title: Structure-activity relationships of precursors and analogs of natural 3-enoyl-tetramic acids.
abstract: 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 β-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.
authors.affiliation: Universität Bayreuth, Bayreuth.
authors.forename: Bertram
authors.initials: B
authors.lastname: Barnickel
authors.forename: Frances
authors.initials: F
authors.lastname: Bayliffe
authors.forename: Randi
authors.initials: R
authors.lastname: Diestel
authors.forename: Karl
authors.initials: K
authors.lastname: Kempf
authors.forename: Sabine
authors.initials: S
authors.lastname: Laschat
authors.forename: Steffen
authors.initials: S
authors.lastname: Pachali
authors.forename: Florenz
authors.initials: F
authors.lastname: Sasse
authors.forename: Andrea
authors.initials: A
authors.lastname: Schlenk
authors.forename: Rainer
authors.initials: R
authors.lastname: Schobert
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000097566:Cyclophanes
chemical_list: D047029:Lactams, Macrocyclic; D011760:Pyrrolidinones; C482758:macrocidin A; D000097566:Cyclophanes; C009435:tetramic acid