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During the course of a screening program for inhibitors of myo-inositol monophosphatase we fermented the strain ATCC 20928, a known producer of L-671,776. We now show that this strain produces a complex of at least three sesquiterpenic compounds, L-671,776 (termed factor B) and two structurally related substances, termed factors A and C. Both factors A and C, like L-671,776, exhibited inhibitory activity against myo-inositol monophosphatase. Six other fungi producing the above mentioned compounds were also isolated and taxonomically characterized.
Sanofi-Synthélabo (formerly Sanofi) is developing SR-121463, a vasopressin V, receptor antagonist, as a potential treatment for cardiovascular indications such as congestive heart failure (CHF) and hypertension [330073], [341858]. By September 2001, it had entered phase IIa trials for these indications [421268]. SR-121463 was in phase I clinical trials for CHF and hypertension in June 2001 [359231], [413342]. It was also being evaluated for the potential treatment of glaucoma but its development has been discontinued for this indication [367094]. In October 1999, Lehman Brothers predicted a 5% chance of the compound reaching market, with a launch anticipated in 2004 and potential peak sales of $100 million in 2012 [346267].
Racemate physicochemical descriptors are employed to probe the quantitative structure-activity relationship of spirosuccinimide type aldose reductase inhibitors and the in vivo inhibitory activity of sorbitol accumulation. The in vivo activity data include the percent inhibition and ED50 assay results on the literature. The derived QSAR equations show that the hydrophobic character of aldose reductase inhibitor is the major contributing factor to enhance in vivo activity. As the hydrophobicity of compounds is related to both the membrane permeability and the binding affinity to the aldose reductase, its contribution to the pharmacokinetic behavior is further scrutinized by evaluating pKa and the Caco-2 cell permeability. The high correlation between ED50 and the Caco-2 cell permeability of in vitro active compounds indicates that the membrane permeability is essential for in vivo efficacy.
The synthesis and antimineralocorticoid potencies of several steroidal spirolactones bearing novel nitrogenous substituents in the 7alpha position are reported. These substituents include the cyano, the isocyanato, and the alkoxycarbonylamino groupings. The nitrile 1b and the N-carbomethoxy compound 1h showed good antimineralocorticoid potency (MED less than or equal to 0.79 mg) on subcutaneous administration to adrenalectomized rats.
OBJECTIVE: To study the chemical constituents of Costus speciosus and C. tonkinensis (Zingiberaceae) distributed in Yunnan province. METHOD: Chromatography and spectral analyses were used to isolate the constituents and elucidate their structure. RESULT: Six compounds were isolated from the rhizome of C. speciosus and elucidated as diosgenin(1), prosapogenin B of dioscin(2), diosgenone(3), cycloartanol(4), 25-en-cycloartenol(5) and octacosanoic acid(6). Four compounds were isolated from the rhizome of Costus tonkinensis and elucidated as tetracosanoic acid(7), succinic acid(8), beta-sitosterol(9) and daucosterin(10). CONCLUSION: Compounds of 3-6 were obtained from C. speciosus for the first time and compounds of 7-10 were obtained from C. tonkinensis for the first time too.
1. Anisatin, a toxic, insecticidally active component of Sikimi plant, is known to act on the GABA system. In order to elucidate the mechanism of anisatin interaction with the GABA system, whole-cell and single-channel patch clamp experiments were performed with rat dorsal root ganglion neurons in primary culture. 2. Repeated co-applications of GABA and anisatin suppressed GABA-induced whole-cell currents with an EC50 of 1.10 microM. No recovery of currents was observed after washout with anisatin-free solution. 3. However, pre-application of anisatin through the bath had no effect on GABA-induced currents. The decay phase of currents was accelerated by anisatin. These results indicate that anisatin suppression of GABA-induced currents requires opening of the channels and is use-dependent. 4. Anisatin suppression of GABA-induced currents was not voltage dependent. 5. Picrotoxinin attenuated anisatin suppression of GABA-induced currents. [3H]-EBOB binding to rat brain membranes was competitively inhibited by anisatin. These data indicated that anisatin bound to the picrotoxinin site. 6. At the single-channel level, anisatin did not alter the open time but prolonged the closed time. The burst duration was reduced and channel openings per burst were decreased indicating that anisatin decreased the probability of openings.
