Structure simplification of GNE-140 and discovery of a pyridone based analogue as a potential lead for hLDHA inhibitors

Structure simplification of GNE-140 and discovery of a pyridone based analogue as a potential lead for hLDHA inhibitors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Structure simplification of GNE-140 and discovery of a pyridone based analogue as a potential lead for hLDHA inhibitors Wen-Hui Mo, Zhi-Yong Luo, Su-You Liu, Da-You Ma This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3807509/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract In this paper, taking GNE-140, a structurally complicated h LDHA inhibitor, as a lead compound, 19 simple analogues with a pyrimidone, pyranone or pyridone core were designed and conveniently synthesized. Subsequent biological evaluation indicated that although the pyrimidone core had a weak contribution to h LDHA inhibition, compounds with pyranone or pyridone core exhibited better anti- h LDHA activity. Notably, pyridone-bearing compound 1c showed significant selective inhibition of h LDHA (IC 50 = 19.5 ± 2.9 µM) over h LDHB (IC 50 = 117.6 ± 13.2 µM). Meanwhile, 1c showed inhibition on the lactate production of lung cancer cell A549. Thus, the result of this study indicated 1c is worthy of further study owing to its convenient synthesis and strong selective h LDHA inhibition. hLDHA inhibitor GNE-140 Pyrimidone Pyranone Pyridone Figures Figure 1 Figure 2 Introduction Human lactate dehydrogenase A ( h LDHA), the critical enzyme in the last step of glycolysis catalyzing the conversion of pyruvate to lactate, is overexpressed in a variety of human cancer tissues and promotes acidification of extracellular matrix (ECM), tumor invasion and metastasis 1 – 4 . Thus, h LDHA is considered as a promising target for the development of antitumor drugs 5 – 8 . At present, many h LDHA inhibitors have been discovered 9 – 14 . However, most of them suffer from either weak anti-tumor proliferative activities or poor pharmacokinetic properties or no selective inhibition of h LDHA over h LDHB 15 – 16 . GNE-140 (Fig. 1 , top) is a strong h LDHA inhibitor (IC 50 = 3 nM) discovered by Purkey in 2016 and entered clinical trial Phase I/II 14 . GNE-140 can inhibit the proliferation and lactate production of MiaPaCa-2 cells at low concentration, and inhibit tumor growth in MiaPaCa-2 mice xenotransplantation model. 17 However, GNE-140 with a complicated chemical structure and large molecular weight (M.W.: 499.04) may lead to its unsatisfactory ADME and pharmacokinetic properties 18 . In addition, due to the complex chiral dihydropyridone based structure, synthesis of GNE-140 is relatively difficult, which hinders its further structure activity relationship exploration. The cocrystal structure of GNE-140 and h LDHA (PDB: 4ZVV) revealed the dihydropyridone core of GNE-140 formed critical multi-hydrogen-bonds with amino acids Arg168, His192 and Thr247 of h LDHA (Fig. 1 a). By molecular modeling, we found that much simpler pyrimidone, pyranone or pyridone based analogues would maintain these main interactions and most likely to possess significant h LDHA inhibiting ability (Fig. 1 b-d). Thus, herein 19 compounds were designed, conveniently synthesized, and evaluated for its h LDHA inhibiting activity. Results and discussion Chemistry As shown in Scheme 1 , compounds 1a , 2a , 8a and 9a with pyrimidinone core were easily obtained by a two-step manipulation, with readily available materials. But compounds 3a and 4a failed to give decent yields with the same synthetic strategy. Alternatively, 3a - 7a , and 10a were synthesized through coupling of diphenyldisulfane with simple pyrimidone intermediates 1 , 12 (Scheme 2 ). Compounds with pyranone core ( 1b - 3b ) and pyridone core ( 1c - 2c ) were also smoothly synthesized using similar coupling reactions of diphenyldisulfane 4 , 5 with pyranone intermediate 13 , 14 and pyridone intermediate 15 , 16 , respectively (scheme 3 ). hLDHA and hLDHB Inhibiting activity h LDHA inhibiting activity of these analogues were evaluated according to the method by Cao et al 19 and the results are listed in Table 1 . Firstly, pyrimidinone-bearing compounds 1 , 12 and 1a - 10a (entries 1–12) showed weak h LDHA inhibiting activity (less than 50% inhibition at 100µM). Secondly, pyranone-bearing compounds 1b - 3b showed better h LDHA inhibiting activity (entries 13–15). However, these compounds