Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non-hydrolysable N-Substituents on Tubuvaline

Monica Sani, Paolo Lazzari, Marco Folini, Marco Spiga, Valentina Zuco, Michelandrea De Cesare, Ilaria Manca, Sergio Dall'Angelo, Massimo Frigerio, Igor Usai, Andrea Testa, Nadia Zaffaroni, Matteo Zanda

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Abstract

Synthetic tubulysins 24a-m, having non-hydrolysable N-substituents on tubuvaline (Tuv), were obtained in high purity and good overall yields using a multi-step synthesis. Key step was the formation of differently N-substituted Ile-Tuv fragments 10 via aza-Michael reaction of azido-Ile derivatives 8 with the α,β-unsaturated oxo-thiazole 5. A SAR study using a panel of human tumor cell lines showed strong anti-proliferative activity for all compounds 24a-m, with IC50 values in the sub-nanomolar range, which were distinctly lower than those of Tubulysin A, vinorelbine, and paclitaxel. Furthermore, 24a-m were able to overcome cross-resistance to paclitaxel and vinorelbine in two tumor cell lines with acquired resistance to doxorubicin. Compounds 24e and 24g were selected as leads to evaluate their mechanism of action. In vitro assays showed that both 24e and 24g 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. Compound 24e also exhibited potent antitumor activity at well tolerated doses on in vivo models of diffuse malignant peritoneal mesothelioma, such as MESOII peritoneal mesothelioma xenografts, whose growth was not significantly affected by vinorelbine. These results indicate that synthetic tubulysins 24 could be used as standalone chemotherapeutic agents in difficult-to-treat cancers.
Original languageEnglish
Pages (from-to)5842-5850
Number of pages9
JournalChemistry : a European Journal
Volume23
Issue number24
Early online date12 Apr 2017
DOIs
Publication statusPublished - 27 Apr 2017

Fingerprint

Paclitaxel
Cells
Tubulin
Tumors
Vinca Alkaloids
Antimitotic Agents
Thiazoles
Alkaloids
Cell death
Heterografts
Doxorubicin
Assays
Polymers
Polymerization
Apoptosis
Derivatives
vinorelbine

Keywords

  • tubulysins
  • antitumor
  • aza-Michael
  • in vitro tests
  • in vivo tests

Cite this

Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non-hydrolysable N-Substituents on Tubuvaline. / 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.

In: Chemistry : a European Journal, Vol. 23, No. 24, 27.04.2017, p. 5842-5850.

Research output: Contribution to journalArticle

Sani, M, Lazzari, P, Folini, M, Spiga, M, Zuco, V, De Cesare, M, Manca, I, Dall'Angelo, S, Frigerio, M, Usai, I, Testa, A, Zaffaroni, N & Zanda, M 2017, 'Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non-hydrolysable N-Substituents on Tubuvaline', Chemistry : a European Journal, vol. 23, no. 24, pp. 5842-5850. https://doi.org/10.1002/chem.201700874
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. / Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non-hydrolysable N-Substituents on Tubuvaline. In: Chemistry : a European Journal. 2017 ; Vol. 23, No. 24. pp. 5842-5850.
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abstract = "Synthetic tubulysins 24a-m, having non-hydrolysable N-substituents on tubuvaline (Tuv), were obtained in high purity and good overall yields using a multi-step synthesis. Key step was the formation of differently N-substituted Ile-Tuv fragments 10 via aza-Michael reaction of azido-Ile derivatives 8 with the α,β-unsaturated oxo-thiazole 5. A SAR study using a panel of human tumor cell lines showed strong anti-proliferative activity for all compounds 24a-m, with IC50 values in the sub-nanomolar range, which were distinctly lower than those of Tubulysin A, vinorelbine, and paclitaxel. Furthermore, 24a-m were able to overcome cross-resistance to paclitaxel and vinorelbine in two tumor cell lines with acquired resistance to doxorubicin. Compounds 24e and 24g were selected as leads to evaluate their mechanism of action. In vitro assays showed that both 24e and 24g 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. Compound 24e also exhibited potent antitumor activity at well tolerated doses on in vivo models of diffuse malignant peritoneal mesothelioma, such as MESOII peritoneal mesothelioma xenografts, whose growth was not significantly affected by vinorelbine. These results indicate that synthetic tubulysins 24 could be used as standalone chemotherapeutic agents in difficult-to-treat cancers.",
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T1 - Synthesis and Superpotent Anticancer Activity of Tubulysins Carrying Non-hydrolysable N-Substituents on Tubuvaline

