Use of odorless thiols: formal asymmetric Michael addition of hydrogen sulfide to alpha-substituted alpha,beta-unsaturated carbonyl compounds.

[reaction: see text] The Michael addition to alpha-substituted alpha,beta-unsaturated esters and amides using complex A containing a chiral odorless thiol proceeded diastereoselectively. The Michael adducts were converted to beta-mercapto esters and amides via a Wagner-Meerwein rearrangement with boron trifluoride etherate and a thiol exchange reaction using odorless 1-dodecanethiol. This conversion constitutes a formal asymmetric Michael addition of hydrogen sulfide to alpha,beta-unsaturated carbonyl compounds using odorless thiols instead of the toxic hydrogen sulfide.

A species-selective allelopathic substance from germinating sunflower (Helianthus annuus L.) seeds.

From the exudate of germinating sunflower (Helianthus annuus L.) seeds was isolated a stereoisomer of diversifolide, 4, 15-dinor-3-hydroxy-1(5)-xanthene-12,8-olide (designated sundiversifolide) as determined by analysis of its IR, APCI-, ESI- and HR-MS and 13C and 1H NMR spectra. This substance inhibited shoot and root growth of cat's-eyes by about 50% at a concentration of 30 ppm. It also showed species-selective activity on the shoot and root growth of tested plants. When cat's-eyes seeds were incubated together with sunflower seeds, the cat's-eyes growth was inhibited. Furthermore, it was detected from an extract of river sand when sunflower seeds were incubated on the sand. These results indicate that sundiversifolide has an allelopathic function in sunflower plants.

An efficient synthesis of (±)-narwedine and (±)-galanthamine by an improved phenolic oxidative coupling.

Old problems, new ideas! The biomimetic phenol coupling of norbelladine derivatives such as 1 (Bn = benzyl) to form galanthamine (2), a drug used in the treatment of Alzheimer's disease, has been greatly improved by the use of the hypervalent-iodine oxidation reagent phenyliodine(III) bis(trifluoroacetate) (PIFA).

A novel intramolecular through-space interaction between F and CN: a strategy for the conformational control of an acyclic system.

X-Ray crystallographic analyses of fluorocyanides anti-1 and 2 revealed a novel intramolecular through-space interaction between F and CN in an acyclic system, which was applied to a stereoselective protonation of acyclic fluorocyanides 2 having flexible conformation.

[Audiological and equilibrium study of perilymphatic fistulas].

We clinically analyzed 15 cases of perilymphatic fistulas--11 caused by barotraumas and 4 idiopathic--identified by surgery between March 1995 and March 1999 at the Hyogo College of Medicine and affiliated hospitals. Subjects were 11 men and 4 women (aged 14 to 79 years (mean: 46.7 years)). All showed hearing loss in audiography and 12 cases reported tinnitus--stream-like in 5 and poping in 4. Dysequilibrium was seen in 9 cases. Perilymph leakage was detected intraoperatively from the oval window in 9, from the round window in 4, and from both windows in 1, while another had leakage from the fissura ante fenestram. After surgery, hearing level improved by over 10 dB in 9 of the 11 cases operated on within 14 days after onset. Hearing did not improve in 3 of 4 operated on later. Vertigo disappeared after surgery. Dizziness tended to persist in those having canal paresis or paralytic nystagmus before surgery. We suggest that patients with progressive hearing loss should be operated on as soon as possible and that patients with dysequilibrium or without response to conservative treatment undergo surgery within 14 days of onset.

Hinokitiol, a selective inhibitor of the platelet-type isozyme of arachidonate 12-lipoxygenase.

Hinokitiol (4-isopropyltropolone), a constituent of Japanese cypress, reversibly inhibited platelet-type 12-lipoxygenase with an IC(50) of 0.1 microM, and the enzyme activity was almost lost at 1 microM. The compound was much less active with other lipoxygenase enzymes with higher IC(50) values (leukocyte-type 12-lipoxygenase, 50 microM; soybean lipoxygenase, 17 microM; 15-lipoxygenase-1, >100 microM; 5-lipoxygenase, 17 microM). Hinokitiol up to 100 microM had almost no effect on cyclooxygenases-1 and -2. Their structure-activity relationship examined with various tropolone derivatives indicated the requirements of the 2-hydroxyl group and 4-alkyl group for the potent and selective inhibition of platelet-type 12-lipoxygenase.

Long-term observation on hearing change in patients with chronic otitis media.

