Article

Synthesis and biological evaluation of tubulysin D analogs related to stereoisomers of tubuvaline

Exploratory Research Laboratories, Kyorin Pharmaceutical Co Ltd, 2399-1 Nogi, Nogi-Machi, Shimotsuga-Gun, Tochigi 329-0114, Japan.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.65). 01/2011; 21(1):431-4. DOI: 10.1016/j.bmcl.2010.10.118
Source: PubMed

ABSTRACT The synthesis and biological evaluation of stereoisomers in tubulysin D are described. The stereoselective synthesis of all possible stereoisomers of C-11 and C-13 positions in tubulysin D was achieved by employing 1'-epi-Tuv-Me, 3'-epi-Tuv-Me, and ent-Tuv-Me and their biological properties were evaluated. It is clear that the stereochemistries of the C-11 and C-13 positions in tubulysin D have no practical impact on the inhibition of tubulin polymerization but play a role in the potent antiproliferative activities.

0 Bookmarks
 · 
118 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Tup fragments of tubulysins were synthesized with a tandem reaction as the key step, and unexpected diastereoselectivity was observed in the first Grignard addition stage. The coupling of the enolate of a thiazolyl ketone with chiral sulfinimines furnished the backbone of the Tuv fragment with over 100:1 d.r. and high yield. Thus, tubulysin U and C-4 epi-tubulysin U were prepared in a highly selective and efficient manner. The results of the MTT assay furthermore indicated that C-4 epi-tubulysin U maintained significant growth inhibition activities against several cancer cell lines.
    Chemistry - An Asian Journal 04/2013; 8(6). DOI:10.1002/asia.201300051 · 4.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Covering: July 2010 to June 2012. Previous review: Nat. Prod. Rep., 2011, 28, 1143-1191.Structurally diverse alkaloids containing five-membered heterocyclic subunits, such as imidazole, oxazole, thiazole, as well as their saturated congeners, are widely distributed in terrestrial and marine organisms and microorganisms. These naturally occurring secondary metabolites often exhibit extensive and pharmacologically important biological activities. The latest progress involving isolation, biological activities, chemical synthetic studies, and biosynthetic pathways of these natural products has been summarized in this review.
    Natural Product Reports 05/2013; DOI:10.1039/c3np70006b · 10.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The development of a new photolabile protecting group containing an additional allyl functionality allows the synthesis of cyclic photoactivatable natural products. Cyclization occurs between the allyl moiety in the protecting group and a second double bond in the target molecule by means of ring-closing metathesis. Cyclization should increase the metabolic stability towards proteases. On the other hand, the conformational change should cause diminished biological activity. As illustrated for tubulysin derivatives, cyclic and photoactivatable drug candidates can easily be obtained in only two steps from simple building blocks through Ugi reaction and ring-closing metathesis. The photolabile protecting group is introduced by means of the isocyanide component during the Ugi reaction.
    Angewandte Chemie International Edition 09/2014; 53(42). DOI:10.1002/anie.201405650 · 11.34 Impact Factor