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The analogy is drawn with the conversion of natural <jats:italic>O<\/jats:italic>\u2010 and <jats:italic>N<\/jats:italic>\u2010glycosides into more stable <jats:italic>C<\/jats:italic>\u2010glycosides that may possess enhanced biological activities and stabilities. Dihydroartemisinin was converted into 10\u03b2\u2010cyano\u201010\u2010deoxyartemisinin that was hydrolyzed to the \u03b1\u2010primary amide. Reduction of the \u03b2\u2010cyanide and the \u03b1\u2010amide provided the respective methylamine epimers that upon treatment with divinyl sulfone gave the \u03b2\u2010 and \u03b1\u2010methylene homologues, respectively, of artemisone. Surprisingly, the compounds were less active in\u2005vitro than artemisone against <jats:italic>P.\u2005falciparum<\/jats:italic> and displayed no appreciable activity against A549, HCT116, and MCF7 tumor cell lines. This loss in activity may be rationalized in terms of one model for the mechanism of action of artemisinins, namely the cofactor model, wherein the presence of a leaving group at C10 assists in driving hydride transfer from reduced flavin cofactors to the peroxide during perturbation of intracellular redox homeostasis by artemisinins. It is noted that the carba analogue of artemether is less active in\u2005vitro than the <jats:italic>O<\/jats:italic>\u2010glycoside parent toward <jats:italic>P.\u2005falciparum<\/jats:italic>, although extrapolation of such activity differences to other artemisinins at this stage is not possible. However, literature data coupled with the leaving group rationale suggest that artemisinins bearing an amino group attached directly to C10 are optimal compounds.<\/jats:p>","DOI":"10.1002\/cmdc.201600011","type":"journal-article","created":{"date-parts":[[2016,6,7]],"date-time":"2016-06-07T06:53:56Z","timestamp":1465282436000},"page":"1469-1479","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Methylene Homologues of Artemisone: An Unexpected Structure\u2013Activity Relationship and a Possible Implication for the Design of C10\u2010Substituted Artemisinins"],"prefix":"10.1002","volume":"11","author":[{"given":"Yuet","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Chemistry The Hong Kong University of Science and Technology  Clear Water Bay Kowloon Hong Kong P.R. 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