Fredericamycin is an antibiotic product of Streptomyces griseus that exhibits modest antitumor activity in vivo and in vitro. Because of its unique structure and the absence of a clearly defined mechanism of action, we examined the effects of this compound on L1210 cells in culture as well as on several enzymes that bind to DNA. Fredericamycin exhibits an IC50 of 4.4 microM toward L1210 cells, and its cytotoxicity is a function of the time of exposure as well as drug dose. No DNA breakage was observed in L1210 cells or isolated nuclei following exposure to highly lethal concentrations of fredericamycin. As a first step toward understanding its mechanism of action, we examined the effect of fredericamycin on several enzymes involved in DNA metabolism. The catalytic activity of both DNA topoisomerases I and II were totally inhibited by fredericamycin concentrations of 4.4 and 7.4 microM, respectively. Fredericamycin blocked etoposide-stimulated DNA cleavage by topoisomerase II both in vitro and in isolated nuclei. In addition, the drug inhibits DNA polymerase a in vitro, exhibiting an IC50 of 93 microM. These diverse actions of fredericamycin do not enable us to draw conclusions regarding its mechanism of antitumor effect but clearly identify it as a compound of pharmacologic interest.
Unlike herpes viruses, human immunodeficiency virus and other retroviruses do not encode specific enzymes required for the metabolism of the purine or pyrimidine nucleotides to their corresponding 5'-triphosphates. Therefore, 2',3'-dideoxynucleosides and acyclic nucleoside phosphonates must be phosphorylated and metabolized by host cell kinases and other enzymes of purine and/or pyrimidine metabolism. Different animal species (or even different cell types within one animal species) may differ in the efficiency of conversion of these drugs to their antivirally active metabolite(s). Three 2',3'-dideoxynucleosides are officially licensed for clinical use [i.e., zidovudine (3'-azido-2',3'-dideoxythymidine, AZT), didanosine (2',3'-dideoxyinosine, DDI) and zalcitabine (2',3'-dideoxycytidine, DDC)]. A number of other 2',3'-dideoxynucleoside analogues [among them stavudine (2',3'-didehydro-2',3'-dideoxythymidine, D4T), 2',3'-dideoxy-3'-thiacytidine (3TC), 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC) and the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA)] are currently under clinical investigation and are candidate compounds for eventual licensing as anti-AIDS drugs. The metabolic pathways, antimetabolic effects and mechanism of antiviral action of these nucleoside analogues will be discussed.
The spiro attachment of an epoxide group to a tetrahydropyran ring in the trichothecene mycotoxins has prompted this study of the mutagenicity and alkylation rates of the trichothecene, anguidine, and 5 related model oxaspiro compounds. While the model compounds were weak alkylating agents of 4-(4-nitrobenzyl)pyridine as a test nucleophile, anguidine lacks such activity. Also, while mutagenicity was not established for anguidine in Salmonella TA100, 3 of the oxaspiro compounds were weakly mutagenic and 2 compounds were toxic to the bacteria. The toxicity and mutagenicity of the model compounds are more related to their polarity than to their alkylation rates.
The releases of [3H]5-hydroxytryptamine ([3H]5-HT) and of endogenous glutamic acid and their modulation through presynaptic h5-HT1B autoreceptors and h5-HT1D heteroreceptors have been investigated in synaptosomal preparations from fresh neocortical samples obtained from patients undergoing neurosurgery. The inhibition by 5-HT of the K+ (15 mM)-evoked overflow of [3H]5-HT was antagonized by the 5-HT1B/5-HT1D receptor ligand GR 127935, which was ineffective on its own; this drug was previously found to behave as a full agonist at the h5-HT1D heteroreceptor regulating glutamate release. The recently proposed selective h5-HT1B receptor ligand SB-224289 also prevented the effect of 5-HT at the autoreceptor, being inactive on its own; in contrast, SB-224289, at 1 microM, was unable to interact with the h5-HT1D heteroreceptor. The inhibitory effect of 5-HT on the K+-evoked overflow of glutamate was antagonized by the h5-HT1D receptor ligand BRL-15572; added in the absence of 5-HT the compound was without effect. BRL-15572 (1 microM) was unable to modify the effect of 5-HT at the autoreceptor regulating [3H]5-HT release. The selective 5-HT1A receptor antagonist (+)-WAY 100135, previously found to be an agonist at the h5-HT1D heteroreceptor regulating glutamate release, could not interact with the h5-HT1B autoreceptor when added at 1 microM. It is concluded that native h5-HT1B and h5-HT1D receptors exhibit a hitherto unexpected pharmacological diversity.
