Antillatoxin is an ichthyotoxic cyclic lipopeptide isolated by Gerwick and co-workers from the marine cyanobacterium Lyngbya majuscula collected in Curacao. Although we have finished the stereoselective total synthesis of antillatoxin having the proposed structure with (4S, 5R) -configuration, we have found that the synthetic sample was not identical with the natural one and the proposed structure should be revised. Further our synthetic efforts have culminated in the first total synthesis of antillatoxin in its natural form, proving that the natural one has (4R, 5R) -configuration. In this account, our total synthesis and synthetic studies by other groups will be discussed.
myol-Inositol, a cyclitol (cyclohexanepolyol) which is classified as a type of carbohydrates, occurs widely in nature and is known as a constituent of a secondary messenger in cells which stimulates the release of calcium from storage site. It is produced in large quantities from plants (rice bran and corn-steep liquors) by food industry. In spite of its abundance in nature and ready availability, myol-inositol has not been utilized widely as the starting material for the synthesis of natural products other than cyclitol derivatives. Given that regioselective ring cleavage of the cyclohexane ring in optically active and functionalized cyclitol derivatives is possible, myol-inositol is expected to be a potential precursor with stereochemical diversity for novel chiral building blocks in the synthesis of various natural products. In this article, preparation and optical resolution of protected myol-inositol derivatives are shortly reviewed. Overview of regioselective ring cleavages of cyclohexanones derived from cyclitols by way of the Baeyer-Villiger reaction, and the syntheses of some natural products based on the methodologies which involve the ring cleavage reaction of myol-inositol, is also described.
Macrocyclic bisbibenzyls specifically occur in the Hepaticae and have been seldom found in other terrestrial plants. We have found most of over 60 congeners which are known so far. Their structural features, biosynthesis and biological activities as well as their distribution in the liverworts are described. Marchantin A (8) and riccardin B (2) which are representative cyclic bisbibenzyls linked via two biphenyl ether C-O bonds have been synthesized by using the intramolecular Wardsworth-Emmons reaction for macrocyclization. Plagiochins A (33) D (36), another cyclic bisbibenzyls having one biphenyl ether C-O and one biaryl C-C bonds, have been synthesized by the intramolecular Pd (0) catalyzed Stine-kelly reaction of the dibromoperrotetin E derivative 93. All of the synthesized plagiochins have been evaluated on neurotrophic activity by rat cortical neuronal culture.
Alkaloids mimicking the structures of sugars inhibit glycosidases because of a structural resemblance to the sugar moiety of the natural substrate. Glycosidases are involved in a wide range of important biological processes, such as intestinal digestion, post-translational processing of glycoproteins and the lysosomal catabolism of glycoconjugates. The realization that alkaloidal glycomimetics might have enormous therapeutic potential in many diseases such as viral infection, cancer and diabetes led to increasing interest and demand for these compounds. The usefulness of alkaloidal glycomimetics might not be restricted to the inhibition of glycosidases since a number of different competitive inhibitors, all known to stabilize proteins in their native conformation, are effective in rescuing the processing defect of the mutant enzyme protein. These compounds, which we call “chemical chaperones”, also may prove to be effective in correcting a number of other protein folding abnormalities in human genetic diseases.
Recent advances in computer technology and dramatic cost reductions for physical memory and operation speed now allow the ability to access the millions of compounds needed to search and analyze three-dimensional (3D) structural as well as conformational information. As a result, 3D database searching methods are considerably useful in finding and designing novel biologically active compounds. In the presence of a protein structure, 3D databases are searched directly for potential compounds fitting a known receptor binding site. In the absence of a protein structure, 3D databases can be searched indirectly, fitting known lead compounds on the basis of pharmacophore. As reviewed in this article, 3D database searching can provide valuable information to medicinal chemists, offering an expanding range of tools to enhance the lead drug discovery and evolution process.
A series of conformationally constrained nucleoside analogues with two hydroxymethyl groups mimicking the 3'- and 5'-hydroxyl groups of the 2'-deoxyribose were prepared and evaluated for their antiherpetic activity. Among those, 9- [[cis-1'-, 2'-bis (hydroxylmethyl) cycloprop-1'-yl] methy] guanine showed extremely potent antiviral activity against HSV-1. One of the enantiomers with (1'S), (2'R) -configuration (A-5021) was proved to be the active form. A-5021 was more active than acyclovir (ACV) against HSV-1, HSV-2, VZV, HCMV and showed superior activity over ACV in animal models. An efficient process for preparation of A-5021 including enantioselective hydrolysis of the intermediate is described. An oral prodrug AV-038 and anti-VZV drug AV-100 are also described.
Mechanistic studies on the enantioselectivity in the hydrolase-catalyzed kinetic resolutions of racemic alcohols are described. Based on kinetic measurements, molecular orbital calculations and computer modeling with X-ray crystal structures of several lipases, we proposed the transition-state model that is consistent with the experimental observations such as (i) high enantioselectivity, (ii) broad substrate specificity and (iii) an empirical rule (R-preference for secondary alcohols). A large secondary alcohol having a tetraphenylporphyrin as the substituent was successfully resolved by several lipases, demonstrating the validity of our transition-state model. The S-preference of subtilisins for secondary alcohols was rationalized by applying the protocol used in the transition-state model for lipases to subtilisins. We also found that the lipasecatalyzed transesterifications of chiral alcohols in organic solvents can proceed even at -40°C. Interestingly, theE value increased with decreasing temperature, and a linear relationship was observed between In E and 1/T, from which the ΔΔH‡and ΔΔS‡ values were calculated. These thermodynamic parameters were useful for investigating the mechanism of the enantioselectivity of the hydrolases toward chiral alcohols.