{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T06:56:36Z","timestamp":1788332196021,"version":"build-2803163510"},"reference-count":74,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,10]],"date-time":"2023-03-10T00:00:00Z","timestamp":1678406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004704","name":"National Research Council of Thailand (NRCT)","doi-asserted-by":"publisher","award":["N41A640075"],"award-info":[{"award-number":["N41A640075"]}],"id":[{"id":"10.13039\/501100004704","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Akt is a key regulatory protein of cancer stem cells (CSCs) and is responsible for cancer aggressiveness and metastasis. Targeting Akt is beneficial for the development of cancer drugs. renieramycin T (RT) has been reported to have Mcl-1 targeting activity, and the study of the structure-activity relationships (SARs) demonstrated that cyanide and the benzene ring are essential for its effects. In this study, novel derivatives of the RT right-half analog with cyanide and the modified ring were synthesized to further investigate the SARs for improving the anticancer effects of RT analogs and evaluate CSC-suppressing activity through Akt inhibition. Among the five derivatives, a compound with a substituted thiazole structure (DH_25) exerts the most potent anticancer activity in lung cancer cells. It has the ability to induce apoptosis, which is accompanied by an increase in PARP cleavage, a decrease in Bcl-2, and a diminishment of Mcl-1, suggesting that residual Mcl-1 inhibitory effects exist even after modifying the benzene ring to thiazole. Furthermore, DH_25 is found to induce CSC death, as well as a decrease in CSC marker CD133, CSC transcription factor Nanog, and CSC-related oncoprotein c-Myc. Notably, an upstream member of these proteins, Akt and p-Akt, are also downregulated, indicating that Akt can be a potential target of action. Computational molecular docking showing a high-affinity interaction between DH_25 and an Akt at the allosteric binding site supports that DH_25 can bind and inhibit Akt. This study has revealed a novel SAR and CSC inhibitory effect of DH_25 via Akt inhibition, which may encourage further development of RT compounds for cancer therapy.<\/jats:p>","DOI":"10.3390\/ijms24065345","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T05:36:21Z","timestamp":1678685781000},"page":"5345","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Novel Synthetic Derivative of Renieramycin T Right-Half Analog Induces Apoptosis and Inhibits Cancer Stem Cells via Targeting the Akt Signal in Lung Cancer Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Korrakod","family":"Petsri","sequence":"first","affiliation":[{"name":"Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0187-7595","authenticated-orcid":false,"given":"Masashi","family":"Yokoya","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satapat","family":"Racha","sequence":"additional","affiliation":[{"name":"Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Interdisciplinary Program in Pharmacology, Graduate School, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunisa","family":"Thongsom","sequence":"additional","affiliation":[{"name":"Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1785-3272","authenticated-orcid":false,"given":"Chorpaka","family":"Thepthanee","sequence":"additional","affiliation":[{"name":"Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhurichaya","family":"Innets","sequence":"additional","affiliation":[{"name":"Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7906-0986","authenticated-orcid":false,"given":"Zin Zin","family":"Ei","sequence":"additional","affiliation":[{"name":"Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiki","family":"Hotta","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbin","family":"Zou","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3103-3249","authenticated-orcid":false,"given":"Pithi","family":"Chanvorachote","sequence":"additional","affiliation":[{"name":"Center of Excellence in Cancer Cell and Molecular Biology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand"},{"name":"Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, 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