New anti-influenza agents, FR198248 and its derivatives. II. Characterization of FR198248, its related compounds and some derivatives.

We isolated FR198248 from the cultured broth of Aspergillus terreus No. 13830 as a new anti-influenza agents. The structure of FR198248 was elucidated by several spectroscopic experiments as a novel tetrahydroxybenzaldehyde compound. Furthermore, we described the characteristics of FR198248, its related compounds and some derivatives.

FR198248, a new anti-influenza agent isolated from Apsergillus terreus No 13830. I. Taxomony, fermentation, isolation, physico-chemical properties and biological activities.

A novel anti-influenza agent, FR198248, was isolated from the cultured broth of a fungal strain No.13830. The strain was identified as Aspergillus terreus from morphological characteristics. FR198248, a new type of hydroxyl benzaldehyde compound, showed antiinfluenza virus activity in Madin-Darby canine kidney (MDCK) cells in vitro. The mode of action of FR198248 against influenza virus A could be ascribed to an inhibitory effect on the stage of virus adsorption. Furthermore, FR198248 possessed potent in vivo anti-influenza activity in a murine model of respiratory tract infection.

Abnormalities in gap junctions and Ca2+ dynamics in cardiomyocytes at the border zone of myocardial infarcts.

Abnormalities in gap junction function and Ca2+ dynamics are believed to be important factors in arrhythmogenesis after myocardial infarction. To elucidate the relationship between changes in Ca2+ dynamics and gap junctions, we analyzed by real-time in situ Ca2+ imaging of fluo-3 loaded whole hearts the spatiotemporal occurrence of Ca2+ waves and the localization of connexin43 (Cx43) at the border zone of myocardial infarcts induced in the rat by coronary ligation. At early time points (2-4 hours postligation), different regions of the left ventricle showed distinct changes in cytosolic free Ca2+ concentrations [Ca2+]i. While some cardiomyocytes of infarcted regions exhibited high levels of resting fluo-3 fluorescence, at border zones frequent Ca2+ waves were observed. Some of the waves were abolished by spontaneous Ca2+ transients and others were not. Intact myocardium apart from infarcted regions exhibited homogenous Ca2+ transients. Confocal imaging of Cx43 and actin filaments in the rat heart fixed 2 hours after coronary ligation revealed that Cx43 was markedly decreased in the area of myocyte necrosis with contraction bands and in the neighboring myocardium. These results suggest that abnormal expression and function of gap junctions could be associated with Ca2+ waves at the border zone of myocardial infarcts, possibly through Ca2+ overload.

Metabolism and mode of inhibition of varicella-zoster virus by L-beta-5-bromovinyl-(2-hydroxymethyl)-(1,3-dioxolanyl)uracil is dependent on viral thymidine kinase.

A nonnaturally occurring L-configuration nucleoside analog, L-beta-5-bromovinyl-(2-hydroxymethyl)-1,3-(dioxolanyl)uracil (L-BVOddU) selectively inhibited varicella-zoster virus growth in human embryonic lung (HEL) 299 cell culture with an EC(50) of 0.055 microM, whereas no inhibition of CEM and HEL 299 cell growth or mitochondrial DNA synthesis was observed at concentrations up to 200 microM. L-BVOddU was phosphorylated by viral thymidine kinase but not by human cytosolic thymidine kinase, and the antiviral activity of this compound is dependent on the viral thymidine kinase. Unlike other D-configuration bromovinyl deoxyuridine analogs, such as E-5-(2-bromovinyl)-2'-deoxyuridine and 1-beta-arabinofuranosyl-E-5-(2-bromovinyl)uracil, this compound was metabolized only to its monophosphate metabolite. The di- or triphosphate metabolites were not detected. This suggested that the inhibitory mechanism may be unique and different from other anti-herpesvirus nucleoside analogs.

Structure-activity relationships of (E)-5-(2-bromovinyl)uracil and related pyrimidine nucleosides as antiviral agents for herpes viruses.

A series of (E)-5-(2-bromovinyl)uracil analogues and related nucleosides was synthesized, and their antiviral activities were evaluated. (E)-5-(2-Bromovinyl)-2'-deoxy-L-uridine (L-BVDU, 2), 1-(beta-L-arabinofuranosyl)-(E)-5-(2-bromovinyl)uracil (L-BVAU, 4), (E)-5-(2-bromovinyl)-1-(2-deoxy-2-fluoro-beta-L-ribofuranosyl)uracil (L-FBVRU, 8) and (E)-5-(2-bromovinyl)-1-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl)urac il (L-FBVAU, 10) were synthesized via appropriate 5-iodouracil analogues from L-arabinose. D- and L-Oxathiolane and -dioxolane derivatives 13, 16, 20, 21, and 29-34 were prepared by glycosylation reaction of the oxathiolane and dioxolane intermediates with silylated uracil analogues using TMSI as the coupling agent. The synthesized compounds were evaluated in cell cultures infected with the following viruses: varicella zoster virus (VZV), Epstein Barr virus (EBV), and herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). Among the tested compounds, beta-L-CV-OddU (29), beta-L-BV-OddU (31), and beta-L-IV-OddU (33) exhibited potent in vitro antiviral activity against VZV with EC(50) values of 0.15, 0. 07, and 0.035 microM, respectively, and against EBV with EC(50) values of 0.49, 0.59, and 3.91 microM, respectively.

