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: 2.42). 01/2011; 21(1):431-4. DOI: 10.1016/j.bmcl.2010.10.118
Source: PubMed


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.

7 Reads
  • [Show abstract] [Hide abstract]
    ABSTRACT: The synthesis of a new generation of highly cytotoxic tubulysin analogues (i.e., tubugis) is described. In the key step, the rare, unstable, and synthetically difficult to introduce tertiary amide-N,O-acetal moiety required for high potency in natural tubulysins is replaced by a dipeptoid element formed in an Ugi four-component reaction. Two of the four components required are themselves produced by other multicomponent reactions (MCRs). Thus, the tubugis represent the first examples of the synthesis of natural-product-inspired compounds using three intertwined isonitrile MCRs.
    Journal of the American Chemical Society 05/2011; 133(20):7692-5. DOI:10.1021/ja2022027 · 12.11 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The syntheses of new tubulysin analogues are described, in which the central amino acid, tubuvaline, is replaced by the rather simple building blocks phenyltubuvaline and phenoxytubuvaline. These analogues can be obtained in only two to three steps from easily accessible starting materials. Although the new derivatives are less active than the tubulysins, their activities towards U-2 OS tumor cells are still in the nanomolar range. New tubulysin analogues are described in which the central amino acid, tubuvaline (Tuv), is replaced by simple building blocks, which can be obtained in two to three steps from easy accessible startingmaterials. Although the new derivatives are less active than the tubulysins, their activities towards tumor cells are still in thenanomolar range.
    European Journal of Organic Chemistry 06/2011; 2011(16):3050–3059. DOI:10.1002/ejoc.201100155 · 3.07 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Ireland-Claisen rearrangement is the central step in the synthesis of tubuphenylalanine, a key building block of the highly antitumor-active tubulysins. The rearrangement of substituted β-amino acid allyl esters, in combination with subsequent decarboxylation and oxidative cleavage of the double bond, allows the highly stereoselective introduction of substituents into the α-position of the resulting γ-amino acids.
    The Journal of Organic Chemistry 10/2012; 78(1). DOI:10.1021/jo301693d · 4.72 Impact Factor
Show more