{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:53:12Z","timestamp":1792176792457,"version":"4.4.0"},"reference-count":38,"publisher":"American Chemical Society (ACS)","issue":"37","license":[{"start":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T00:00:00Z","timestamp":1725840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100023581","name":"National Science Foundation Graduate Research Fellowship Program","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100023581","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006732","name":"New York University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006732","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM-127778"],"award-info":[{"award-number":["R01 GM-127778"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,9,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Calicheamicin \u03b31 and related natural products are renowned for their potency in DNA cleavage, serving as the warheads in commercial ADCs used for treating leukemia. Their mechanism of action involves the formation of aryl radicals, which abstract hydrogen atoms from nucleic acids. However, the complex strained enediyne structure of calicheamicin \u03b31 presents significant challenges in synthesis, resulting in high production costs and limited structural and activity modularity for tuning the therapeutic window. This report describes the development of simple molecular mimics based on diazonium salts, synthesized in fewer than 3 steps, capable of generating aryl radicals upon green or red light irradiation. SAR studies conducted on over 30 analogues reveal a wide range of potencies in DNA cleavage, with EC50 values ranging from low nanomolar to micromolar. Forming benzenoid diradicals does not appear to be necessary for potent DNA cleavage; instead, DNA cleavage can be achieved with radicals distributed among different arenes when connected with proper linkages. The potency is influenced by electronic effects, stereochemistry, orbital orientations, the distance between multiradicals, and the number of diazonium motifs within the molecule. In addition to providing a more cost-effective, efficient, and modular alternative to calicheamicin \u03b31, this technology offers the potential for enhanced specificity through spatiotemporal control.<\/jats:p>","DOI":"10.1021\/jacs.4c07754","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T09:54:31Z","timestamp":1725875671000},"page":"25416-25421","source":"Crossref","is-referenced-by-count":7,"title":["Tunable\nand Photoactivatable Mimics of Calicheamicin\n\u03b31 for DNA Cleavage"],"prefix":"10.1021","volume":"146","author":[{"given":"Benjamin","family":"Ben-Zvi","sequence":"first","affiliation":[{"name":"New York University , , 100 Washington Square East , , ,","place":["New York, New York, United States, 10003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Lian","sequence":"additional","affiliation":[{"name":"New York University , , 100 Washington Square East , , ,","place":["New York, New York, United States, 10003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen F.","family":"Brusco","sequence":"additional","affiliation":[{"name":"New York University , , 100 Washington Square East , , ,","place":["New York, New York, United States, 10003"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3916-8372","authenticated-orcid":true,"given":"Tianning","family":"Diao","sequence":"additional","affiliation":[{"name":"New York University , , 100 Washington Square East , , ,","place":["New York, New York, United States, 10003"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2024,9,9]]},"reference":[{"issue":"1","key":"2026101614071657900_cit1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1021\/bc010021y","article-title":"Gemtuzumab\nOzogamicin, A Potent and Selective Anti-CD33 Antibody\u2013Calicheamicin\nConjugate for Treatment of Acute Myeloid Leukemia","volume":"13","author":"Hamann","year":"2002","journal-title":"Bioconjugate Chem."},{"issue":"4","key":"2026101614071657900_cit2","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/S1471-4892(03)00083-3","article-title":"Antibody-targeted chemotherapy\nwith immunoconjugates of calicheamicin","volume":"3","author":"Damle","year":"2003","journal-title":"Curr.\nOpin. Pharmacol."},{"key":"2026101614071657900_cit3","doi-asserted-by":"publisher","first-page":"1198","DOI":"10.1126\/science.3240341","article-title":"Calicheamicin\n\u03b31I: an Antitumor Antibiotic That Cleaves\nDouble-Stranded\nDNA Site Specifically","volume":"240","author":"Zein","year":"1988","journal-title":"Science"},{"key":"2026101614071657900_cit4","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1021\/ar00008a003","article-title":"Calicheamicins:\ndiscovery, structure,\nchemistry, and interaction with DNA","volume":"24","author":"Lee","year":"1991","journal-title":"Acc. Chem.\nRes."