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 ( 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

Chemical and Biological Aspects of Nutritional Immunity—Perspectives for New Anti‐Infectives that Target Iron Uptake Systems

“…[101,102] It was also shown that synthetic analogues and precursors of the macrocyclic 3ATA aburatubolactam and macrocidin A (61)c an have antibacterial activities. [103,104] An antibacterial screening of the fungus metabolite torrubiellone D( 62) revealed distinctly different activities of its four stereoisomers against drug-susceptible E. coli strains (Figure 18). [105] The influence of the metal-ion concentrations,i np articular of Fe 3+ ,h as not yet been studied.…”

Synthesis of 3-acyltetramates by side chain manipulation and their antibacterial activity

“…[1][2][3] Several are of interest for their antibacterial activity, notable examples being equisetin, 4 reutericyclin, 5 kibdelomycin, 6 and streptolodygin, 7 and significant progress in the development of synthetic routes to such systems 8 and their analogues has recently been made. 3 Interestingly, methodology for the general preparation of β-tricarbonyl systems is scarce, 9 and we have recently reported methodology providing access to highly substituted 3-acyltetramates, which relies upon Dieckmann cyclisation of templates 2 derived from serine, 10 threonine 11 or cysteine, 12 the chemoselectivity of which can be controlled by judicious use of reaction conditions and substituents to give products 3 and/or 4 (Scheme 1). 13 Moreover, we have established a reliable approach for the introduction of diverse 3-acyl groups into either of 3 or 4, 14 and this permits rapid generation of chemical diversity around the core tetramate scaffold.…”

Chemische und biologische Aspekte von “Nutritional Immunity” – Perspektiven für neue Antiinfektiva mit Fokus auf bakterielle Eisenaufnahmesysteme

“…[99,100] Die Bildungskonstanten der Komplexe von Fe 3+ mit 3ATA sind denen von typischen Siderophoren, wie Pyoverdin, ähnlich. [103,104] Ein antibakterielles Screening mit dem Pilzmetaboliten Torrubiellon D( 62)zeigte unterschiedliche Aktivitäten seiner vier Stereoisomere gegen empfindliche E.-coli-Mutanten (Abbildung 18). Deshalb haben Fe 3+ (3ATA-H) 3 -Komplexe pM-Werte,d ie deutlich niedriger sind als die von Ferrisiderophoren.…”

“…[101,102] Auch synthetische Analoga und Vorstufen der makrocyclischen 3ATA Aburatubolactam und Macrocidin A( 61)k çnnen antibakterielle Eigenschaften haben. [103,104] Ein antibakterielles Screening mit dem Pilzmetaboliten Torrubiellon D( 62)zeigte unterschiedliche Aktivitäten seiner vier Stereoisomere gegen empfindliche E.-coli-Mutanten (Abbildung 18). [105] Der Einfluss von Metallionenkonzentrationen, insbesondere von Fe 3+ ,w urde noch nicht untersucht.…”