Synthesis of plaunotol derivatives and their antibacterial activities against Helicobacter pylori.

Plaunotol, a known antiulcer drug, has antibacterial activities against Helicobacter pylori. Plaunotol thiourea derivatives 2--4 and diol derivatives 6--10 were designed in search for a compound with high antibacterial activities. Thiourea derivatives 2--4 were synthesized regioselectively using our effective synthetic route for plaunotol (1), and diol derivatives 6--10 were also synthesized. Their antibacterial activities against H. pylori are described and we found that the most potent antibacterial agent was C1-thiourea derivative 2c.

Bis(2,2,2-trifluoroethyl)bromophosphonoacetate, a Novel HWE Reagent for the Preparation of (E)-alpha-Bromoacrylates: A General and Stereoselective Method for the Synthesis of Trisubstituted Alkenes.

A novel reagent, methyl bis(2,2,2-trifluoroethoxy)bromophosphonoacetate (3a), was designed and prepared in order to efficiently synthesize (E)-alpha-bromoacrylates, which are useful precursors for various C-C bond formations. Honer-Wadsworth-Emmons (HWE) reaction of various aldehydes with 3a in the presence of t-BuOK and 18-C-6 gave the corresponding (E)-alpha-bromoacrylate derivatives with high stereoselectivity. Using the (E)-alpha-bromoacrylate as a key intermediate, a general stereoselective synthesis of trisubstituted alkenes via Pd-catalyzed cross-coupling was developed.

Absolute configuration of scyphostatin

[reaction: see text] The absolute configuration of the side chain of scyphostatin (1) has been established. The chemical degradation of 1 gave 4 and 9, which correspond to the C7'-C12' and C13'-C16' fragments of the natural products, respectively. The spectroscopic data and [alpha]D values of both compounds were compared to those of authentic samples. The results show that the absolute configuration of 1 is 8'R,10'S,14'R.

Conformational analysis and docking study of potent factor XIIIa inhibitors having a cyclopropenone ring.

A conformational analysis and docking study of potent factor XIIIa inhibitors having a cyclopropenone ring were carried out in an attempt to obtain structural insight into the inhibition mechanism. First, stable conformers of the inhibitors alone were obtained from the conformational analysis by systematic search and molecular dynamics. Next, a binding form model of factor XIIIa was built based on an X-ray crystal structure of the enzyme. Finally, the docking study of the inhibitors into the model's binding site was performed. From the resulting stable complex structures, it was found that the cyclopropenone ring fits the active site located at the base of the binding cavity with high complementarity. The carbonyl oxygen of the cyclopropenone ring formed a hydrogen bond to the indole NH group of Trp279 and the terminal carbon atom of the reactive C=C double bond was in close proximity to the sulfur atom of the catalytic residue, Cys314. This binding mode suggests a possible inhibition mechanism, whereby the cysteine residue reacts with the cyclopropenone ring of the inhibitor, forming an enzyme-ligand adduct. In addition, the higher interaction energies between factor XIIIa and the inhibitors alluded to the probable binding sites of the ligand side chain.

A highly stereoselective synthesis of plaunotol and its thiourea derivatives as potent antibacterial agents against Helicobacter pylori.

Practical and highly stereoselective synthesis of diterpene alcohol, plaunotol (1) and its thiourea derivatives 2a, 3a and 4a, via Z-selective Wittig reaction between alpha-acetal ketone 5 and phosphonium salt 6 and their antibacterial activity against Helicobacter pylori are described.

Schizostatin, a novel squalene synthase inhibitor produced by the mushroom, Schizophyllum commune. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activities.

In the process of screening for squalene synthase inhibitors from microbial fermentation products we have isolated a novel compound, named schizostatin (Fig. 1), from the culture broth of the mushroom, Schizophyllum commune SANK 17785. Schizostatin inhibited rat liver microsomal squalene synthase dose dependently and the IC50 value was 0.84 microM. The inhibition was competitive with respect to farnesylpyrophosphate with a Ki value of 0.45 microM.

Schizostatin, a novel squalene synthase inhibitor produced by the mushroom, Schizophyllum commune. II. Structure elucidation and total synthesis.

Schizostatin (1) has been isolated as a potent and selective inhibitor of squalene synthase. Its structure has been determined using spectroscopic methods: the compound is shown to be a diterpenoid which has a trans-dicarboxylic acid moiety. Total synthesis of schizostatin (1) was achieved by the highly regio- and stereoselective coupling reaction of an allylic bromide with a barium reagent. The Z-isomer 16 was also prepared using the stereoselective syn-addition of an organocopper reagent to acetylenedicarboxylate.

Highly potent and specific inhibitors of human renin.

We designed aldehyde derivatives of small peptides representing the C-terminal portion of angiotensin I sequence as an inhibitor of human renin. Among compounds that we synthesized, benzyloxycarbonyl (Z)-Phe-His-Leucinal (compound V), Z-Pro-Phe-His-Leucinal (Compound IV) and Z-[3-(1'-naphthyl)Ala]-His-Leucinal (compound VII) markedly inhibited human renin (IC50, 7.5 X 10(-7), 3.2 X 10(-7) and 8.0 X 10(-8) mol/l, respectively). Compound VII was shown to be noncompetitive (Ki = 2.4 X 10(-7) mol/l). It did not inhibit either cathepsin D or pepsin. Compound V had slight or no inhibitory effect at the concentration of 10(-5) mol/l on six animal renins except for monkey and rabbit renins. Results obtained show that these aldehyde compounds are highly selective and species specific inhibitors for human and monkey renins.