},{"key":"2026101614071657900_cit5","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1021\/ja00757a071","article-title":"p-Benzyne. Generation as an Intermediate\nin a Thermal Isomerization Reaction and Trapping Evidence for the\n1,4-Benzenediyl Structure","volume":"94","author":"Jones","year":"1972","journal-title":"J. Am. Chem. Soc."},{"key":"2026101614071657900_cit6","doi-asserted-by":"publisher","first-page":"7011","DOI":"10.1021\/cr400056a","article-title":"Diradicals","volume":"113","author":"Abe","year":"2013","journal-title":"Chem. Rev."},{"issue":"23","key":"2026101614071657900_cit7","doi-asserted-by":"publisher","first-page":"9200","DOI":"10.1021\/ja00049a069","article-title":"Specific abstraction of the 5\u2032S-\nand 4\u2019-deoxyribosyl hydrogen atoms from DNA by calicheamicin\n\u03b31I","volume":"114","author":"Hangeland","year":"1992","journal-title":"J. Am. Chem.\nSoc."},{"issue":"4","key":"2026101614071657900_cit8","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1021\/ja00083a012","article-title":"A Study of the Reaction of Calicheamicin\n\u03b31I with Glutathione in the Presence of\nDouble-Stranded DNA","volume":"116","author":"Myers","year":"1994","journal-title":"J. Am. Chem. Soc."},{"issue":"14","key":"2026101614071657900_cit9","doi-asserted-by":"publisher","first-page":"5434","DOI":"10.1021\/ja00014a040","article-title":"Coupled\nkinetic analysis of cleavage of DNA by esperamicin and calicheamicin","volume":"113","author":"Kishikawa","year":"1991","journal-title":"J. Am. Chem. Soc."},{"key":"2026101614071657900_cit10","doi-asserted-by":"publisher","first-page":"7842","DOI":"10.1021\/jacs.9b01800","article-title":"DNA Binding and\nCleavage Modes of Shishijimicin A","volume":"141","author":"Zhang","year":"2019","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026101614071657900_cit11","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1002\/anie.199113873","article-title":"Chemistry and Biology of the Enediyne Anticancer Antibiotics","volume":"30","author":"Nicolaou","year":"1991","journal-title":"Angew. Chem., Int. Ed. Engl."},{"issue":"3","key":"2026101614071657900_cit12","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1021\/ja00029a030","article-title":"Calicheamicins,\na novel family of antitumor antibiotics. 4. Structure elucidation\nof calicheamicins \u03b21Br, \u03b31Br, \u03b12I, \u03b13I, \u03b21I, \u03b31I, and \u03b41I","volume":"114","author":"Lee","year":"1992","journal-title":"J. Am. Chem. Soc."},{"key":"2026101614071657900_cit13","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1021\/cr030117g","article-title":"Antitumor Antibiotics: Bleomycin,\nEnediynes, and Mitomycin","volume":"105","author":"Galm","year":"2005","journal-title":"Chem. Rev."},{"key":"2026101614071657900_cit14","doi-asserted-by":"publisher","first-page":"4077","DOI":"10.1021\/cr020069k","article-title":"Chelation-Controlled\nBergman Cyclization:\nSynthesis and Reactivity of Enediynyl Ligands","volume":"103","author":"Basak","year":"2003","journal-title":"Chem. Rev."},{"issue":"25","key":"2026101614071657900_cit15","doi-asserted-by":"publisher","first-page":"10082","DOI":"10.1021\/ja00051a063","article-title":"Total synthesis of calicheamicin\n\u03b31I","volume":"114","author":"Nicolaou","year":"1992","journal-title":"J. Am. Chem.\nSoc."},{"key":"2026101614071657900_cit16","unstructured":"Lee, M. D.; Greenstein, M.; Labeda, D. P.; Fantini, A. A.\n          Antitumor antibiotics\n(LL-E33288 complex). US5108912A, Apr. 28, 1992."},{"issue":"1","key":"2026101614071657900_cit17","doi-asserted-by":"publisher","first-page":"S132","DOI":"10.1134\/S0003683822100040","article-title":"Improving\nthe Production of Antitumor Calicheamicin by the Micromonospora echinospora\nMutant Coupled with in situ Resin Adsorption in Fermentation Process","volume":"58","author":"Chen","year":"2022","journal-title":"Appl. Biochem. Microbiol."},{"issue":"3","key":"2026101614071657900_cit18","doi-asserted-by":"publisher","first-page":"713","DOI":"10.3390\/cancers15030713","article-title":"Mechanisms\nof ADC Toxicity and Strategies\nto Increase ADC Tolerability","volume":"15","author":"Nguyen","year":"2023","journal-title":"Cancers"},{"issue":"2","key":"2026101614071657900_cit19","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1002\/hep.30222","article-title":"Liver Complications\nFollowing Treatment of Hematologic Malignancy With Anti-CD22-Calicheamicin\n(Inotuzumab Ozogamicin)","volume":"69","author":"McDonald","year":"2019","journal-title":"Hepatology"},{"key":"2026101614071657900_cit20","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1126\/science.256.5060.1172","article-title":"Designed Enediynes:\nA New Class of DNA-Cleaving Molecules with Potent and Selective Anticancer\nActivity","volume":"256","author":"Nicolaou","year":"1992","journal-title":"Science."},{"key":"2026101614071657900_cit21","doi-asserted-by":"publisher","first-page":"7247","DOI":"10.1021\/ja00229a068","article-title":"DNA Cleavage by a Synthetic\nMimic of the Calicheamicin-Esperamicin Class of Antibiotics","volume":"110","author":"Nicolaou","year":"1988","journal-title":"J. Am. Chem. Soc."