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Here, we report an innovative strategy for the in situ synthesis of these compounds within cancer cells, using a rationally designed precursor that is nontoxic, non\u2010ionic, and membrane permeable. The synthesis is initiated by endogenous acrolein, an oncometabolite elevated in cancer cells, which triggers a cascade involving 1,3\u2010dipolar cycloaddition, diazo formation, carbamate cleavage, imine formation, intramolecular 6\u03c0\u2010azaelectrocyclization, oxidative aromatization, and ester hydrolysis. We validated this methodology in human lung adenocarcinoma (A549) cells, where the in situ\u2010synthesized zwitterionic heterocycle exhibited anticancer activity. Conversely, its pre\u2010synthesized congener showed minimal cytotoxicity, underscoring the poor membrane permeability of the zwitterionic form. Precursor optimization resulted in a lead compound that, upon administration to A549 cells, converted into a cytotoxic zwitterionic heterocycle with a half\u2010maximal inhibitory concentration (IC\n                    <jats:sub>50<\/jats:sub>\n                    ) of 6.2 \u00b5M. The lead precursor showed exceptional selectivity, with no cytotoxicity in normal human diploid (TIG3) cells. This selectivity arises because healthy cells contain low acrolein levels, insufficient to trigger the activation cascade. Our approach effectively addresses the key therapeutic challenges associated with zwitterionic heterocycles.\n                  <\/jats:p>","DOI":"10.1002\/anie.202525535","type":"journal-article","created":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T06:21:47Z","timestamp":1766816507000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["In Cellulo Multistep Synthesis of Antitumor Zwitterionic Heterocycles Triggered by Cancer\u2010Specific Acrolein"],"prefix":"10.1002","volume":"65","author":[{"given":"Kazuki","family":"Terashima","sequence":"first","affiliation":[{"name":"Department of Chemical Science and Engineering School of Materials and Chemical Technology Institute of Science Tokyo  2\u201012\u20101 Ookayama Meguro Tokyo 152\u20138552 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9056-447X","authenticated-orcid":false,"given":"Ambara R.","family":"Pradipta","sequence":"additional","affiliation":[{"name":"Department of Chemical Science and Engineering School of Materials and Chemical Technology Institute of Science Tokyo  2\u201012\u20101 Ookayama Meguro Tokyo 152\u20138552 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihiro","family":"Ishiwata","sequence":"additional","affiliation":[{"name":"Biofunctional Synthetic Chemistry Laboratory RIKEN Pioneering Research Institute  2\u20101 Hirosawa Wako Saitama 351\u20100198 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6932-4802","authenticated-orcid":false,"given":"Katsunori","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Chemical Science and Engineering School of Materials and Chemical Technology Institute of Science Tokyo  2\u201012\u20101 Ookayama Meguro Tokyo 152\u20138552 Japan"},{"name":"Biofunctional Synthetic Chemistry Laboratory RIKEN Pioneering Research Institute  2\u20101 Hirosawa Wako Saitama 351\u20100198 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,26]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaw8412"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3835(88)90235-2"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.48.757"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja00876a031"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)78938-6"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)96702-9"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1039\/C6RA00086J"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt19741661045"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-198428040-00002"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-199651060-00010"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40360-019-0363-1"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0021-9797(68)90023-4"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biomac.0c00497"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202000164"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c00596"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00245"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.3987\/COM-14-S(K)46"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(98)01197-1"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0030-1261192"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo005779"},{"key":"e_1_2_8_21_1","volume-title":"Thermal electrocyclic reactions","author":"Marvell E. 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