Fragments and synthetic precursors prepared en route to the macrocyclic 3-acyltetramic acids ( ¼ 3-acyl-1,5-dihydro-4-hydroxy-2H-pyrrol-2-ones) aburatubolactam and macrocidin A, as well as other analogs with variance in the ring heteroatom (N, O, S), and the residues at N(1), C(3), and C(5) were tested for cytotoxic and antimicrobial effects. Anticancer activity against various tumor cell lines in vitro did not necessarily require an intact pyrrolidin-2,4-dione ring. An acyclic b-hydroxy-octatrienoyl amide precursor to aburatubolactam also exhibited distinct activity with an IC 50 (120 h) value of < 2.5 mm. The length of 3-oligoenoyl residues had little influence on the anticancer activity, but 3-alka-oligoenoyl tetramic acids were far more efficacious than their 3-(4-methoxycinnamoyl) congeners. N-H-3-acyltetramic acids were generally more active than their N-Me or N-Boc analogs, unless further polar groups necessitated an increased lipophilicity for sufficient uptake. Tetronic and thiotetronic acids were far less antiproliferative in cancer cells when compared with identically substituted tetramic acids.Introduction. -Tetramic acids (i.e., 1,5-dihydro-4-hydroxy-2H-pyrrol-2-ones) are produced by a variety of marine and terrestrial organisms such as sponges, cyanobacteria, bacteria, and fungi. They frequently show biological activity in man, including antibiotic, anticancer and anti-inflammatory effects, which had been assessed in reviews by Rosen . Pharmacologically most interesting are 3-acyltetramic acids 1 (Fig.). They are thought to act by chelating essential metal ions and by mimicking phosphate groups in the binding site of kinases and phosphatases. Their precise molecular targets are mostly unknown. Lately, Waldmann and co-workers [6] showed that the sponge metabolite melophlin A [7] [8] targets dynamins in cells and thus modulates signal transduction via the RAS network leading to a phenotype reversal in MDCK-F3 cells.As a sideline to our synthetic studies of natural bioactive 3-acyl-tetramic acids featuring macrocyclic rings, e.g., cylindramide [9] [10], aburatubolactam (2) [11] [12], and macrocidin A (3) [13], we looked for potential anticancer and antimicrobial activity in fragments and synthetic precursors prepared en route. This study was to clarify whether an intact heterocyclic ring is a prerequisite for activity, and how the latter is affected by the nature of the heteroatom, and the residues at N(1), C(3), and

The three-component reaction between ylide Ph 3 PCCO, amines and aldehydes is known to afford selectively (E)-α,β-unsaturated amides. We applied a variant of this methodology to the preparation of (2E,4Z)-dienamides 11 utilizing the phosphonium salt formation from ethyl 5-aminopentanoate hydrochloride and Ph 3 PCCO followed by deprotonation with DBU and a Wittig olefination of the corresponding ylide with