spiro compounds

..The remaining benzylic asymmetric center is set by a diastereoselective hydroboration followed by cyclization to the spirobicyclic system...

..Analysis of the NMR data reported for spirofungins A and B as well as related spiroketals allowed for the reassignment of the stereochemistry of spirofungin B to be that corresponding to 15-epi-spirofungin A (27)...

..As a consequence of the spirocyclic rigidity fluorescence lifetimes and quantum yields are rather high in some cases...

..The potential of 9, which hydrolyzes readily in CDCl(3) solution, as a useful precursor for chiral polymer applications is highlighted...

..MI-63 has excellent specificity over cancer cells with deleted p53 and shows a minimal toxicity to normal cells...

..For comparison purpose, MI-319, MI-219 and Nutlin-3 were assessed side by side against FSCCL and three other B-cell hematological tumor cell lines in growth inhibition and gene expression profiling experiments...

..On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone...

..No tumor inhibition was found in mut-p53 BxPC-3 xenografts. In light of our results, the inhibitors of MDM2 warrant clinical investigation as new agents for PC treatment...

..Thus, the inhibition of pre-mRNA splicing during early steps involving SF3b allows unspliced mRNA leakage and translation...

..Based on these data, we propose that the decision as to whether TCR engagement will lead to productive activation or tolerance is dictated by a rapamycin -inhibitable pathway, independent of the G(1)-->S phase cell cycle progression...

..In contrast, FcalphaRI (CD89) and FcgammaRII (CD32) were increased by SFA. The explicit effect of SFA on the expression of Ag uptake receptors and Ag capture by DCs makes SFA unique among immunophilin-binding immunosuppressive drugs...

..Real-time RT-PCR reveals 84-94% suppression of IL-12p40, IL-12p35, and IL-23-specific p19 transcription. These novel insights into the immunosuppressive action of SFA are likely to impact on the clinical use of this agent...

..This observation raises the possibility that the dimer of CypA.SFA complexes is the molecular species mediating the immunosuppressive effect...

....

..We propose that SFA represents a novel class of immunophilin-binding immunosuppressants with high activity against DCs and the development of graft vasculopathy in CsA-treated recipients...

..Key biosynthetic studies are described, along with classical synthetic approaches as well as those inspired by Nature for the synthesis of these interesting molecules...

..Their structures were elucidated by spectroscopic methods and X-ray crystallography. These asperparalines showed paralytic activity against silk worms...

..In conclusion, this study highlights a new role of MDM2 inhibitors in combination with cisplatin, and thus warrants further clinical investigation in human pancreatic tumours containing both wt-p53 and mut-p53...

..Figure Aliquots of freeze-dried and wet mussel tissue reference materials containing the various shellfish toxins examined in the study...

..Our data also suggest that heterotrophic dinoflagellates may accumulate toxins from their prey...

....

..It does, however, merit further investigation as a stabilisation procedure for preparation of shellfish tissue materials for some lipophilic toxins, in particular azaspiracids. Chemical structures of the toxins investigated in the study...

..Thus, both analogues seem to involve an AC pathway, although its effects on [Ca(2+)](i) and pH(i) are quite different...

..The possibility that azaspiracids and YTXs might share their molecular mechanism(s) of action in defined biological settings should be considered...

..AZA-1-induced reorganization of the actin cytoskeleton concurred with detachment and growth inhibition, three events that are probably related...

..It is noteworthy that trichothecane mycotoxins are present in Paecilomyces tenuipes, which is typically used in medicinal health food...

..Very little azaspiracids were detected in mussels from the same locations at the same time, and no proposed microalgal source of azaspiracids was reported in the water previous to or at the time of collection of the toxic crabs...

..This result suggests that the antibodies also have a similar affinity for AZA2, AZA3, and AZA6 as they do for AZA1 and that such antibodies are suitable for analysis of AZAs in shellfish samples...

..The fragmentation of the A-ring was the most facile and was exploited in the development of LC/MS(n) methods for the analysis of azaspiracids...

