Synthesis and biological activities of new conformationally fixed analogues of (−)-indolactam-V, the core structure of tumor-promoting teleocidins

Bioorganic & Medicinal Chemistry Letters
1995.0

Abstract

(-)-lndolactam-V (1) exists as two stable conformers, the twist and the sofa form, in solution at room temperature. 3-Aza-Cope rearrangement of (-)-N13-desmethyl-N13-allylindolactam-V (5) gave new conformationally restricted analogues (2a and 3) along with a normal rearrangement product (7). Both 2a and 3, whose fixed conformation was the twist form, showed significant biological activities related to tumor promotion.Tumor-promoting teleocidins 1,2 and their core structure (-)-indolactam-V (1) 3,4 exist as two stable conformers, the twist and the sofa form, in solution at room temperature (Figure 1 and 2). 5 To elucidate the common structural features among several TPA-type tumor promoters with different skeletons and quite similar biological activities (teleocidins, phorbol esters and aplysiatoxins), 2 it is indispensable to know the active conformation of teleocidins. Synthesis of conformationally restricted analogues of 1 is one of the most promising approaches. We have previously reported the synthesis of (-)-5-fluoroindolactam-V existing mainly as the sofa conformation, and shown that at least the sofa conformation is not the biologically active form. 6 This communication describes the synthesis and biological activities of novel twist-restricted analogues (2a and 3) along with those of a sofa-restricted analogue, (-)-5-methylindolactam-V (4) as a negative control.

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