OBJECTIVE: Very few reports are available in the literature to clarify the natural long course of hearing change in an individual patient with chronic otitis media (COM). We reviewed hearing change in patients suffering from perforated COM without an operation. METHODS: Eighty-seven ears of 70 patients had COM with tympanic perforation and were observed without an operation. The mean follow-up period was 10.7 years (5-22 years) and the mean age at the first examination was 51.3 years. To minimize the effect of aging, 23 patients with normal ear drums on the other side were further analyzed. RESULTS: All 87 ears tended to show deterioration of hearing gradually under long observation. In 23 patients, hearing deterioration was 0.13 dB/year in the control side and 0.61 dB/year in the COM side (P < 0.02). Although elevation of bone conduction hearing level tended to be larger at high frequencies than at low and middle frequencies, there was no significant difference between COM and normal ears. CONCLUSIONS: Air conduction hearing levels deteriorated with the passage of time and surgery is recommended at the early stage of COM to prevent progress of hearing loss.

Synthesis and anti-influenza virus activity of novel pyrimidine derivatives.

Efficient synthetic routes of 2-amino-4-(omega-hydroxyalkylamino)pyrimidine derivatives were investigated in relation to the anti-influenza virus activity of these compounds. The derivatives in which cyclobutyl and cyclopentyl groups were introduced to the beta-position of the aminoalkyl group (especially the cyclobutyl group substituted by a phenylalkyl group at the 3'-position) resulted in improved antiviral potency: i.e. an average 50% effective concentration for inhibition of plaque formation (EC50, microM) of 0.1-0.01 microM for both types A and B influenza virus. The antiviral efficacies were in the order of amino group > hydroxyiminomethyl group > halogen substitution at the 5-position, and chlorine or methoxy group > hydrogen at the 6-position of the pyrimidine ring. The antiviral indices of these compounds were 2-6 with respect to the 50% inhibitory concentration for cell proliferation (IC50, microM) for growing cells, but > 500 to > 10(4) with respect to the IC50 for stationary cells, indicating that these compounds may be efficacious for the topical treatment of influenza virus infection.

Cholesteatoma otitis media with intact ossicular chain.

Thirty-one cases of cholesteatoma with intact ossicular chain were reviewed to examine the extension of cholesteatoma, operation procedures, pre- and postoperative hearing levels, and postoperative condition of the ear drum. They were operated on at Departments of Hyogo College of Medicine and Osaka University Medical School from 1989-1996, which were 20.4% of all of the primary cholesteatoma cases (n = 152). Twelve cases located at attic were operated by atticotomy or canal wall up and scutumplasty, 17 cases located at attic/antrum were operated by canal wall down and reconstruction, and two cases located around stapes were operated through the ear canal. Preoperative hearing level was mild (34.2 +/- 18.4 dB) and postoperative one was slightly improved (28.7 +/- 11.2 dB). In ossicular reconstruction, modified Wullstein type III method showed better hearing gain than Wullstein type I method. Postoperative attic retraction and/or pocket occurred in 15 cases (48.4%), but no recurrent cholesteatoma was found during the present follow-up period. These findings suggested that cholesteatoma with intact ossicular chain showed good postoperative hearing results, but postoperative retraction of the ear drum should be followed up for a long time.

[Sensorineural hearing loss caused by middle ear surgery].

It is well known that sensorineural hearing loss rarely occurs after middle ear surgery. Five cases of postoperative sensorineural hearing loss were reviewed. These operations amounted to 0.9% of all middle ear operations in which the first author was involved. The causes of hearing loss were believed to be labyrinthitis through the fistula in cholesteatoma case 1, and acoustic trauma from the bone-cutting burr in cases 2 and 3. In cases 4 and 5 postoperative sensorineural hearing loss occurred several months after stapes surgery and the causes of hearing loss were unknown. On the basis of the available literature discussion focused on management of labyrinthine fistula, the acoustic effect of the bone-cutting burr and the possibility of sensorineural hearing loss caused by stapes surgery.

[Tympanoplasty on only hearing ears].

Tympanoplasty on only hearing ears was performed on 11 patients in Osaka University Hospital and Osaka Rosai Hospital during 1986 1994; this was 0.68% of all cases of middle ear surgery. The patients consisted of 5 with cholesteatoma, 5 with chronic otitis media and 1 with cholesterin granuloma. The mean age was 47.6 years (13-68 years) and the mean follow-up period was 2 years and 7 months (6 months-4 years). Postoperative hearing results was obtained in 9 patients (81.8%) according to the criteria of Otology Japan (1987), and all ears were dry at the final examination. Compared with the preoperative hearing level, postoperative hearing level showed improvement in 3 cases, not in 7 cases (within difference of 5 dB) and deterioration by 10-15 dB in 1 case. Although indications for surgery on only hearing ears are still controversial, we suggest the following: 1) patients with cholesteatoma should be operated on in the ordinary way; 2) patients with chronic otitis media should be operated on only by myringoplasty; 3) all patients must be operated on very carefully by skillful surgeons.