..The strict regulatory control of azaspiracids in shellfish now requires frequent testing of shellfish using highly specific and sensitive methods involving liquid chromatography-mass spectrometry...

..These results point to a structure-activity relationship in AZAs pH effect that affects the modulation and the coupling of intracellular pH and Ca2+...

....

..This work will complement future investigations on AZA-1 accumulation in marine food webs and provide a basis for understanding its toxicity at different trophic levels...

..In addition to the total synthesis of azaspiracid-1 (1), the syntheses of its C(1)-C(20) epimer (2) and of several truncated analogues for biological investigations are described...

..We aimed to determine whether ranirestat, an aldose reductase inhibitor, maintains the improved nerve function observed in patients with diabetic sensorimotor polyneuropathy (DSP) after completing a 12-week nerve biopsy study...

..These data strongly suggest that combination therapies consisting of microtubule-disturbing and lysosome-destabilizing drugs may prove useful in the treatment of otherwise therapy-resistant human cancers...

..Therefore, the effect of AZA-1 on [Ca2+]c depends on the presence of the ABCD or the ABCDE-ring structure, but the complete chemical structure is needed to produce neurotoxic effects...

..Duplicate extraction using 100% methanol was found to be the best combination of parameters...

..Although these phycotoxin-specific effects of AZA-1 suggest a possible site of action, further work using cell-based approaches is needed to determine the precise mode of action of AZA-1...

..Thus, AZ-4 appeared to be a novel inhibitor of plasma membrane Ca2+ channels, affecting at least to store operated channels, showing an effect clearly different from other azaspiracid analogues...

....

..pneumonia and Salmonella sp. Further tests conducted using dilution method showed both compounds as having bacteriostatic mode of action against the tested bacteria...

..It was concluded that to improve food safety, only the adductor muscle and gonad of scallops should be permitted for sale to the public...

..These data suggest that meayamycin is a useful chemical probe to study pre-mRNA splicing in live cells and is a promising lead as an anticancer agent...

....

..These data collectively detail the inhibition of de novo cholesterol synthesis, which is the likely cause of cytotoxicity and potentially a target pathway of the toxin...

..Overall, these data are consistent with [(3)H]Lu 28-179 labelling a sigma(2)-like binding site...

..This assay should play an important role in shellfish monitoring in the future...

..Phase III trials are expected to take place in 2002 [387270]. A series of compounds have been synthesized by Lundbeck, the most potent of which may serve as a backup compound [179036]...

..This is the first report of the occurrence of these azaspiracids outside Ireland with the significant implications that these toxins may occur in shellfish throughout northern Europe...

..It was also observed that the toxin profiles differed significantly in various mussel tissues with AZA1 as the predominant toxin in the digestive glands and AZA3 predominant in the remaining tissues...

..The effect of AZ-1 in cAMP is not extracellularly Ca(2+) dependent and insensitive to okadaic acid (OA)...

..Tumors were not observed in 11 mice treated at lower doses and in 19 control mice. Hyperplasia of epithelial cells was also observed in the stomach of six mice out of ten administered at 20 microg/kg...

..Threrefore, the combination of siramesine with inhibitors of autophagosome formation appears as a promising approach for future cancer therapy...

..Although human intoxications have so far only been associated with mussel consumption, the discovery of significant azaspiracid accumulation in other bivalve mollusks could pose a threat to human health...

..24 microg/g, from Galicia, Spain, and scallops (Pecten maximus), 0.32 microg/g, from Brittany, France. Toxin profiles were similar to those found in the equivalent shellfish in Ireland in which AZA1 was the predominant toxin...

..An additional aim was to determine whether any changes in nerve function would manifest with AS-3201 therapy...

..In summary, we have identified a novel immunosuppressant, which represents, in addition to CsA, FK506 and rapamycin, a fourth class of immunophilin-binding metabolites with a new, yet undefined mechanism of action...

