[Successful treatment with the combination of recombinant human soluble thrombomodulin and gabexate mesilate in three patients with obstetric disseminated intravascular coagulation].

Recombinant human soluble thrombomodulin (rTM) is a new drug for the treatment of disseminated intravascular coagulation (DIC), although the effects on obstetric DIC have not yet been fully elucidated. We report herein three patients with obstetric DIC caused by placental abruption, hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, and atonic bleeding, respectively. In all three cases, treatment with rTM proved successful, suggesting that rTM is an efficient method for treating obstetric DIC.

Development of novel EDG3 antagonists using a 3D database search and their structure-activity relationships.

Sphingosine-1-phosphate (S1P) is an intracellular second messenger and an extracellular mediator through endothelial differentiation gene (EDG) receptors, which are a novel class of G-protein-coupled receptors. Although EDG has attracted much attention because of its various roles, no selective agonists or antagonists have yet been developed. This could account for the delay in clarifying the physiological roles of members of the EDG family. Because precise structural information on EDG receptors is not yet available, pharmacophore models were generated based on structural information for S1P using the rational drug design software Catalyst. Novel antagonists, 2-alkylthiazolidine-4-carboxylic acids, were retrieved from a three-dimensional database search using the pharmacophore models, and these showed activity for EDG3. On the basis of their nonphosphoric acid structure, more potent antagonists, 2-(m- or p-heptylphenyl)thiazolidine-4-carboxylic acid, were developed.

Asymmetric Addition of Alkyllithium to Chiral Imines: alpha-Naphthylethyl Group as a Chiral Auxiliary.

The diastereoselective nucleophilic addition of alkyllithium to N-alkylidene-alpha-naphthylethylamine was carried out. In the presence of Lewis acids or Lewis bases, organolithiums reacted smoothly with imines to give the corresponding amines in high stereoselectivity (up to 100% de). Furthermore, the resulting optically active amines were found to be useful for asymmetric reactions as chiral ligands.

Lewis Acid-Promoted Coupling Reactions of Acid Chlorides with Organoaluminum and Organozinc Reagents.

An efficient synthesis of alpha,beta-unsaturated ketones by the reaction of acid chlorides with trialkylaluminum (1/3 mole equiv) in the presence of AlCl(3) (1 mol equiv) is described. Dialkylzincs were also useful and are easier to prepare than trialkylaluminum. Reaction of RCOCl with R'AlCl(2) or R'(2)AlCl gave R'COR, without AlCl(3), in high yield.

Chiral Lewis Acid-Mediated Enantioselective Pictet-Spengler Reaction of N(b)-Hydroxytryptamine with Aldehydes.

The first example of a reagent-controlled enantioselective Pictet-Spengler reaction is demonstrated. Using diisopinocampheylchloroborane as a chiral Lewis acid catalyst, the Pictet-Spengler reaction of N(b)-hydroxytryptamine with aldehydes gave the corresponding 2-hydroxytetrahydro-beta-carbolines in up to 90% ee. The enantioselective Pictet-Spengler reaction catalyzed by chiral binaphthol-derived Brønsted acid-assisted Lewis acids, with up to 91% ee, is also demonstrated.

Recent developments in marine indole alkaloid synthesis.

The manzamine alkaloids such as manzamine A, B, and C belongs to a unique family of cyctotoxic beta-carbline linked azacycles, which have been isolated from several marine sponges. Manzamine A has recently been shown to exhibit in vivo antimalarial activity against parasite Plasmodium berghei. Further progress was added recently by the isolation of the new and closely related members such as nakadomarin A, as well as an ingenious proposal for their biosynthetic pathway. Martefragin A, isolated from the Japan sea alga Martensia fragilis Harvey, has been shown to have a potent inhibitory activity against lipid peroxidation. Our recen, efforts to develop total synthesis entries to manzamine A, manzamine B, manzamine C, nakadomarin A, and martefragin A are presented.

[Synthetic study of biologically important nitrogen containing natural products: development of new methodology and design of leading compounds for new pharmaceuticals].

Synthetic study of biologically important nitrogen-containing natural products and development of new methodologies and design of leading compounds for new pharmaceuticals are described. The first total synthesis of eudistomines, manzamine C, martefragin A, cerebroside B1b, and symbioramide was accomplished and the absolute configurations of the stereogenic centers were determined. A novel methodology useful for the synthesis of alkaloids that have perhydroisoquinoline ring system such as manzamine A and B, and related alkaloids, nakadomarin A and dynemicin A, is presented. Sphingolipids, 4-stereoisomers of 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol, were synthesized and antimalaria activity was investigated. Inhibition of DNA primase by sphingosine and its analogues is described. A new synthetic methodology for alkylation and reduction of imines has been developed, and the first example of a reagent-controlled enantioselective Pictet-Spengler reaction is described. Also novel and convenient methods using transition metal and rare earth metals including alkene metathesis, asymmetric Diels-Alder reaction, imino ene reaction, selective allylic halogenation, enantioselective Pictet-Spengler reaction, and enantioselective physostigmine synthesis are described.

