{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:01:09Z","timestamp":1790776869474,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82304420"],"award-info":[{"award-number":["82304420"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82404434"],"award-info":[{"award-number":["82404434"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Hypoxia\u2010inducible factor\u20101 \u03b1 (HIF\u20101\u03b1) is a key transcription factor for tumor cells to sense and adapt to the hypoxic microenvironment, regulate tumor progression such as tumor glycolysis, and is an important target for the development of anti\u2010tumor drugs. YC\u20101 (1\u2010benzyl\u20103\u2010(5\u2019\u2010hydroxymethyl\u20102\u2019\u2010furyl)indazole), as a classic inhibitor of HIF\u20101\u03b1, has received extensive attention in multiple anti\u2010tumor studies. Some derivatives that replace YC\u20101 indazole with the benzimidazole skeleton have shown certain HIF\u20101\u03b1 inhibitory and anti\u2010tumor potential. In this study, a series of substituted benzimidazole derivatives were designed and synthesized, and their HIF\u20101\u03b1 inhibitory and anti\u2010tumor effects were screened and investigated. In vitro anti\u2010proliferation and dual\u2010luciferase reports showed that compound\n                    <jats:bold>9o<\/jats:bold>\n                    had superior in vitro anti\u2010tumor (IC\n                    <jats:sub>50<\/jats:sub>\n                    \u2009=\u200933.85\u2009\u03bcM) and HIF\u20101\u03b1 transcriptional inhibitory activity (79.59% inhibition rate) compared with the positive control YC\u20101. Meanwhile, compound\n                    <jats:bold>9o<\/jats:bold>\n                    can also significantly inhibit the colony formation and survival rate of HCT\u2010116 cells. In addition, Western blotting, real\u2010time PCR and and lactic acid content experiments verified its inhibitory effect on HIF\u20101\u03b1 and downstream glycolysis. In addition, compound\n                    <jats:bold>9o<\/jats:bold>\n                    was found to reduce platelet aggregation more than YC\u20101, and the molecular docking results suggested that compound\n                    <jats:bold>9o<\/jats:bold>\n                    weakened its interaction with soluble guanylate cyclase (sGC), which is beneficial for avoiding the bleeding risk during tumor treatment. In vivo studies have shown that compound\n                    <jats:bold>9o<\/jats:bold>\n                    can inhibit tumor growth and reduce the levels of HIF\u20101\u03b1 and glycolysis rate\u2010limiting enzyme HK2 in HCT\u2010116 tumor\u2010bearing mice. The acute toxicity results also demonstrated the safety of compound\n                    <jats:bold>9o<\/jats:bold>\n                    in vivo. Finally, we also explored its pharmacokinetic properties in rats, suggesting its potential for subsequent intravenous administration. These findings provide a basis for the further discovery of anti\u2010tumor candidate compounds based on HIF\u20101\u03b1 inhibitors.\n                  <\/jats:p>","DOI":"10.1002\/ddr.70347","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T15:42:38Z","timestamp":1783525358000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Design, Synthesis, and Evaluation of the Novel Benzimidazole Derivatives Inspired YC\u20101 as HIF\u20101\u03b1 Inhibitor That Possess Anti\u2010Colon Cancer Potential"],"prefix":"10.1002","volume":"87","author":[{"given":"Qixian","family":"Yang","sequence":"first","affiliation":[{"name":"Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, Institute of Pharmacy and Pharmacology, The Second Affiliated Hospital University of South China Hengyang Hunan China"},{"name":"School of Pharmaceutical Science, Hengyang Medical School University of South China Hengyang Hunan China"},{"name":"Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, Institute of Pharmacy and Pharmacology, The Second Affiliated Hospital University of South China Hengyang Hunan China"},{"name":"School of Pharmaceutical Science, Hengyang Medical School University of South China Hengyang Hunan China"},{"name":"Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meijing","family":"Liu","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, Institute of Pharmacy and Pharmacology, The Second Affiliated Hospital University of South China Hengyang Hunan China"},{"name":"School of Pharmaceutical Science, Hengyang Medical School University of South China Hengyang Hunan China"},{"name":"Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangping","family":"Deng","sequence":"additional","affiliation":[{"name":"Hengyang Medical School University of South China Hengyang Hunan China"},{"name":"Department of Pharmacy, The First Affiliated Hospital University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhizhong","family":"Xie","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, Institute of Pharmacy and Pharmacology, The Second Affiliated Hospital University of South China Hengyang Hunan China"},{"name":"School of