..In conclusion, this study provides the first demonstration of specific GHS binding sites, other than GHS-R1, in breast cancer. These receptors probably mediate growth inhibitory effects on breast carcinoma cells in vitro...

..These receptors are the specific binding sites for GHS and their antagonists, as well as for SRIH analogs (vapreotide and cortistatin- 14), but not for native SRIH...

..This strategy represents a general platform for accessing the chamigrene natural product family, as demonstrated by the synthesis of (+)-laurencenone B as an intermediate in our route...

....

....

..The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds ( R)- 58 and ( R)- 71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug...

....

..The relative and absolute stereochemistry of the side chain was established by comparison of the (1)H NMR spectra and the chiral GC chromatograms of the degradation product with the synthetic samples...

..We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection...

..Key steps of the syntheses are stereoselective Ferrier-type O- and C-glycosidation, ring-closing metathesis, and stereoselective Prins cyclization...

..Our results indicate that azatriborospiropentane gives off most energy when combusted, as evidenced by its specific enthalpy of combustion of about -52 kJ per gram...

..The reaction with other aryl groups such as naphthalene and indole rings is also described...

..A highly stereoselective [4 + 3] cycloaddition of N-substituted pyrroles with allenamide-derived nitrogen-stabilized chiral oxyallyl cations is described here. This method provides an approach for constructing tropinone alkaloids...

..These studies have led to reassignment of the 5,5-spiroketal stereochemistry of ritterazines B and F, and they have enabled us to propose a quantitative description of the natural distribution of these ritterazine compounds...

..3.0]octane ring system of palau'amine and congeners...

..Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE...

..Most compounds were shown to be more active than the compared meropenem and imipenem against Escherichia coli. One particular compound, IIIb, having hydroxy a moiety showed the most potent antibacterial activity...

..The synthesis of the corresponding C3 epimers from the same starting material is also described. Each stereoisomer was assayed for heparanase inhibition...

..Total synthesis of stemonamide and isostemonamide is described. The concise construction of the tricyclic core of these alkaloids was achieved by radical cascade involving 7-endo and 5-endo cyclizations...

..syn-Pentane-like interactions between this substituent and the C3 of the cyclohexene are avoided in the favored insertion topography. These two effects, when combined, produce a highly diastereoselective process...

..Comparison of proton and carbon NMR data of the synthetic diastereomers with those published for DTX-2 indicates that DTX-2 possesses the (30S *,34R *,35S *)-relative configuration with an axial C35 methyl substituent...

....

..The reaction of enediynes, where two alkyne moieties are connected by a 1,1-disubstituted alkene, was also examined, and sterically strained tricyclic compounds with two carbon stereocenters were obtained...

..Further diversification using consecutive cyclopropanation-Cope rearrangement affords novel chemotypes including spiroindane frameworks...

..The formation of the spiro compounds may serve as a model reaction in the interpretation of the stereoselectivity of the coupling reaction of ..

..New stereoselective intramolecular iminium ion spirocyclization methodology for the construction of spiro[pyrrolidine-3,3'-oxindoles] is outlined in synthetic studies of elacomine (1) and isoelacomine (2). [reaction: see text]..

..The results are in reasonable agreement with the available experimental data...

..The stereochemical outcome of the glycosylation-spiroketalization process is governed by the geometrical constraints imposed by the rigid tetracyclic structure of the final compound...

..The known compound 4-(2-hydroxybutynoxy)benzoic acid (11) was also obtained, and its absolute stereochemistry was assigned. Several of these metabolites showed antibiotic activity against Gram-positive bacteria...

..This property was applied to the synthesis of the racemic and optically active spirocyclic alkaloid sibirine...

....

..The carbocyclic nucleoside 5 is considerably more stable against ring opening than the deoxyribosyl derivative 4. Both compounds present enhanced hydrogen bonding capacity with diacetyladenosine...

..In general, Grignard reagents added syn to the C(6)-substituent and Li reagents added anti, although some exceptions were found. Selectivities could be increased in some cases by appropriate choice of solvent and/or cosolvent...