FR191512, a novel anti-influenza agent isolated from a fungus strain No.17415. I. Taxonomy, fermentation, isolation, physico-chemical properties and structure elucidation.

In the course of our screening for anti-influenza agents of microbial origin, FR191512 was isolated from the cultured broth of fungus strain No. 17415 as colorless powder. The structure of FR191512 was determined by several spectroscopic experiments as a novel polyphenolic compound. This compound showed potent antiviral activity against influenza A virus.

FR191512, a novel anti-influenza agent isolated from a fungus strain No.17415. II. Biological properties.

FR191512, a novel polyphenolic compound, inhibited the infectivity of influenza A virus in Madin-Darby canine kidney (MDCK) cells in vitro. Furthermore, FR191512 showed good in vivo anti-influenza activity in a mouse model of intranasal infection with influenza A virus. The cytotoxic activity of FR191512 against MDCK cells was very weak.

Primary uterine T-cell lymphoma.

A uterine CD8-positive, HTLV-1-negative T-cell lymphoma associated with atypical endometrial hyperplasia was found in a 63-year-old Japanese woman. Primary T-cell lymphoma of the uterus has not been previously reported.

[Two surgical cases of right parasternal minimal incision for aortic valve replacement].

Although median sternotomy has been used as a good approach to all cardiac valves and coronary arteries, advantages of the minimal invasive cardiac operation have been reported recently. We employed the right parasternal minial incision, reported by Cosgrove et al. for two cases of aortic valve replacement. In the first case, we were able to get a good operation field and easily implanted a mechanical prosthesis. In contrast, we had some difficulties with the second case where in addition to the third and fourth cartilages, a second cartilage resection was necessary because the aortic root lay at a cephalic level. Moreover, the operation field was restricted because we left several rib cartilages to preserve the right internal thoracic artery. The cannula had to be inserted via the right atrium as we failed to insert it in the right femoral vein, and the aortic root deviated more medially than usual. From these experiences, it is important to check the position of aortic root, and if the cannula cannot be inserted in the femoral vein, cannulation via the right atrium can ve utilized in the minimal invasive cardiac operation.

[An operative case of congenital fistula of the right coronary artery to the left ventricle with congestive heart failure].

We reported an extremely rare case of congenital fistula of the right coronary artery to the left ventricle in a 71-year-old man who suffered from difficulty in breathing and palpitation. The diagnosis was confirmed by the right coronary angiography. The fistula was closed by Symbas's operation under cardiopulmonary bypass. Postoperative recovery was uneventful. Coronary angiography performed one year after the operation revealed that the right coronary artery was completely occluded by thrombus. But there were no signs of myocardial ischemia or infarction. And so we suspected that the dilated right coronary artery had not work as functional vessel.

FR901724, a novel anti-human immunodeficiency virus (HIV) peptide produced by Streptomyces, shows synergistic antiviral activities with HIV protease inhibitor and 2',3'-dideoxynucleosides.

A novel tricyclic 21-amino-acid peptide, FR901724, was isolated from the cultured broth of Streptomyces sp. No. 73264. This peptide appears to possess potent anti-human immunodeficiency virus (HIV) activity in vitro and might represent a lead to a new class of anti-HIV agents; it qualifies as an HIV-cell fusion inhibitor because of its weak inhibition of virus-cell binding and strong inhibition of syncytium formation. From the time-of-addition experiments, the mode of action of FR901724 was found to definitely differ from that of KNI-272, a peptide mimetic allophenylnorstatine-derivative HIV protease inhibitor. FR901724 appears to interact with a stage of the virus replicative cycle that may well correspond to virus-cell fusion. We also found that FR901724 was synergistic or had a strong tendency toward synergism when combined with other antiviral drugs, such as KNI-272, AZT, ddI and dextran sulfate.

Nectrisine is a potent inhibitor of alpha-glucosidases, demonstrating activities similarly at enzyme and cellular levels.