},{"key":"2026101614071657900_cit22","doi-asserted-by":"publisher","first-page":"7823","DOI":"10.1016\/S0040-4039(00)61485-5","article-title":"Development of new DNA-binding and\ncleaving molecules: Design, synthesis and activity of a bisdiazonium\nsalt","volume":"34","author":"Arya","year":"1993","journal-title":"Tetrahedron Lett."},{"key":"2026101614071657900_cit23","doi-asserted-by":"publisher","first-page":"4369","DOI":"10.1016\/0040-4039(95)00815-T","article-title":"Towards\nthe development of non-enediyne approaches\nfor mimicking enediyne chemistry: Design, synthesis and activity of\na 1,4-bisdiazonium compound","volume":"36","author":"Arya","year":"1995","journal-title":"Tetrahedron Lett."},{"issue":"5","key":"2026101614071657900_cit24","first-page":"539","article-title":"DNA Cleavage Activity\nof Diazonium Salts: Chemical Nucleases","volume":"27","author":"Kizil","year":"2003","journal-title":"Turk.\nJ. 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Direct Observation of a Ground-State Triplet p-Benzyne\nBiradical","volume":"31","author":"Ylijoki","year":"2012","journal-title":"Organometallics"},{"key":"2026101614071657900_cit27","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1021\/acs.molpharmaceut.7b00911","article-title":"Photochemical Activation\nof Enediyne Warheads: A Potential Tool for Targeted Antitumor Therapy","volume":"15","author":"Bhattacharya","year":"2018","journal-title":"Mol. Pharmaceutics"},{"key":"2026101614071657900_cit28","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1007\/7081_018","article-title":"Diazo and\nDiazonium DNA Cleavage Agents: Studies on Model Systems and Natural\nProduct Mechanisms of Action Top","volume":"2","author":"Arya","year":"2006","journal-title":"Heterocycl. Chem."},{"issue":"2","key":"2026101614071657900_cit29","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1039\/c39890000101","article-title":"Photohydrolysis\nof DNA by polyaminobenzenediazonium salts","author":"Behr","year":"1989","journal-title":"J.\nChem. Soc., Chem. Commun."},{"key":"2026101614071657900_cit30","doi-asserted-by":"publisher","first-page":"2958","DOI":"10.1021\/ja212099r","article-title":"Metal-Free, Visible-Light-Mediated\nDirect C\u2013H Arylation of Heteroarenes with Aryl Diazonium Salts","volume":"134","author":"Hari","year":"2012","journal-title":"J. Am. Chem. Soc."},{"key":"2026101614071657900_cit31","doi-asserted-by":"publisher","first-page":"10075","DOI":"10.1021\/acs.chemrev.6b00057","article-title":"Organic Photoredox Catalysis","volume":"116","author":"Romero","year":"2016","journal-title":"Chem. 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Biol."},{"issue":"1","key":"2026101614071657900_cit35","doi-asserted-by":"publisher","first-page":"193","DOI":"10.3390\/molecules28010193","article-title":"Acridine as an Anti-Tumour Agent:\nA Critical Review","volume":"28","author":"Varakumar","year":"2023","journal-title":"Molecules"},{"issue":"23","key":"2026101614071657900_cit37","doi-asserted-by":"publisher","first-page":"10506","DOI":"10.1073\/pnas.92.23.10506","article-title":"Calicheamicin-DNA\ncomplexes: warhead alignment and\nsaccharide recognition of the minor groove","volume":"92","author":"Ikemoto","year":"1995","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"21","key":"2026101614071657900_cit38","doi-asserted-by":"publisher","first-page":"9733","DOI":"10.1021\/ja00100a044","article-title":"The Deoxyfucose-Anthranilate\nof Esperamicin A1 Confers Intercalative DNA Binding and Causes a Switch\nin the Chemistry of Bistranded DNA Lesions","volume":"116","author":"Yu","year":"1994","journal-title":"J. Am. Chem. Soc."},{"issue":"3","key":"2026101614071657900_cit39","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1021\/ja962255b","article-title":"How Easily\nOxidizable Is DNA? One-Electron Reduction\nPotentials of Adenosine and Guanosine Radicals in Aqueous Solution","volume":"119","author":"Steenken","year":"1997","journal-title":"J. Am. Chem. Soc."}],"container-title":["Journal of the American\nChemical Society"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacs.4c07754","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/146\/37\/25416\/68893244\/jacs.4c07754.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jacsat\/article-pdf\/146\/37\/25416\/68893244\/jacs.4c07754.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:29:06Z","timestamp":1792175346000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jacsat\/article\/146\/37\/25416\/157645\/Tunable-and-Photoactivatable-Mimics-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,9]]},"references-count":38,"journal-issue":{"issue":"37","published-online":{"date-parts":[[2024,9,9]]},"published-print":{"date-parts":[[2024,9,18]]}},"URL":"https:\/\/doi.org\/10.1021\/jacs.4c07754","relation":{},"ISSN":["0002-7863","1520-5126"],"issn-type":[{"value":"0002-7863","type":"print"},{"value":"1520-5126","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,9]]}}}