only showed slightly selective inhibition of h LDHA over h LDHB. Finally, to our delight, although the pyridone-bearing compound 2c (entry 17) with a chlorine substitution at the C3-position showed low h LDHA inhibiting activity, 1c (entry 16) showed both strong inhibition on h LDHA (IC 50 = 19.5 ± 2.7 µM) and selectively over h LDHB (IC 50 = 117.6 ± 13.2 µM). Table 1 anti- h LDHA and anti- h LDHB activities of synthesized compounds. Entry Compds h LDH inhibiting rate (%) at 100 µM IC 50 (µM) h LDHA h LDHB h LDHA h LDHB 1 1 17.6 18.9 > 100 > 100 2 12 14.6 29.9 > 100 > 100 3 1a 40.3 39.8 > 100 > 100 4 2a 31.0 37.2 > 100 > 100 5 3a 34.6 25.1 > 100 > 100 6 4a 27.6 35.1 > 100 > 100 7 5a 32.4 45.7 > 100 > 100 8 6a 32.6 44.1 > 100 > 100 9 7a 31.8 46.8 > 100 > 100 10 8a 43.1 36.6 > 100 > 100 11 9a 37.3 39.3 > 100 > 100 12 10a 22.5 22.6 > 100 > 100 13 1b 87.7 74.9 13.6 ± 1.4 27.0 ± 6.5 14 2b 45.8 36.6 > 100 > 100 15 3b 100 77.2 12.3 ± 1.8 21.9 ± 4.1 16 1c 100 45.5 19.5 ± 2.7 117.6 ± 13.2 17 2c 43.7 31.3 > 100 > 100 18 GNE-140 88.5 a 57.8 a 0.0022 0.0121 a h LDHA and h LDHB inhibiting rates (%) at 10 nM. However, although compound 1c showed potent h LDHA inhibitory activity, there is still a big gap to that of GNE-140. Considering of the easy preparation and derivatization, pridone-core based analogues still has a large room for structural optimization, which deserves further study. Lactate production inhibiting activity h LDHA is the key enzyme in glycolysis, catalyzing the conversion of pyruvate to lactate. Thus, compounds 1b , 3b and 1c with good h LDHA inhibiting activity were subjected to lactate production inhibiting test using human lung cancer cell line A549. As shown in Fig. 2 , compound 1b , 3b and especially 1c significantly inhibited lactate formation of human lung cancer A549 cells at concentrations of 50 and 25 µM. Conclusion In this paper, the potent but structurally complicated h LDHA inhibitor GNE-140 was used as a lead compound, and a total of 19 compounds with simple pyrimidone, pyranone or pyridone core were designed, synthesized and evaluated for h LDHA/ h LDHB inhibiting activity. It’s worth noting that the pyridone-bearing compound 1c showed selective inhibition of h LDHA over h LDHB and good inhibition on lactate production in lung cancer A549 cells. Considering of its simple structure and decent h LDHA inhibiting activity, 1c is worthy of further exploration as a potential lead compound. Declarations Acknowledgements This work was supported by the grants from the Natural Science Foundation of Hunan Province (No. 2021JJ30903), the National Natural Science Foundation of China (No. 22177137) and Central South University Research Program of Advanced Interdisciplinary Studies (Grant No. 2023QYJC032). Data availability The data that support the findings of this study are available in the supplementary material of this article. Conflict of interest The authors declare no competing interests. References Sharma D, Singh M, Rani R (2022) Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics. Semin Cancer Biol 87:184–195. https://doi.org/10.1016/j.semcancer.2022.11.007 Wang J, Wang H, Liu A, Fang C, Hao J et al (2015) Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer. Oncotarget 6:19456–19468. https://doi.org/10.18632/oncotarget.3318 Li XB, Gu JD, Zhou QH (2015) Review of aerobic glycolysis and its key enzymes - new targets for lung cancer therapy. Thorac cancer 6:17–24. https://doi.org/10.1111/1759-7714.12148 Woodford MR, Chen VZ, Backe SJ, Bratslavsky G, Mollapour M (2020) Structural and functional regulation of lactate dehydrogenase-A in cancer. Future Med Chem 12:439–455. https://doi.org/10.4155/fmc-2019-0287 Zhang SL, He Y, Tam KY (2018) Targeting cancer metabolism to develop human lactate dehydrogenase (hLDH)5 inhibitors. Drug Discov Today 23:1407–1415. https://doi.org/10.1016/j.drudis.2018.05.014 Sharma D, Singh M, Joshi J, Garg M, Chaudhary V et al (2023) Design and Synthesis of Thiazole Scaffold-Based Small Molecules as Anticancer Agents Targeting the Human Lactate Dehydrogenase A Enzyme. ACS Omega 8:17552–17562. https://doi.org/10.1021/acsomega.2c07569 Mengyan D, Ting Y, Qinjinge Z, Han L, Yiping Z et al (2022) Development of a novel lactate dehydrogenase A inhibitor with potent antitumor activity and immune activation. Cancer Sci 113:2974–2985. https://doi.org/10.1111/cas.15468 Díaz I, Salido S, Nogueras M, Cobo J (2022) Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel hLDHA. Inhibitors Pharmaceuticals 15:792–821. https://doi.org/10.3390/ph15070792 Chen CY, Feng Y, Chen JY, Deng H (2016) Identification of a potent inhibitor targeting human lactate dehydrogenase A and its metabolic modulation for cancer cell line. Bioorg Med Chem Lett 26:72–75. https://doi.org/10.1016/j.bmcl.2015.11.025 Wang F, Zhao Q, Liu J, Wang Z, Kong D (2020) Identification of human lactate dehydrogenase A inhibitors with anti-osteosarcoma activity through cell-based phenotypic screening. Bioorg Med Chem Lett 30:1–5. https://doi.org/10.1016/j.bmcl.2019.126909 Zhou Y, Tao P, Wang M, Xu P, Lu W et al (2019) Development of novel human lactate dehydrogenase A inhibitors: High-throughput screening, synthesis, and biological evaluations. Eur J Med Chem 177:105–115. https://doi.org/10.1016/j.ejmech.2019.05.033 He S, Wang Q (2019) Discovery of human lactate dehydrogenase 5 inhibitors (hLDH5) with anti-lung cancer activity through an in silico method and biological validation. Bioorg Med Chem Lett 29:2459–2463. https://doi.org/10.1016/j.bmcl.2019.07.029 Rai G, Brimacombe KR, Mott BT, Urban DJ, Hu X et al (2017) Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH). J Med Chem 60:9184–9204. https://doi.org/10.1021/acs.jmedchem.7b00941 Purkey HE, Robarge K, Chen J, Chen Z, Corson LB et al (2016) Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice. ACS Med Chem Lett 7:896–901. https://doi.org/10.1021/acsmedchemlett.6b00190 Ward RA, Brassington C, Breeze AL, Caputo A, Critchlow S et al (2012) Design and synthesis of novel lactate dehydrogenase A inhibitors by fragment-based lead generation. J Med Chem 55:3285–3306. https://doi.org/10.1021/jm201734r Billiard J, Dennison JB, Briand J, Annan RS, Chai D et al (2013) Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells. Cancer Metab 1:19–35. https://doi.org/10.1186/2049-3002-1-19 Boudreau A, Purkey HE, Hitz A, Robarge K, Peterson D et al (2016) Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. Nat Chem Biol 12:779–786. https://doi.org/10.1038/nchembio.2143 Rai G, Urban DJ, Mott BT, Hu X, Maloney DJJJMC (2020) Pyrazole-Based Lactate Dehydrogenase (LDH) Inhibitors with Optimized Cell Activity and Pharmacokinetic Properties. J Med Chem 63:10984–11011. https://doi.org/10.1021/acs.jmedchem.0c00916 Cao W, Fang L, Teng S, Chen H, Wang Z (2018) Computer-aided discovery and biological characterization of human lactate dehydrogenase 5 inhibitors with anti-osteosarcoma activity. Bioorg Med Chem Lett 28:2229–2233. https://doi.org/10.1016/j.bmcl.2018.05.052 Scheme Scheme 1 to 3 are available in the Supplementary Files section. Supplementary Files GA.png S1.png Scheme 1. Syntheses of compounds 1a, 2a, 8a and 9a S2.png Scheme 2. Syntheses of compounds 3a-7a and 10a S3.png Scheme 3. Syntheses of compounds 1b-3b and1c-2c supportinginformation.doc Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3807509","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":264519791,"identity":"72e7a9b9-3554-4eaf-a158-14855dc331f4","order_by":0,"name":"Wen-Hui Mo","email":"","orcid":"","institution":"Central South University Xiangya School of Pharmaceutical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wen-Hui","middleName":"","lastName":"Mo","suffix":""},{"id":264519792,"identity":"f4055d75-3c44-46fa-87a7-50135318529d","order_by":1,"name":"Zhi-Yong Luo","email":"","orcid":"","institution":"Central South University School of Life Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhi-Yong","middleName":"","lastName":"Luo","suffix":""},{"id":264519793,"identity":"b1cb8021-e4b7-46c0-9201-9d06ab81ca22","order_by":2,"name":"Su-You Liu","email":"","orcid":"","institution":"Central South University Xiangya School of Pharmaceutical Sciences","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Su-You","middleName":"","lastName":"Liu","suffix":""},{"id":264519794,"identity":"3804f62b-0de5-49e9-8c57-2e409ebfab8e","order_by":3,"name":"Da-You Ma","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYHACAxAhZ3AAzLYgXouxwQFmEFuCeC2JG8BaGIjQott+eONnnorD6RuO9x/d8KNAgoG/vTsBrxazM2nF0jxnDufuP3OY7WYP0GESZ85uwK/lQI6BNG/b4dwNN5LZbvAAtRhI5BLQcv6N8W+glnQDoJabf4jSciPHDGRLAkjLbeJsufGszHLOmXTDDWcOm92WMZDgIeyX88mbb7ypsJY3ON747OabPzZy/O29+LWAABMPEocHpzJkwPiDKGWjYBSMglEwYgEAdh9MIfmWEi8AAAAASUVORK5CYII=","orcid":"","institution":"Central South University Xiangya School of Pharmaceutical