AU - Sani, Monica

AU - Lazzari, Paolo

AU - Folini, Marco

AU - Spiga, Marco

AU - Zuco, Valentina

AU - De Cesare, Michelandrea

AU - Manca, Ilaria

AU - Dall'Angelo, Sergio

AU - Frigerio, Massimo

AU - Usai, Igor

AU - Testa, Andrea

AU - Zaffaroni, Nadia

AU - Zanda, Matteo

N1 - We thank Regione Autonoma della Sardegna RAS (Italy) for economic support by covering in part the costs of this research. I.U. acknowledges RAS for his fellowship (for grant numbers see the Supporting Information)

PY - 2017/4/27

Y1 - 2017/4/27

N2 - Synthetic tubulysins 24a-m, having non-hydrolysable N-substituents on tubuvaline (Tuv), were obtained in high purity and good overall yields using a multi-step synthesis. Key step was the formation of differently N-substituted Ile-Tuv fragments 10 via aza-Michael reaction of azido-Ile derivatives 8 with the α,β-unsaturated oxo-thiazole 5. A SAR study using a panel of human tumor cell lines showed strong anti-proliferative activity for all compounds 24a-m, with IC50 values in the sub-nanomolar range, which were distinctly lower than those of Tubulysin A, vinorelbine, and paclitaxel. Furthermore, 24a-m were able to overcome cross-resistance to paclitaxel and vinorelbine in two tumor cell lines with acquired resistance to doxorubicin. Compounds 24e and 24g were selected as leads to evaluate their mechanism of action. In vitro assays showed that both 24e and 24g 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. Compound 24e also exhibited potent antitumor activity at well tolerated doses on in vivo models of diffuse malignant peritoneal mesothelioma, such as MESOII peritoneal mesothelioma xenografts, whose growth was not significantly affected by vinorelbine. These results indicate that synthetic tubulysins 24 could be used as standalone chemotherapeutic agents in difficult-to-treat cancers.

AB - Synthetic tubulysins 24a-m, having non-hydrolysable N-substituents on tubuvaline (Tuv), were obtained in high purity and good overall yields using a multi-step synthesis. Key step was the formation of differently N-substituted Ile-Tuv fragments 10 via aza-Michael reaction of azido-Ile derivatives 8 with the α,β-unsaturated oxo-thiazole 5. A SAR study using a panel of human tumor cell lines showed strong anti-proliferative activity for all compounds 24a-m, with IC50 values in the sub-nanomolar range, which were distinctly lower than those of Tubulysin A, vinorelbine, and paclitaxel. Furthermore, 24a-m were able to overcome cross-resistance to paclitaxel and vinorelbine in two tumor cell lines with acquired resistance to doxorubicin. Compounds 24e and 24g were selected as leads to evaluate their mechanism of action. In vitro assays showed that both 24e and 24g 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. Compound 24e also exhibited potent antitumor activity at well tolerated doses on in vivo models of diffuse malignant peritoneal mesothelioma, such as MESOII peritoneal mesothelioma xenografts, whose growth was not significantly affected by vinorelbine. These results indicate that synthetic tubulysins 24 could be used as standalone chemotherapeutic agents in difficult-to-treat cancers.

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KW - antitumor

KW - aza-Michael

KW - in vitro tests

KW - in vivo tests

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JO - Chemistry : a European Journal

JF - Chemistry : a European Journal

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ER -