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RGH-2716 is a novel 1-oxa-3,8-diazaspiro[4.5] decan 2-one, which was published to have potent inhibitory effect on neuronal Na and Ca movement and stimulatory action on nerve growth factor (NGF)-production, as well as to show significant antiamnesic activity in experimental amnesia models. The aim of the present experiments was to study the effect of the compound on the learning process and on the different stages of memory using water-labyrinth in normal and memory impaired young animals, as well as to study cognitive effect of RGH-2716 on aged animals. At the doses of 0.5 mg/kg i.p. or 3 mg/kg p.o. given before daily swimming, this compound improved the learning process of young animals impaired by either diazepam (DIA) or scopolamine (SCOP). In retrograde amnesia model RGH-2716 (3 mg/kg p.o.) significantly ameliorated consolidation process and retrieval of information impaired by SCOP or DIA. Nimodipine and vinpocetine (10 mg/kg p.o.) showed moderate effect compared to RGH-2716. Aged rats pretreated with daily i.p. RGH-2716 performed the tasks with significantly fewer errors and shorter swimming time than untreated aged rats. When aged animals had to solve a new labyrinth problem, treated aged rats showed significantly better learning ability than aged controls. One month of oral treatment of aged rats with 3 mg/kg dose of RGH-2716 two times daily resulted in a "tendency-like" improvement in learning of aged Fischer 344 and spontaneously hypertensive (SH) rats. The present results make RGH-2716 an interesting compound for the treatment of cognitive disorders.
Anomeric spirohydantoin derivatives from monosaccharides are known for various biological properties. We describe herein the synthesis of the 3-spirohydantoin derivatives of D-allose and D-ribose. The key step is the stereoselective glyco-alpha-aminonitrile formation from ulose derivatives of D-glucose and D-xylose using titanium tetra-isopropoxide as a mild and efficient catalyst. Target compounds were synthesized from these intermediates. The glucidic moiety was partially or totally deprotected under acidic conditions. These new heterocyclic monosaccharidic derivatives are potent glycogen phosphorylase inhibitors.
The absorption spectra of fluram, lysozyme, horse-radish peroxidase, and mixtures of lysozyme + fluram and peroxidase + fluram and the fluorescence and fluorescence excitation spectra of the mixtures in 0.05 M phosphate buffer with 1 per cent dioxane are determined. Due to formation of a protein-fluram compound, the absorption spectra of the mixtures are not algebraic sums of the components. From the fluorescence intensities the number of bonding sites is found 6 in both cases. The fluorescence spectrum of the peroxidase-fluram compound has maxima at 305, 350, 400, 450 nm due to peroxidase and at 480 nm originating from fluram. In mixtures of 10(-5) M lysozyme + 10(-4) M fluram, 3/4 of the excitation energy is transferred from lysozyme to fluram within the compound under 280 nm excitation. Under similar conditions 4/5 of the excitation energy is transferred from peroxidase to fluram.
The structures of four new, naturally occurring bioactive spiroditerpenoids, (+)-breviones B, C, D, and E, potential allelopathic agents, have been determined from extracts of semisolid fermented Penicillium brevicompactum Dierckx. The structures display the novel breviane spiroditerpenoid skeleton. Structure elucidation was performed by chemical transformations and by homo- and heteronuclear 2D-NMR spectral data. On the basis of combined studies of the theoretical conformations and NOEDIFF data, their relative stereochemistry is proposed. A mixed biogenesis for this novel family of spiroditerpenoids is tendered. The levels of activity shown by breviones B, C, and E in the etiolated wheat coleoptiles bioassay, especially breviones E (100% inhibition) and C (80% inhibition) both at 10(-4) M, suggest them as lead compounds for new agrochemicals.
[structure: see text] The absolute stereochemistry of the heptaprenoids didemnaketals B (2) and C (3), isolated from a Palauan ascidian, was determined using a combination of degradation and derivatization experiments, chiral shift methods, and comparison of fragments to known compounds.