Nectrisine, discovered as an immunomodulator, was found to inhibit alpha-glucosidase, alpha- and beta-mannosidases, beta-glucosidase and beta-N-acetylglucosaminidase, in that order of inhibition strength. Beta-Galactosidase, alpha-fucosidase, and neuraminidase were insensitive to this antibiotic. Also sensitive was the trimming glucosidase I which participates in the first step of modifying N-glycosidic oligosaccharide. Nectrisine demonstrated an inhibitory effect at the cellular level as strong as expected based on its action at enzyme levels; castanospermine and 1-deoxynojirimycin did not. Nectrisine and castanospermine suppressed syncytium formation and hemolytic activity in Newcastle disease virus (NDV)-infected BHK cells, without blocking the synthesis and cell-surface expression of HANA glycoprotein of NDV.

FR901483, a novel immunosuppressant isolated from Cladobotryum sp. No. 11231. Taxonomy of the producing organism, fermentation, isolation, physico-chemical properties and biological activities.

FR901483, a novel immunosuppressant, has been isolated from the fermentation broth of Cladobotryum sp. No. 11231. The molecular formula of FR901483 has been determined as C20H31N2O6P. FR901483 exerts a potent immunosuppressive activity in vitro and significantly prolongs graft survival time in the rat skin allograft model. This compound has an intriguing tricyclic structure possessing a phosphate ester in its molecule. The ester residue may play an important role in exerting immunosuppressive activity because the desphosphoryl compound is devoid of activity. It is thought that the primary target of immunosuppression by this compound is inhibition of purine nucleotide biosynthesis.

[A case of synchronous double cancer in the same pulmonary lobe].

We have experienced a case of synchronous double cancer developing in the right lower lobe in a 75-year-old male. He was asymptomatic. His chest X-ray film showed two nodular shadows, one in the right proximal S8 and another in peripheral S9. The serum CEA level was elevated to 9.5 ng/ml. Bronchoscopic brush cytology revealed adenocarcinoma from the tumor in orifice of B8. He was therefore diagnosed preoperatively as having adenocarcinoma of the right S9 with metastasis to #12 hilar lymph node. Right lower lobectomy was performed. The final histological diagnosis was double primary lung cancer consisting of squamous cell carcinoma (S9) with rare mucoepidermoid carcinoma in the same lobe. His postoperative course was uneventful.

FR901459, a novel immunosuppressant isolated from Stachybotrys chartarum No. 19392. Taxonomy of the producing organism, fermentation, isolation, physico-chemical properties and biological activities.

FR901459, a novel immunosuppressant, has been isolated from the fermentation broth of Stachybotrys chartarum No. 19392. The molecular formula of FR901459 was determined as C62H111N11O13. FR901459 was found to be a member of the cyclosporin family. However, it is structurally distinct from any other cyclosporins discovered so far, in that Leu is present at position 5 instead of Val. FR901459 was capable of prolonging the survival time of skin allografts in rats with one third the potency of cyclosporin A.

[A case report of aorto-pulmonary window associated with atrial septal defect].

The patient was a one-year-old boy, who underwent surgery with a diagnosis of atrial septal defect (ASD). During operation, aorto-pulmonary window (A-P window) which had not been detected by the preoperative examinations, was found. Therefore, the A-P window was divided prior to closing ASD. The patient is in good condition six months after the operation. The causes of the inaccurate preoperative diagnosis were discussed.

WF11605, an antagonist of leukotriene B4 produced by a fungus. I. Producing strain, fermentation, isolation and biological activity.

WF11605, a new antagonist of leukotriene B4 (LTB4) was isolated as a product of fungal strain F11605. The molecular formula of WF11605 was determined to be C38H60O11. WF11605 inhibited LTB4-induced chemotaxis of rabbit polymorphonuclear leukocytes (PMNLs) with an IC50 value of 1.7 x 10(-7) M and blocked 3H-LTB4 binding to PMNL membranes at 5.6 x 10(-6) M (IC50). WF11605 also inhibited LTB4-induced degranulation of rabbit PMNLs at 3.0 x 10(-6) M (IC50). However, WF11605 did not show any inhibitory effect on platelet activating factor (PAF)- and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-induced degranulation at concentrations up to 10(-4) M. These results suggest that WF11605 is a specific antagonist of LTB4.

WF11605, an antagonist of leukotriene B4 produced by a fungus. II. Structure determination.

The structure of WF11605, a novel tetracyclic triterpene glucoside, was determined to be 1. The plane structure of deacetyl-WF11605 aglycone was elucidated as 2 through the concerted application of a series of 2D NMR techniques. The relative configurations were established by X-ray crystallographic analysis of bis(p-bromobenzoyl) derivative 3 and absolute stereochemistry by CD exciton chirality method.

FR109615, a new antifungal antibiotic from Streptomyces setonii. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity.

FR109615, a new antibiotic active against Candida, was isolated from Streptomyces setonii No. 7562. Based on the spectroscopic data, the structure of FR109615 was elucidated as cis-2-aminocyclopentane-1-carboxylic acid (1). The compound showed the excellent in vivo efficacy in a generalized infection test of mice.