..The structures of 1 and 2 were elucidated by analysis of spectroscopic data, including 2D NMR, and comparison with literature data...

..The in vitro activity of compounds 1-12 against the parasitant stage of Nippostrongylus brasiliensis (L4) has been studied...

..The key step is a highly stereoselective construction of the dispiroketal (BCD ring) system employing an intramolecular hetero-Michael reaction of a reversibly formed hemiketal alkoxide through the use of LiOMe...

..Both form intermolecular hydrogen bonds involving only the oxindole, with N.O distances in the range 2.759 (4)-2.894 (5) A...

..3] sigmatropic rearrangement and a radical based ring closure to form the bicyclic skeleton. ..

..g. lung, liver, spleen and lymphocyte damage as well as cancer) health hazards. The project is also expected to advance our knowledge in chemical synthesis and impact favorably the drug discovery and development process. ..

..abstract_text> ..

..The disease areas likely to benefit most from the proposed investigations are bacterial-caused diseases and malaria. ..

..The significance of the proposed work will lie specifically in the area of cancer chemotherapy research, and in the development of new synthetic strategies and technologies for general use in the drug discovery and development process. ..

....

..The proposed work is expected to impact the general areas of pharmaceutical and agricultural research, and infectious diseases in particular, through discoveries in synthetic organic chemistry and chemical biology. ..

..abstract_text> ..

..abstract_text> ..

..The proposed work is expected to have significant impact in the area of cancer chemotherapy and should provide enabling technologies and tools for biology and medicine. ..

..The project is also expected to significantly advance our knowledge in chemical synthesis, chemical biology, and medicine ..

..The project is also expected to significantly advance our knowledge in chemical synthesis, chemical biology, and medicine ..

..This new concept sets the stage for solutions to a long standing problem, the ion channel blockers, the grayanotoxins. as well as the more recently discovered rameswaralide, a potent antiinflamatory. ..

..Ring expansion methods may convert these cores into the taxoid skeleton with appropriate functionality at key points for analog development. ..

..Equally important, new avenues to vary structure around these cores in order to establish structure-activity relationships with the aim to create better therapeutic agents become available. ..

..The diversity of the challenges posed by antiviral and antitumor agents represent highly meaningful tests of their use...

..By accessing a very diverse range of structural types, the best opportunities to discover new therapeutic agents arise. ..

..These new synthetic methods apply to many structural types beyond those illustrated and constitutes a significant to gain access to complex molecular targets more easily. ..

..By expediting access to very diverse arrays of structural types, the best opportunities to discover new therapeutic agents arise. ..

..These new synthetic methods apply to many structural types beyond those illustrated and constitutes a significant to gain access to complex molecular targets more easily. ..

..These new synthetic methods apply to many structural types beyond those illustrated and constitutes a significant to gain access to complex molecular targets more easily. ..

..These new synthetic methods apply to many structural types beyond those illustrated and constitutes a significant to gain access to complex molecular targets more easily. ..

..A strategy to one family of tumor promoters represented by teleocidin explores the concept of chemical chameleons. In most cases, the strategy also considers the problem of absolute stereochemistry...

..This proposal helps to address this key challenge by developing the underlying initial technology within classes of compounds having demonstrably antitumor or antiviral activities. ..

..These studies would provide a systematic understanding of the pharmacology of intrathecal morphine-induced pruritus in primates and establish the basis for identifying potential therapeutically effective antipruritics. ..

....

..FK506 is therefore an important target for total synthesis, not only for its intrinsic synthetic challenge, but also due to its extrinsic worth to the field of medicine...

....

..This research integrates organic synthesis, protein-ligand x-ray crystallography, molecular modeling and in-depth virus and cell-biological studies to design the next generation of HIV-1 protease inhibitors. ..

..Our experience with discodermolide gives us great confidence in this area. ..

..The areas of public health research include, among others, cancer, infectious diseases, neurodegenerative diseases such as Alzheimer's disease, and heart and cardiovascular disease. ..