Synthesis and evaluation of microtubule assembly inhibition and cytotoxicity of prenylated derivatives of cyclo-l-Trp-l-Pro

The synthesis of three isoprenylated derivatives of cyclo-L-Trp-L-Pro is described. These substances have been evaluated for cytotoxic activity in rat normal fibroblast 3Y1 cells and have also been evaluated in vitro for the inhibition of microtubule assembly.

A Synthetic Model for the [4+2] Cycloaddition in the Biosynthesis of the Brevianamides, Paraherquamides, and Related Compounds

Abstract The reactivity of model systems for the proposed [4+2] cycloaddition in the biosynthesis of the brevianamides, paraherquamides, and marcfortines is explored. The model for the intermolecular reaction reveals that the cycloaddition takes place under mild conditions only if activated, very reactive dienophiles are used. When relatively unreactive dienophiles such as cyclopentene and cyclohexene are used, harsh reaction conditions and/or a Lewis acid catalyst are necessary for the reaction. In contrast, the model for the intramolecular reaction demonstrates that the cycloaddition takes place within a few hours at room temperature, even in the absence of a Lewis acid catalyst. Conclusi…

Reverse versus Normal Prenyl Transferases in Paraherquamide Biosynthesis Exhibit Distinct Facial Selectivities

Both a face-selective and a non-face-selective mode of formation of quaternary centers of isoprene-derived structural moieties of the natural alkaloid paraherquamide A (1) have been discovered by feeding experiments on Penicillium fellutanum with [U-13 C6 ]-glucose and [13 C2 ]-acetate. The labeling patterns suggest that the methyl groups (C22, C23) are introduced in a non-face-selective manner by a reverse prenyl transferase. The C5 unit comprising the dioxepin moiety retains stereochemical integrity indicative of a single, face-selective addition of the phenolic group to the dimethylallyl group.

ChemInform Abstract: Studies on the Biosynthesis of Paraherquamide. Construction of the Amino Acid Framework.

Abstract It has been previously established in this laboratory that the β-methyl-β-hydroxyproline moiety of the potent anthelmintic agent paraherquamide A, is biosynthetically derived from l -isoleucine. The downstream events from l -Ile to paraherquamide A have now been investigated. The synthesis of [1- 13 C]-labeled l -β-methylproline is described by means of a Hoffman–Loeffler–Freytag reaction sequence from [1- 13 C]- l -Ile. This amino acid is shown to be a direct biosynthetic precursor to paraherquamide A by feeding and incorporation experiments in growing cultures of Penicillium fellutanum . Three tryptophan-containing dipeptides of l -β-methylproline have been constructed: [ 13 C 2 …

Reverse und „normale”︁ Prenyltransferasen haben unterschiedliche Seitenselektivitäten bei der Biosynthese von Paraherquamid

Sowohl eine seitenspezifische als auch eine seitenunspezifische Bildung quartarer C-Zentren aus von Isopren abgeleiteten Strukturelementen im Alkaloid Paraherquamid A 1 wurden durch [U-13C6]Glucose- und [13C2]Acetat-Futterungsexperimente mit Penicilliumfellutanum entdeckt. Aus dem Markierungsmuster last sich ableiten, das die Methylgruppen (C22, C23) seitenunspezifisch durch eine Reverse Prenyltransferase eingefuhrt werden. In der C5-Einheit, die den Dioxepinrest umfast, bleibt die relative Konfiguration erhalten, was fur eine einzige, seitenspezifische Addition einer Phenoleinheit an die Dimethylallylgruppe spricht.

Biomimetic diels–alder cyclizations for the construction of the brevianamide, paraherquamide, sclerotamide, asperparaline and VM55599 ring systems

Abstract A potentially bio-mimetic Diels–Alder cyclization to construct the bicyclo[2.2.2] ring system common to the paraherquamides, marcfortines, sclerotamides, brevianamides, VM55599, and asperparaline is reported. Epi-deoxybrevianamide E (22) is converted into the corresponding lactim ether (23) and then oxidized with DDQ to provide an azadiene (24) which is tautomerized in the presence of base to azadiene 25 which, spontaneously cyclizes to give a 2:1 mixture of cycloadducts 26 and 27. These cycloadducts are each in turn, converted into d , l -C-19-epi-brevianamide A (20) and d , l -brevianamide B (6). The stereochemical implications of the [4+2] cycloaddition is discussed in the conte…

Studies on the biosynthesis of paraherquamide. Construction of the amino acid framework

Abstract It has been previously established in this laboratory that the β-methyl-β-hydroxyproline moiety of the potent anthelmintic agent paraherquamide A, is biosynthetically derived from l -isoleucine. The downstream events from l -Ile to paraherquamide A have now been investigated. The synthesis of [1- 13 C]-labeled l -β-methylproline is described by means of a Hoffman–Loeffler–Freytag reaction sequence from [1- 13 C]- l -Ile. This amino acid is shown to be a direct biosynthetic precursor to paraherquamide A by feeding and incorporation experiments in growing cultures of Penicillium fellutanum . Three tryptophan-containing dipeptides of l -β-methylproline have been constructed: [ 13 C 2 …

Studies on the Biosynthesis of Paraherquamide: Synthesis and Incorporation of a Hexacyclic Indole Derivative as an Advanced Metabolite