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2004
Fused pyrrole derivatives
R 0160
Structure—Activity Relationships of Epolactaene Derivatives: Structural
for Inhibition of Hsp60 Chaperone Activity. — New derivatives of
52- 102 Requirements
epolactaene, a fungal metabolite containing an epoxide, a γ-lactam ring and an alkyl
side chain bearing a triene moiety are prepared. Derivatives (X) are prepared from aldehydes (II) by diastereoselective reactions. Aldehydes (II) are treated with the newly
developed Horner—Emmons reagent (I) to give the β-ketonitriles (III), which upon
Knoevenagel condensation with propanal (IV) in the presence of a catalyst afford adducts (V) as single E-isomers. Both the bulky nucleophile and the Tes protecting group
are essential for the high selectivity observed for the formation of epoxides (VI). Finally, deprotection, mild nitrile hydrolysis and oxidation afford epolactaene derivatives
(X). Potent derivatives like ETB, EPO-L (Xb), and EPO-M (XI) are identified. The
lactam moiety is critical to the growth inhibition of human cancer cells and to the modification of human Hsp60. Furthermore, the length of the alkyl chain and the α,β-unsaturated ketone are important features for inhibition of Hsp60 chaperone activity. —
(NAGUMO, Y.; KAKEYA, H.; YAMAGUCHI, J.; UNO, T.; SHOJI, M.; HAYASHI,
Y.; OSADA*, H.; Bioorg. Med. Chem. Lett. 14 (2004) 17, 4425-4429; Antibiot. Lab.,
RIKEN Inst., Wako, Saitama 351-01, Japan; Eng.) — H. Hoennerscheid
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