Structure-activity relationships of precursors and analogs of natural 3-enoyl-tetramic acids.

Fragments and synthetic precursors prepared en route to the macrocyclic 3-acyltetramic acids (=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 ß-hydroxy-octatrienoyl amide precursor to aburatubolactam also exhibited distinct activity with an IC50 (120 h) value of <2.5 µM. 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.

A selective 3-acylation of tetramic acids and the first synthesis of ravenic acid.

3-Acyltetramic acids, including delicate 3-oligoenoyl derivatives, such as the Penicillium metabolite ravenic acid, were prepared in two high-yielding steps. Reaction of tetramic acids with the ylide Ph(3)PCCO afforded exclusively the corresponding 3-acylylidenetetramic acids. These were amenable to Wittig olefinations with aliphatic, aromatic, saturated and unsaturated aldehydes after deprotonation with KOtBu. Due to its simplicity, selectivity and tolerance of pH-sensitive groups this method is superior to the established acylation protocols by Jones and Yoshii. It is also applicable to the synthesis of 3-acyltetronic acids. The new 3-oligoenoyl tetramic acids exhibited structure-dependent antimicrobial and cytotoxic activity.

Tetramic and tetronic acids: an update on new derivatives and biological aspects.

Significant developments in the isolation of tetramic acids and tetronic acids, in the elucidation of their biosyntheses and their biological activities and in laboratory syntheses are reviewed with a focus on those derivatives with medicinal and pharmacological relevance. Important new members of the title compound families isolated since the year 2000 are covered as well as new biological aspects of some earlier congeners.