1 inhibitor with robust efficacy both in vitro and in vivo, establishing it as a promising lead compound for further anticancer drug development.
我们合成了一组名为磺酰基苯甲酰肼衍生物的新化合物，并使用细胞检测法进行了测试。通过从一般结构 S-1 开始的系统优化，化合物 10e 成为极具潜力的化合物。它具有强效的抑制活性，IC50 值为 0.8 nM，并具有适度的 ClogP。化合物 10e 能明显抑制实体瘤细胞的增殖。此外，10e 还能诱导细胞凋亡并阻滞细胞周期。此外，使用 HCT116 异种移植模型进行的体内研究显示，化合物 10e 可大幅抑制肿瘤生长，同时具有良好的安全性。这些研究结果表明，化合物 10e 是一种新型 LSD1 抑制剂，在体外和体内都有很强的疗效，有望成为进一步开发抗癌药物的先导化合物。
{"title":"Synthesis, optimization and antitumor activity evaluation of sulfonyl benzoyl hydrazide derivatives as novel human LSD1 inhibitors","authors":"Wei Ai , Zeping Zuo","doi":"10.1016/j.bmcl.2024.129982","DOIUrl":"10.1016/j.bmcl.2024.129982","url":null,"abstract":"<div><div>A new set of compounds known as sulfonyl benzoyl hydrazide derivatives were synthesized and tested using cellular assays. Through systematic optimization starting from general structure S-1, compound <strong>10e</strong> emerged as highly promising. It exhibited potent inhibitory activity with an IC<sub>50</sub> value of 0.8 nM and possessed moderate clogP. Compounds <strong>10e</strong> significantly inhibited solid tumor cells proliferation. Additionally, <strong>10e</strong> induced apoptosis and arrested the cell cycle. Furthermore, <em>in vivo</em> studies using an HCT116 xenograft model showed substantial growth inhibition of tumors, accompanied by a favorable safety profile. These findings underscored compound <strong>10e</strong> as a novel LSD1 inhibitor with robust efficacy both <em>in vitro</em> and <em>in vivo</em>, establishing it as a promising lead compound for further anticancer drug development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"114 ","pages":"Article 129982"},"PeriodicalIF":2.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386766","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}
The continued research of novel reversible inhibitors targeting monoamine oxidase (MAO) B remains crucial for effectively symptomatic treatment of Parkinson’s disease. In this study we synthesized and evaluated a new series of 3-aryl benzo[g] and benzo[h] coumarin derivatives as MAO-B inhibitors. Compound A6 has been found to display the most potent inhibitory activity and selectivity against the MAO-B isoform (IC50 = 13 nM and SI = >7693.31 respectively). Inhibition mode of A6 on MAO-B was predicted as mixed reversible inhibition with a Ki value of 3.274 nM. Furthermore, in order to elaborate structure–activity relationships, the binding mode of A6 was investigated by molecular docking simulations.
{"title":"Design, synthesis and biological evaluation of novel benzocoumarin derivatives as potent inhibitors of MAO-B activity","authors":"Furkan Meletli , Cihan Gündüz , Mustafa Muhlis Alparslan , Azade Attar , Serap Demir , Ece İskit , Özkan Danış","doi":"10.1016/j.bmcl.2024.129984","DOIUrl":"10.1016/j.bmcl.2024.129984","url":null,"abstract":"<div><div>The continued research of novel reversible inhibitors targeting monoamine oxidase (MAO) B remains crucial for effectively symptomatic treatment of Parkinson’s disease. In this study we synthesized and evaluated a new series of 3-aryl benzo[<em>g</em>] and benzo[<em>h</em>] coumarin derivatives as MAO-B inhibitors. Compound <strong>A6</strong> has been found to display the most potent inhibitory activity and selectivity against the MAO-B isoform (IC<sub>50</sub> = 13 nM and SI = >7693.31 respectively). Inhibition mode of <strong>A6</strong> on MAO-B was predicted as mixed reversible inhibition with a <em>K</em>i value of 3.274 nM. Furthermore, in order to elaborate structure–activity relationships, the binding mode of <strong>A6</strong> was investigated by molecular docking simulations.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129984"},"PeriodicalIF":2.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386756","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 : 2024-10-05DOI: 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
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 1, 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.
{"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}
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":"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}
Pub Date : 2024-09-26DOI: 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
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":"<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}
Pub Date : 2024-09-26DOI: 10.1016/j.bmcl.2024.129979
Laura Calvo-Barreiro , Longfei Zhang , Yasir Ali , Ashfaq Ur Rehman , Moustafa Gabr
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":"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}
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":"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}
Pub Date : 2024-09-25DOI: 10.1016/j.bmcl.2024.129974
Lei-Yin Zheng , Nai-Yu Zhang , Hui Zheng , Kai-Ming Wang , Juan Zhang , Ning Meng , Cheng-Shi Jiang
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":"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}
Pub Date : 2024-09-25DOI: 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
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":"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}
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