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A key step was the formation of differently N\u2010substituted Ile\u2010Tuv fragments <jats:bold>10<\/jats:bold> by using an aza\u2010Michael reaction of azido\u2010Ile derivatives <jats:bold>8<\/jats:bold> with the \u03b1,\u03b2\u2010unsaturated oxo\u2010thiazole <jats:bold>5<\/jats:bold>. A structure\u2013activity relationship study using a panel of human tumour cell lines showed strong anti\u2010proliferative activity for all compounds <jats:bold>24\u2009a<\/jats:bold>\u2013<jats:bold>m<\/jats:bold>, with IC<jats:sub>50<\/jats:sub> values in the sub\u2010nanomolar range, which were distinctly lower than those of tubulysin\u2005A, vinorelbine and paclitaxel. Furthermore, <jats:bold>24\u2009a<\/jats:bold>\u2013<jats:bold>m<\/jats:bold> were able to overcome cross\u2010resistance to paclitaxel and vinorelbine in two tumour cell lines with acquired resistance to doxorubicin. Compounds <jats:bold>24\u2009e<\/jats:bold> and <jats:bold>24\u2009g<\/jats:bold> were selected as leads to evaluate their mechanism of action. In vitro assays showed that both <jats:bold>24\u2009e<\/jats:bold> and <jats:bold>24\u2009g<\/jats:bold> interfere with tubulin polymerization in a vinca alkaloid\u2010like manner and prevent paclitaxel\u2010induced assembly of tubulin polymers. Both compounds exerted antimitotic activity and induced apoptosis in cancer cells at very low concentrations. Compound <jats:bold>24\u2009e<\/jats:bold> also exhibited potent antitumor activity at well tolerated doses on in vivo models of diffuse malignant peritoneal mesothelioma, such as MESOII peritoneal mesothelioma xenografts, the growth of which was not significantly affected by vinorelbine. These results indicate that synthetic tubulysins <jats:bold>24<\/jats:bold> could be used as standalone chemotherapeutic agents in difficult\u2010to\u2010treat cancers.<\/jats:p>","DOI":"10.1002\/chem.201700874","type":"journal-article","created":{"date-parts":[[2017,3,16]],"date-time":"2017-03-16T11:32:29Z","timestamp":1489663949000},"page":"5842-5850","source":"Crossref","is-referenced-by-count":12,"title":["Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non\u2010hydrolysable N\u2010Substituents on Tubuvaline"],"prefix":"10.1002","volume":"23","author":[{"given":"Monica","family":"Sani","sequence":"first","affiliation":[{"name":"KemoTech Srl, Edificio 3 Localit\u00e0 Piscinamanna  09010 Pula (CA Italy"},{"name":"C.N.R. 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