Sciences","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Da-You","middleName":"","lastName":"Ma","suffix":""}],"badges":[],"createdAt":"2023-12-26 10:05:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3807509/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3807509/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49114704,"identity":"c6d180e8-5a00-4d1c-b7d3-212dca22c780","added_by":"auto","created_at":"2024-01-03 10:26:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":459950,"visible":true,"origin":"","legend":"\u003cp\u003eGNE-140 and (a): GNE-140 interaction with \u003cem\u003eh\u003c/em\u003eLDHA (PDB: 4ZVV,GNE-140: green, NAD: brown). (b-d): docked (MOE interactions of pyrimidone-based (blue), pyranone-based (offwhite) and pyridone-based (green) GNE-140 analogues to \u003cem\u003eh\u003c/em\u003eLDHA.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3807509/v1/ca5b219a751535a2098c9c29.png"},{"id":49115158,"identity":"458cd2b1-30fc-415f-b2b1-9b50809519ab","added_by":"auto","created_at":"2024-01-03 10:34:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":31027,"visible":true,"origin":"","legend":"\u003cp\u003eCompound \u003cstrong\u003e1b, 3b\u003c/strong\u003e and\u003cstrong\u003e 1c\u003c/strong\u003e (25 and 50 μM) reduced the lactate production in A549 cells.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3807509/v1/a3558c989705b868b61d7d86.png"},{"id":49957244,"identity":"05634604-6552-47ca-b3c9-3d872f2cb6ed","added_by":"auto","created_at":"2024-01-22 08:25:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":677790,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3807509/v1/6e94f951-5076-4477-8fc9-27b4a0f3d28a.pdf"},{"id":49114700,"identity":"3068e72f-cbf7-4eff-b662-69e7c636fc2b","added_by":"auto","created_at":"2024-01-03 10:26:58","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":21891,"visible":true,"origin":"","legend":"","description":"","filename":"GA.png","url":"https://assets-eu.researchsquare.com/files/rs-3807509/v1/6a8da41882f6785125ce3c60.png"},{"id":49114705,"identity":"4c687fb3-5af3-4c06-91ac-6a0702bbc34e","added_by":"auto","created_at":"2024-01-03 10:26:58","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":27399,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1.\u003c/strong\u003e Syntheses of compounds \u003cstrong\u003e1a\u003c/strong\u003e, \u003cstrong\u003e2a\u003c/strong\u003e, \u003cstrong\u003e8a\u003c/strong\u003e and\u003cstrong\u003e 9a\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"S1.png","url":"https://assets-eu.researchsquare.com/files/rs-3807509/v1/404297353e00dec197537577.png"},{"id":49114703,"identity":"e3168030-42f8-4b69-864e-5d104beac747","added_by":"auto","created_at":"2024-01-03 10:26:58","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":35671,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 2.\u003c/strong\u003e Syntheses of compounds \u003cstrong\u003e3a\u003c/strong\u003e-\u003cstrong\u003e7a\u003c/strong\u003e and \u003cstrong\u003e10a\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"S2.png","url":"https://assets-eu.researchsquare.com/files/rs-3807509/v1/28bb3c4196c83fb10357669e.png"},{"id":49115159,"identity":"4ea6c679-6114-45aa-b3ca-23c2a5a238a7","added_by":"auto","created_at":"2024-01-03 10:34:58","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":34164,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 3. \u003c/strong\u003eSyntheses of compounds \u003cstrong\u003e1b\u003c/strong\u003e-\u003cstrong\u003e3b \u003c/strong\u003eand\u003cstrong\u003e1c\u003c/strong\u003e-\u003cstrong\u003e2c\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"S3.png","url":"https://assets-eu.researchsquare.com/files/rs-3807509/v1/063454b3397f4cee6e8aa5b7.png"},{"id":49114707,"identity":"03c05137-8433-41c2-a77b-edc54592e8cf","added_by":"auto","created_at":"2024-01-03 10:26:58","extension":"doc","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":2470912,"visible":true,"origin":"","legend":"","description":"","filename":"supportinginformation.doc","url":"https://assets-eu.researchsquare.com/files/rs-3807509/v1/6709074f7f641b14fecca867.doc"}],"financialInterests":"","formattedTitle":"Structure simplification of GNE-140 and discovery of a pyridone based analogue as a potential lead for hLDHA inhibitors","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHuman lactate dehydrogenase A (\u003cem\u003eh\u003c/em\u003eLDHA), the critical enzyme in the last step of glycolysis