Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non‐hydrolysable N‐Substituents on Tubuvaline. Issue 24 (12th April 2017)

• Record Type: Journal Article
• Authors: Sani, Monica; Lazzari, Paolo; Folini, Marco; Spiga, Marco; Zuco, Valentina; De Cesare, Michelandrea; Manca, Ilaria; Dall'Angelo, Sergio; Frigerio, Massimo; Usai, Igor; Testa, Andrea; Zaffaroni, Nadia; Zanda, Matteo
• Is Part Of: Chemistry. Volume 23:Issue 24(2017)
• Page Start: 5842
• Page End: 5850
• Publication Date: 2017-04-12
• Subjects: antitumor agents -- Michael addition -- peptides -- structure–activity relationships -- tubulysins; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201700874
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: Synthetic tubulysins24 a –m, containing non‐hydrolysable N‐substituents on tubuvaline (Tuv), were obtained in high purity and good overall yields using a multistep synthesis. A key step was the formation of differently N‐substituted Ile‐Tuv fragments10 by using an aza‐Michael reaction of azido‐Ile derivatives8 with the α, β‐unsaturated oxo‐thiazole5 . A structure–activity relationship study using a panel of human tumour cell lines showed strong anti‐proliferative activity for all compounds24 a –m, with IC50 values in the sub‐nanomolar range, which were distinctly lower than those of tubulysin A, vinorelbine and paclitaxel. Furthermore, 24 a –m were able to overcome cross‐resistance to paclitaxel and vinorelbine in two tumour cell lines with acquired resistance to doxorubicin. Compounds24 e and24 g were selected as leads to evaluate their mechanism of action. In vitro assays showed that both24 e and24 g interfere with tubulin polymerization in a vinca alkaloid‐like manner and prevent paclitaxel‐induced assembly of tubulin polymers. Both compounds exerted antimitotic activity and induced apoptosis in cancer cells at very low concentrations. Compound24 e 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 tubulysins24 could be used as standalone chemotherapeutic agents in difficult‐to‐treat cancers. Abstract : Resisting division : Antimitotic synthetic tubulysins carrying non‐hydrolysable residues on the tubuvaline nitrogen atom were synthesized (see scheme); these tubulysins were tested in vitro and found to display picomolar anticancer activity. The two lead compounds were tested in vivo on peritoneal mesothelioma xenografts and exhibited potent antitumor activity at well‐tolerated doses.