Non-metathesis reactions of ruthenium carbene catalysts and their application to the synthesis of nitrogen-containing heterocycles.

Non-metathesis reactions of ruthenium carbene catalysts, such as olefin isomerization, hydrogenation, radical reaction, activation of silane, cyclopropanation, epimerization cocyclopropane, [3 + 2] cycloaddition, and cycloisomerization, are summarized. The utility of these reactions was demonstrated by the synthesis of indole using olefin isomerization and subsequent ring-closing metathesis, the synthesis of indoline using cycloisomerization, and the synthesis of the putative structure of fistulosin using cycloisomerization as a key step.

Development of isomerization and cycloisomerization with use of a ruthenium hydride with N-heterocyclic carbene and its application to the synthesis of heterocycles.

A pure ruthenium hydride complex with N-heterocyclic carbene (NHC) ligand was efficiently generated from the reaction of a second-generation Grubbs ruthenium catalyst with vinyloxytrimethylsilane and unambiguously characterized. This ruthenium hydride complex showed high catalytic activity for the selective isomerization of terminal olefin and for the cycloisomerization of 1,6-dienes. These reactions of N-allyl-o-vinylaniline lead to novel synthetic methods for heterocycles such as indoles and 3-methylene-2,3-dihydroindoles, which are useful synthons for bioactive natural products. These procedures address an important issue in diversity-oriented synthesis.

Imino ene reaction catalyzed by ytterbium(III) triflate and TMSCl or TMSOTf.

A novel combined system of Yb(OTf)(3) with TMSCl or TMSOTf catalyzed an imino ene reaction. The reaction of N-tosylbenzaldimine (1) with alpha-methylstyrene (2) proceeded smoothly to give homoallylic amine 3 in the presence of a catalytic amount of Yb(OTf)(3) and TMSCl. This catalytic system was successfully applied to the imino ene reactions of various aldimines with alkenes. This new imino ene reaction provides a unique method for the three-component coupling reaction of an aldehyde, tosylamide, and alpha-methylstyrene in the presence of Yb(OTf)(3) and TMSOTf, to give the corresponding homoallylic amine.

The first total synthesis of nakadomarin A.

(-)-Nakadomarin A is a member of manzamine alkaloid isolated from a marine sponge and have a unique hexacyclic structure. The first total synthesis of (+)-nakadomarin A, an enantiomer of natural product, has been accomplished from stereochemically defined 4-oxopiperidin-3-carboxylic acid derivative. The synthesis established the structure of nakadomarin A including absolute configuration.

Minimum 10-year radiographic follow-up of a cementless acetabular component for primary total hip arthroplasty with a bulk autograft.

We radiographically investigated 36 hips in 34 patients with osteoarthritis of the hip who had undergone total hip arthroplasty. Their mean age was 59.2 years (range 36-79 years), and the mean follow-up period was 11.2 years (range 10-14 years). The long-term outcome and the chronological changes in the bulk autograft were examined. The acetabular component of the prosthesis was a Lord-type threaded cup with a smooth surface. At follow-up, bone absorption was minor in 17 joints, moderate in 11, and major in 8. The hips with graft coverage of >==20% (group A) had a significantly higher loosening rate than hips with coverage of <<20% (group B) ( P << 0.05). The cup position changed markedly in group A. Our findings indicate that graft coverage should be less than 20% when a bulk graft is used together with a smooth-surfaced cementless cup.

Risk factors for nontraumatic osteonecrosis of the femoral head after renal transplantation.

We investigated risk factors for osteonecrosis of the femoral head (ONF) in renal transplant recipients, who are susceptible to the disease. Among 287 renal transplant recipients, 18 ONF patients with enough data were included, and 18 age- and sex-matched recipients without ONF were nominated as reference cases. Risk factors were analyzed using a conditional logistic regression method. There were no differences between the ONF patients and the reference cases regarding the types of immunosuppressant or the donor (living or cadaveric, father or mother, matching blood type and human leukocyte antigens). The daily oral steroid dosage (prednisolone 25.0 mg/day or more) and blood urea nitrogen level 2 months after transplantation were the only factors with relevance to the occurrence of ONF. We propose that oral steroid dosages should be low or reduced after renal transplantation, and acute rejection should be controlled with pulsed therapy.