catalyzing the conversion of pyruvate to lactate, is overexpressed in a variety of human cancer tissues and promotes acidification of extracellular matrix (ECM), tumor invasion and metastasis\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Thus, \u003cem\u003eh\u003c/em\u003eLDHA is considered as a promising target for the development of antitumor drugs\u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. At present, many \u003cem\u003eh\u003c/em\u003eLDHA inhibitors have been discovered\u003csup\u003e\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. However, most of them suffer from either weak anti-tumor proliferative activities or poor pharmacokinetic properties or no selective inhibition of \u003cem\u003eh\u003c/em\u003eLDHA over \u003cem\u003eh\u003c/em\u003eLDHB\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. GNE-140 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, top) is a strong \u003cem\u003eh\u003c/em\u003eLDHA inhibitor (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;3 nM) discovered by Purkey in 2016 and entered clinical trial Phase I/II\u003csup\u003e14\u003c/sup\u003e. GNE-140 can inhibit the proliferation and lactate production of MiaPaCa-2 cells at low concentration, and inhibit tumor growth in MiaPaCa-2 mice xenotransplantation model.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e However, GNE-140 with a complicated chemical structure and large molecular weight (M.W.: 499.04) may lead to its unsatisfactory ADME and pharmacokinetic properties\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. In addition, due to the complex chiral dihydropyridone based structure, synthesis of GNE-140 is relatively difficult, which hinders its further structure activity relationship exploration.\u003c/p\u003e \u003cp\u003eThe cocrystal structure of GNE-140 and \u003cem\u003eh\u003c/em\u003eLDHA (PDB: 4ZVV) revealed the dihydropyridone core of GNE-140 formed critical multi-hydrogen-bonds with amino acids Arg168, His192 and Thr247 of \u003cem\u003eh\u003c/em\u003eLDHA (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). By molecular modeling, we found that much simpler pyrimidone, pyranone or pyridone based analogues would maintain these main interactions and most likely to possess significant \u003cem\u003eh\u003c/em\u003eLDHA inhibiting ability (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb-d). Thus, herein 19 compounds were designed, conveniently synthesized, and evaluated for its \u003cem\u003eh\u003c/em\u003eLDHA inhibiting activity.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eChemistry\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAs shown in Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, compounds \u003cb\u003e1a\u003c/b\u003e, \u003cb\u003e2a\u003c/b\u003e, \u003cb\u003e8a\u003c/b\u003e and \u003cb\u003e9a\u003c/b\u003e with pyrimidinone core were easily obtained by a two-step manipulation, with readily available materials.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBut compounds \u003cb\u003e3a\u003c/b\u003e and \u003cb\u003e4a\u003c/b\u003e failed to give decent yields with the same synthetic strategy. Alternatively, \u003cb\u003e3a\u003c/b\u003e-\u003cb\u003e7a\u003c/b\u003e, and \u003cb\u003e10a\u003c/b\u003e were synthesized through coupling of diphenyldisulfane with simple pyrimidone intermediates \u003cb\u003e1\u003c/b\u003e, \u003cb\u003e12\u003c/b\u003e (Scheme \u003cspan refid=\"Sch2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCompounds with pyranone core (\u003cb\u003e1b\u003c/b\u003e-\u003cb\u003e3b\u003c/b\u003e) and pyridone core (\u003cb\u003e1c\u003c/b\u003e-\u003cb\u003e2c\u003c/b\u003e) were also smoothly synthesized using similar coupling reactions of diphenyldisulfane \u003cb\u003e4\u003c/b\u003e, \u003cb\u003e5\u003c/b\u003e with pyranone intermediate \u003cb\u003e13\u003c/b\u003e, \u003cb\u003e14\u003c/b\u003e and pyridone intermediate \u003cb\u003e15\u003c/b\u003e, \u003cb\u003e16\u003c/b\u003e, respectively (scheme \u003cspan refid=\"Sch3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ehLDHA and hLDHB Inhibiting activity\u003c/h2\u003e \u003cp\u003e \u003cem\u003eh\u003c/em\u003eLDHA inhibiting activity of these analogues were evaluated according to the method by Cao et al\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e and the results are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Firstly, pyrimidinone-bearing compounds \u003cb\u003e1\u003c/b\u003e, \u003cb\u003e12\u003c/b\u003e and \u003cb\u003e1a\u003c/b\u003e-\u003cb\u003e10a\u003c/b\u003e (entries 1\u0026ndash;12) showed weak \u003cem\u003eh\u003c/em\u003eLDHA inhibiting activity (less than 50% inhibition at 100\u0026micro;M). Secondly, pyranone-bearing compounds \u003cb\u003e1b\u003c/b\u003e-\u003cb\u003e3b\u003c/b\u003e showed better \u003cem\u003eh\u003c/em\u003eLDHA inhibiting activity (entries 13\u0026ndash;15). However, these compounds only showed slightly selective inhibition of \u003cem\u003eh\u003c/em\u003eLDHA over \u003cem\u003eh\u003c/em\u003eLDHB. Finally, to our delight, although the pyridone-bearing compound \u003cb\u003e2c\u003c/b\u003e (entry 17) with a chlorine substitution at the C3-position showed low \u003cem\u003eh\u003c/em\u003eLDHA inhibiting activity, \u003cb\u003e1c\u003c/b\u003e (entry 16) showed both strong inhibition on \u003cem\u003eh\u003c/em\u003eLDHA (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;19.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7 \u0026micro;M) and selectively over \u003cem\u003eh\u003c/em\u003eLDHB (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;117.6\u0026thinsp;\u0026plusmn;\u0026thinsp;13.2 \u0026micro;M).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eanti-\u003cem\u003eh\u003c/em\u003eLDHA and anti-\u003cem\u003eh\u003c/em\u003eLDHB activities of synthesized compounds.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eEntry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCompds\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e\u003cem\u003eh\u003c/em\u003eLDH inhibiting rate (%) at 100 \u0026micro;M\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eIC\u003csub\u003e50\u003c/sub\u003e (\u0026micro;M)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eh\u003c/em\u003eLDHA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eh\u003c/em\u003eLDHB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eh\u003c/em\u003eLDHA\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eh\u003c/em\u003eLDHB\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e37.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e4a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e5a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e6a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e7a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e8a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e9a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e39.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e10a\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1b\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e87.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27.0\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2b\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3b\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.3\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e1c\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e19.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e117.6\u0026thinsp;\u0026plusmn;\u0026thinsp;13.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e2c\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e43.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGNE-140\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88.5 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57.8 \u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0121\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003ea\u003c/sup\u003e \u003cem\u003eh\u003c/em\u003eLDHA and \u003cem\u003eh\u003c/em\u003eLDHB inhibiting rates (%) at 10 nM.\u003c/p\u003e \u003cp\u003eHowever, although compound \u003cb\u003e1c\u003c/b\u003e showed potent \u003cem\u003eh\u003c/em\u003eLDHA inhibitory activity, there is still a big gap to that of GNE-140. Considering of the easy preparation and derivatization, pridone-core based analogues still has a large room for structural optimization, which deserves further study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eLactate production inhibiting activity\u003c/h2\u003e \u003cp\u003e \u003cem\u003eh\u003c/em\u003eLDHA is the key enzyme in glycolysis, catalyzing the conversion of pyruvate to lactate. Thus, compounds \u003cb\u003e1b\u003c/b\u003e, \u003cb\u003e3b\u003c/b\u003e and \u003cb\u003e1c\u003c/b\u003e with good \u003cem\u003eh\u003c/em\u003eLDHA inhibiting activity were subjected to lactate production inhibiting test using human lung cancer cell line A549. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, compound \u003cb\u003e1b\u003c/b\u003e, \u003cb\u003e3b\u003c/b\u003e and especially \u003cb\u003e1c\u003c/b\u003e significantly inhibited lactate formation of human lung cancer A549 cells at concentrations of 50 and 25 \u0026micro;M.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this paper, the potent but structurally complicated \u003cem\u003eh\u003c/em\u003eLDHA inhibitor GNE-140 was used as a lead compound, and a total of 19 compounds with simple pyrimidone, pyranone or pyridone core were designed, synthesized and evaluated for \u003cem\u003eh\u003c/em\u003eLDHA/\u003cem\u003eh\u003c/em\u003eLDHB inhibiting activity. It\u0026rsquo;s worth noting that the pyridone-bearing compound \u003cb\u003e1c\u003c/b\u003e showed selective inhibition of \u003cem\u003eh\u003c/em\u003eLDHA over \u003cem\u003eh\u003c/em\u003eLDHB and good inhibition on lactate production in lung cancer A549 cells. Considering of its simple structure and decent \u003cem\u003eh\u003c/em\u003eLDHA inhibiting activity, \u003cb\u003e1c\u003c/b\u003e is worthy of further exploration as a potential lead compound.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the grants from the Natural Science Foundation of Hunan Province (No. 2021JJ30903), the National Natural Science Foundation of China (No. 22177137) and Central South University Research Program of Advanced Interdisciplinary Studies (Grant No. 2023QYJC032).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available in the supplementary material of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSharma D, Singh M, Rani R (2022) Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics. 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Bioorg Med Chem Lett 28:2229\u0026ndash;2233. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.bmcl.2018.05.052\u003c/span\u003e\u003cspan address=\"10.1016/j.bmcl.2018.05.052\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Scheme ","content":"\u003cp\u003eScheme 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"hLDHA inhibitor, GNE-140, Pyrimidone, Pyranone, Pyridone","lastPublishedDoi":"10.21203/rs.3.rs-3807509/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3807509/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn this paper, taking GNE-140, a structurally complicated \u003cem\u003eh\u003c/em\u003eLDHA inhibitor, as a lead compound, 19 simple analogues with a pyrimidone, pyranone or pyridone core were designed and conveniently synthesized. Subsequent biological evaluation indicated that although the pyrimidone core had a weak contribution to \u003cem\u003eh\u003c/em\u003eLDHA inhibition, compounds with pyranone or pyridone core exhibited better anti-\u003cem\u003eh\u003c/em\u003eLDHA activity. Notably, pyridone-bearing compound \u003cb\u003e1c\u003c/b\u003e showed significant selective inhibition of \u003cem\u003eh\u003c/em\u003eLDHA (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;19.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9 \u0026micro;M) over \u003cem\u003eh\u003c/em\u003eLDHB (IC\u003csub\u003e50\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;117.6\u0026thinsp;\u0026plusmn;\u0026thinsp;13.2 \u0026micro;M). Meanwhile, \u003cb\u003e1c\u003c/b\u003e showed inhibition on the lactate production of lung cancer cell A549. Thus, the result of this study indicated \u003cb\u003e1c\u003c/b\u003e is worthy of further study owing to its convenient synthesis and strong selective \u003cem\u003eh\u003c/em\u003eLDHA inhibition.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e","manuscriptTitle":"Structure simplification of GNE-140 and discovery of a pyridone based analogue as a potential lead for hLDHA inhibitors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-03 10:26:53","doi":"10.21203/rs.3.rs-3807509/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b7abe96f-e06d-41a4-9613-84f0917e33a6","owner":[],"postedDate":"January 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-01-22T08:17:06+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-03 10:26:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3807509","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3807509","identity":"rs-3807509","version":["v1"]},"buildId":"rHA-KDH7Qsr4HCuvH75dn","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}