Pharmaceutical Science, Hengyang Medical School University of South China Hengyang Hunan China"},{"name":"Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9113-452X","authenticated-orcid":false,"given":"Xiaoyong","family":"Lei","sequence":"additional","affiliation":[{"name":"Hengyang Medical School University of South China Hengyang Hunan China"},{"name":"The College of Pharmacy Xiangnan University Chenzhou Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7591-7505","authenticated-orcid":false,"given":"Xiaoyan","family":"Yang","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, Institute of Pharmacy and Pharmacology, The Second Affiliated Hospital University of South China Hengyang Hunan China"},{"name":"School of Pharmaceutical Science, Hengyang Medical School University of South China Hengyang Hunan China"},{"name":"Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guotao","family":"Tang","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, Institute of Pharmacy and Pharmacology, The Second Affiliated Hospital University of South China Hengyang Hunan China"},{"name":"School of Pharmaceutical Science, Hengyang Medical School University of South China Hengyang Hunan China"},{"name":"Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Wang","sequence":"additional","affiliation":[{"name":"Hunan Provincial Key Laboratory of Basic and Clinical Pharmacological Research of Gastrointestinal Cancer, Department of Pharmacy, Institute of Pharmacy and Pharmacology, The Second Affiliated Hospital University of South China Hengyang Hunan China"},{"name":"School of Pharmaceutical Science, Hengyang Medical School University of South China Hengyang Hunan China"},{"name":"Hengyang Medical School University of South China Hengyang Hunan China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1915928"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-022-01645-2"},{"key":"e_1_2_8_4_1","first-page":"3891","article-title":"Benzimidazole Analogs as Potent Hypoxia Inducible Factor Inhibitors: Synthesis, Biological Evaluation, and Profiling Drug\u2010Like Properties","volume":"34","author":"Chen J.","year":"2014","journal-title":"Anticancer Research"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01332-8"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2009.12.039"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2004.01.005"},{"key":"e_1_2_8_8_1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s13046-020-01629-4","article-title":"Emerging Roles and the Regulation of Aerobic Glycolysis in Hepatocellular Carcinoma","volume":"39","author":"Feng J.","year":"2020","journal-title":"Journal of Experimental & Clinical Cancer Research: CR"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000082524.34487.31"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1209655"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/jrr\/rraa024"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10147-016-1031-8"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059817"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059796"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1089-9"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP280572"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V84.12.4226.bloodjournal84124226"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm010001h"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.12.011"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2015.05.007"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/20459"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bioorg.2023.106400"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(00)00194-0"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1210169"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2014.01.063"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.12.5510"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-022-01292-6"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/95.7.516"},{"key":"e_1_2_8_29_1","first-page":"5830","article-title":"Overexpression of Hypoxia\u2010Inducible Factor 1alpha in Common Human Cancers and Their Metastases","volume":"59","author":"Zhong H.","year":"1999","journal-title":"Cancer Research"}],"container-title":["Drug Development Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.70347","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ddr.70347","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.70347","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:34:58Z","timestamp":1790775298000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/ddr.70347"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,8]]},"references-count":28,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/ddr.70347"],"URL":"https:\/\/doi.org\/10.1002\/ddr.70347","archive":["Portico"],"relation":{},"ISSN":["0272-4391","1098-2299"],"issn-type":[{"value":"0272-4391","type":"print"},{"value":"1098-2299","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,8]]},"assertion":[{"value":"2025-12-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70347"}}