Allograft stapes surgery for conductive hearing loss in patients with ossicular chain anomalies.

An allograft stapes was used during surgical intervention for conductive hearing loss due to ossicular malformations in 11 ears of seven patients. The external auditory canal and tympanic membrane were normal in all ears. The surgical findings for the ossicles were stapes fixation (7 ears), stapes fixation with discontinuity of the incudostapedial joint (in both ears of one patient), a deformed incus and stapes crura compressed by the facial nerve (one ear in which the stapes was not fixed) and an anomaly of the incus and stapes combined with a dermoid cyst (in one ear in which the stapes was also not fixed). In all ears, the following procedures were performed: stapedectomy followed by sealing the oval window with a vein graft and placing an allograft stapes between the oval window and the lenticular process of the incus or the handle of the malleus. The allograft stapes was placed with its capitulum on the oval window in all cases, and fibrin glue was used for stabilizing the seal and the allograft stapes. The indications for stapedectomy for conductive hearing loss due to ossicular chain anomalies and the utility of allograft stapes are discussed.

Dermoid cyst in the middle ear.

A case of a moderate essentially low tone unilateral conductive hearing loss without a previous history of secretory otitis media in a six-year-old female patient is described. The condition was found to be due to a dermoid cyst in the tympanic cavity, which was confirmed by pathological examination of the surgically removed specimen. This is the sixth documented case of dermoid cyst in the tympanic cavity.

Design and synthesis of antitumor compounds based on the cytotoxic diterpenoids from the genus Rabdosia.

Two active sites responsible for antitumor activity, an oxirane ring and an alpha-methylene-cyclopentanone moiety, have been extracted from studies on the structure-activity relationship of the cytotoxic diterpenoids isolated from Rabdosia shikokiana. Series of the simplified cyclopentanone derivatives containing both of the two active sites in the molecule have been synthesized and evaluated for cytotoxicity against P 388 cells. The compounds possessing both of two active sites displayed cytotoxicity at a concentration of 1 microgram/ml, while those possessing a single active site showed no activity.

[Anterior sacral meningocele. Case report].

A 53-year-old male presented with an abdominal mass and urinary disturbance. Plain pelvic X-rays revealed a scimitar deformity of the sacrum. Computed tomography (CT) of the abdomen and lumbosacral spine showed a 13 X 17 X 17 cm, hypodense, cystic mass. Metrizamide myelography disclosed a bony defect at the S2 level through which contrast material entered the pelvic cyst, confirming the diagnosis of anterior sacral meningocele. Magnetic resonance imaging demonstrated the extent of the abdominal mass and its communication with the thecal sac through the anterior sacral defect. The patient underwent surgery via the transabdominal approach. The mass was extremely adherent to the intestine and it was difficult to reach the stalk of the sac. The wall of the meningocele was resected to the extent possible, and was tightly sutured following a meningocele-peritoneal shunting procedure. Postoperatively, the patient was neurologically normal, but 4 months later he was readmitted because of headaches and clouding consciousness. CT showed bilateral chronic subdural hematomas. Following their evacuation, the patient recovered uneventfully. The clinical and neuroradiological features and the surgical approaches to anterior sacral meningoceles are discussed.

Terpenoids. LIII. Antitumor activity of trichorabdals and related compounds.

Among the three types, enmein-, oridonin-, and trichorabdal-type, of diterpenoids from Rabdosia trichocarpa, the latter showed the highest antitumor activity against Ehrlich ascites carcinoma in mice. Their potent activities were attributed to synergistic increase arising from the presence of two active sites in one molecule. In vitro activity against HeLa cells and in vivo activity against P 388 lymphocytic leukemia of diterpenoids and related compounds were also determined, but no synergistic increase in activity due to plural active sites was observed in those cases.

Steroidogenic effect of ent-kaur-16-en-15 beta-ol (kaurenol) on isolated rat adrenal cells.

In an in vitro bioassay system for adrenocorticotropic hormone using isolated rat adrenal cells, kaurenol, a diterpene alcohol, stimulated corticosterone production and augmented the steroidogenic effect of adrenocorticotropin or forskolin, dose-dependently. Kaurenol had no effect on cyclic AMP production by the cells. The diterpene also had no stimulatory effect on the adrenal adenylate cyclase activity in a cell free system. The results suggest that this particular diterpene exerts a steroidogenic effect through a mechanism independent of cyclic AMP generation.