Synthesis and structure–activity relationship studies of novel tubulysin U analogues – effect on cytotoxicity of structural variations in the tubuvaline fragment

Sreejith P. Shankar, Monika Jagodzinska, Luciana Malpezzi, Paolo Lazzari, Ilaria Manca, Iain Robert Greig, Monica Sani, Matteo Zanda

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Tubulysins are cytotoxic natural products with promising anti-cancer properties, originally isolated from myxobacterial cultures. Structurally, tubulysins are tetrapeptides, incorporating three unusual (Mep, Tuv and Tup) and one proteinogenic amino acid (Ile). Here we describe the synthesis and structure-activity relationship studies of novel tubulysin U and V analogues, with variations in the central Tuv fragment, which is known to be of paramount importance for tubulysins' potency and hence cytotoxicity, but has seldom been modified in previous studies. Specifically, we replaced the natural iso-propyl and acetoxy functionalities with other structurally related groups. In general, the new analogues showed much lower potency relative to native tubulysin U. However, one of the synthetic analogues (1f) having a MOM function replacing the acetyl group exhibited a 22 nM IC50 on the HT-29 cell line which is comparable to the IC(50) displayed by tubulysin U (3.8 nM). Furthermore, the synthetic methodology reported herein was found to be flexible enough to deliver different core-modified tubulysin analogues and hence may be regarded as a scalable and convenient strategy for the chemical generation of novel tubulysin analogues.
Original languageEnglish
Pages (from-to)2273-2287
Number of pages15
JournalOrganic & Biomolecular Chemistry
Volume11
Issue number14
Early online date16 Jan 2013
DOIs
Publication statusPublished - 1 Apr 2013

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Cytotoxicity
fragments
analogs
synthesis
HT29 Cells
Structure-Activity Relationship
Biological Products
Inhibitory Concentration 50
MOM (semiconductors)
Cells
Amino Acids
Cell Line
cultured cells
amino acids
cancer
tubulysin U
methodology
Neoplasms
products

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Synthesis and structure–activity relationship studies of novel tubulysin U analogues – effect on cytotoxicity of structural variations in the tubuvaline fragment. / Shankar, Sreejith P.; Jagodzinska, Monika; Malpezzi, Luciana; Lazzari, Paolo; Manca, Ilaria; Greig, Iain Robert; Sani, Monica; Zanda, Matteo.

In: Organic & Biomolecular Chemistry, Vol. 11, No. 14, 01.04.2013, p. 2273-2287.

Research output: Contribution to journalArticle

Shankar, Sreejith P. ; Jagodzinska, Monika ; Malpezzi, Luciana ; Lazzari, Paolo ; Manca, Ilaria ; Greig, Iain Robert ; Sani, Monica ; Zanda, Matteo. / Synthesis and structure–activity relationship studies of novel tubulysin U analogues – effect on cytotoxicity of structural variations in the tubuvaline fragment. In: Organic & Biomolecular Chemistry. 2013 ; Vol. 11, No. 14. pp. 2273-2287.
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