Pironetin

A surprising feature of the recently discovered compound pironetin is that its binding to a-tubulin inhibits the binding of vinblastine to /i-tubulin... 

Kondoh, M., Usui, T., Nishikiori, T., Mayumi, T., and Osada, H. (1999). Apoptosis induction via microtubule disassembly by an antitumour compound, pironetin. Biochem.J. 340, 411-416. 

K, Watanabe, H., Nishikawa, K, Kitahara, T., and Osada, H. (2004). The anti-cancer natural product pironetin selectively targets Lys352 of a-tubulin. Chem. Biol. 11, 799-806. 

Usui T, Watanabe H, Nakayama H, Tada Y, Kanoh N, Kondoh M, Asao T, Takio K, Watanabe H, Nishikawa K, Kitahara T, Osada H (2004) The anticancer natural product pironetin selectively targets Lys352 of a-tubulin. Chem Biol 11 799-806... 

The efficiency and practicality of pseudoephedrine-based asymmetric alkylation reactions has been exploited in syntheses of several complex natural products, including cylindrocyclo-phane A, fumonisin B2, pironetin, epothilones A and B, salicylihalamide A, 6,7-dideoxysqualestatin H5, saframycin A,34,35 gjjjj terpestacin. ... 

The total synthesis of the immunosuppressant (-)-pironetin (PA48153C) was accomplished by G.E. Keck and co-workers. The six-membered a,(3-unsaturated lactone moiety was installed using a lactone annulation reaction by reacting the advanced aldehyde intermediate with the lithium enolate of methyl acetate. The aldehyde was prepared by the Ley oxidation of the corresponding primary alcohol and was used without purification in the subsequent annulation step. 

Scheme 4.15 Catalytic asymmetric total synthesis of natural product (-)-pironetin.

Discovery Pironetin (1) was isolated as a plant growth regulator that induces shortening of the plant height of rice [1,2] and as an immunosuppressor that inhibites the blastogenesis of both T and B cells [3]. 

Biochemical Studies Pironetin showed antitumor activity against a murine tumor cell line, P388 leukemia, transplanted in mice [4], and induced the... 

Identification of Molecular Target According to the structure-activity relationship analyses, it was speculated that pironetin binds to tubulin covalently by Michael addition via its a,P-unsaturated 8-lactone [6], The biotinylated pironetin... 

Kobayashi, S., Tsuchiya, K., Harada, T., et al. (1994). Pironetin, a novel plant growth regulator produced by Streptomyces sp. NK10958 I. Taxonomy, production, isolation and preliminary characterization. J. Antibiot., 47, 697-702. 

Kondoh, M., Usui, T., Kobayashi, S., et al. (1998). Cell cycle arrest and antitumor activity of pironetin and its derivatives. Cancer Lett, 126, 29-32. 

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