Current Organic Chemistry - Volume 8, Issue 17, 2004

Metabolites of the thermophilic fungi Myriococcum albomyces and Mycelia sterilia such as myriocin (1), the mycestericins (2-8) and the sphingofungins (13-18) structurally resemble the sphingosines, important components of cell membranes. All the compounds revealed in vitro remarkable immunosuppressive activity and their pharmaceutical potential has led to the development of promising novel immunosuppressants. This review article describes the abundance, biology and chemistry of these metabolites.

Regio- and stereoselective hydroxylation of non-activated carbon atom is a very important reaction, but it remains a significant challenge in classic chemistry. Biohydroxylation provides a useful alternative, and considerable progress has been made recently in the discovery of new catalysts and the improvement of catalysis by substrate engineering. High throughput screening of microorganisms with a miniaturized system enables the fast identification of several new bacterial catalysts. One of them, Sphingomonas sp. HXN-200, exhibiting a broad substrate range, high activity, and high regio- and stereoselectivity, has been successfully used for practical hydroxylation. Substrate engineering based on “docking / protecting” group concept increases the substrate acceptance and regio- and stereoselectivity of known enzymatic systems, significantly extending the scope of biohydroxylations in organic synthesis. Directed evolution and site-directed mutagenesis of P450 monooxygenases, such as P450BM-3 and P450cam, have created enzymes with new substrate specificity, high activity, high selectivity, or high stability.

In this review, recent application of trifluoroacetaldehyde ethyl hemiacetal (TFAE) in the preparation of α-trifluoromethyl alcohols and α-trifluoromethyl amines, especially by the direct regioselective and stereoselective substitution of TFAE and its derivatives like imines with various aromatic and heteroaromatic compounds, is reviewed. Moreover, some useful methods for preparing important potentially bioactive fluorinated compounds, such as o- and p-substituted fluoroalkylphenols and β-trifluoromethyl amino acids, are also introduced.

Phospholipases A2 constitute the major components from Bothrops snake venoms and have been extensively investigated not only because they are relatively very abundant in these venoms but mainly because they display a range of many relevant biological effects, including: myotoxic, cytotoxic, edemainducing, artificial membrane disrupting, anticoagulant, neuromuscular, platelet aggregation inhibiting, hypotensive, bactericidal, anti-HIV, anti-tumoural, anti-malarial and anti-parasitic. The primary structures of several PLA2s have been elucidated through direct amino acid sequencing or, inderectly, through the corresponding nucleotide sequencing. Two main subgroups were thus described: (i) Asp49 PLA2s, showing low (basic, highly myotoxic) to relatively high (acidic, less or non myotoxic) Ca++-dependent hydrolytic activity upon artificial substrates; (ii) Lys49 PLA2s (basic, highly myotoxic), showing no detectable hydrolytic activity on artificial substrates. Several crystal structures of Lys49 PLA2s from genus Bothrops have already been solved, revealing very similar fold patterns. Lack of catalytic activity of myotoxic Lys49- PLA2s, first related solely with the fact that Lys49 occupies the position of the calcium ion in the catalyticly active site of Asp49 PLA2s, is now also attributed to Lys122 which interacts with the carbonyl of Cys29 hyperpolarising the peptide bond between Cys29 and Gly30 and trapping the fatty acid product in the active site, thus interrupting the catalytic cycle. This hypothesis, supported for three recent structures, is also discussed here. All Asp49 myotoxins showed to be pharmacologically more potent when compared with the Lys49 variants, but phospholipid hydrolysis is not an indispensable condition for the myotoxic, cytotoxic, bactericidal, anti-HIV, anti-parasitic, liposome disrupting or edema-inducing activities. Recent studies on site directed mutagenesis of the recombinant Lys49 myotoxin from Bothrops jararacussu revealed the participation of important amino acid residues in the membrane damaging and myotoxic activities.

The marine sponges are the source of a unique group of natural products featuring a novel skeleton, the two indole rings were directed linked by a central heterocyclic moiety. Since topsentin, a bis(indolyl)imidazole, and its analogues were isolated from Topsentia genitrix about a decade ago, scientists have isolated various novel bis(indole) alkaloids from marine organisms especially from deep-water sponges in succession. Over the last 15 years there has been an ever-increasing interest in the biological activity of these molecules. These studies became possible as a result of the scientific development of isolation, purification and total synthesis methods concomitant with the development of fairly simple in vitro tests. This paper offers a general view of the recent progress in the field of novel marine bis(indole) alkaloids, including the topsentins, nortopsentins, rhopaladins, hamacanthins, and dragmacidins family natural products. It focuses on the isolation, structure determination, and total synthesis of these bioactive alkaloids.

The redox chemistry of different quinones is focused to understand how the reduction products can be stabilized by supramolecular interactions or how they can react through different proton transfer mechanisms. This reactivity depends not only on the electronic properties of the substituents, but also on different structural effects related to the formation of intra and intermolecular hydrogen bonds. In order to explore a wider spectrum for covalent and non-covalent interactions, several proton donors and substituted quinone structures have been tested in two aprotic solvents as dimethyl sulfoxide and acetonitrile. The presence of an amino group between the quinone system and a substituted aromatic ring, allows the smooth transmission of the substituent electronic effect provoking a gradual modification of the quinone redox and basicity properties. It has been shown, in α-phenolicnaphthoquinones ¸ that intramolecular hydrogen bond association stabilizes both electrogenerated radical-anion and dianion, which modifies the reactivity of both intermediaries. Regarding the presence of external hydrogen-bond donors, it has been proposed that the stoichiometry and thermodynamics of the intermolecular hydrogen bond association process can be related to: the basicity properties of the quinone and the acidity constant values of both, electroreduced quinone intermediaries and proton donor species. In the same way, the number of α-hydrogens contained in the quinone nucleus and the geometry of the association complexes involving the intermediaries are both related to their stability, which alternatively is totally modified when direct protonation reactions appear in the reaction pathways. The self-protonation reactions of quinones (α-hydroxy quinones) afford a very illustrative example to do this kind of modifications. From the examples discussed here, it was concluded that the different strategies reviewed could allow tuning the reactivity of a specific quinone system, in order to test and to predict new molecules for biological applications.