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In this study, we report the efficient synthesis of caerulomycin A and a series of novel analogs via a five\u2010step synthetic route using readily available reagents. The structural diversification focused on the replacing the methoxy group with various benzyl ether substituents at C\u20104 and subsequent oxidation and condensation steps at C\u20106 to generate caerulomycin E and caerulomycin A analogs. These compounds were evaluated for their cytotoxic activity against six human cancer cell lines. Notably, several benzyl ether derivatives exhibited significantly enhanced cytotoxicity compared to the parent compound, with some analogs demonstrating greater potency than the reference drug ellipticine. The structure\u2013activity relationship (SAR) analysis revealed that halogenated substituted benzyl ether groups at C\u20104 positions played a critical role in modulating cytotoxic activity and selectivity. These findings underscore the potential of synthetic caerulomycin derivatives as promising lead compounds for further development in cancer therapeutics.<\/jats:p>","DOI":"10.1002\/cmdc.202500594","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T23:51:28Z","timestamp":1758585088000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis of Caerulomycins E and A Analogs for Studying Cytotoxic Activity"],"prefix":"10.1002","volume":"20","author":[{"given":"Pansachon","family":"Intamalee","sequence":"first","affiliation":[{"name":"Department of Chemistry and Center for Innovation in Chemistry Faculty of Science Burapha University  Chonburi 20131 Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesada","family":"Maneewong","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Center for Innovation in Chemistry Faculty of Science 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