heterocyclic compounds with 4 or more rings

..The relative and absolute stereochemistry of 1 was determined by combination of NOESY correlations and a modified Mosher method...

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..We report the results of long-term treatment with asenapine in patients with bipolar I disorder...

..Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes...

..This 6-week trial assessed the efficacy, tolerability, and safety of the investigational psychopharmacologic agent asenapine versus placebo and risperidone in patients with acute schizophrenia (DSM-IV criteria)...

..Altogether, this work reinforces the pharmacologic interest of the lamellarins and defines lamellarin D as a lead in the search for treatments against chemoresistant cancer cells...

..We conclude that myosin IIA negatively regulates cell migration and suggest that it maintains a balance between the actomyosin and microtubule systems by regulating microtubule dynamics...

..Securinine has minimal toxicity in vivo, suggesting it or structurally similar compounds may represent novel, therapeutic adjuvants, which increase resistance to intracellular pathogens...

..In this study, the aim was to investigate whether HX could affect the AD-related neuropathology in vivo in two mouse models...

..Results obtained herein using a sample of aged animals strongly suggest that huprine X constitutes a promising therapeutic agent for the treatment of cholinergic dysfunction underlying aging and/or dementias...

..These studies reveal a novel approach to specifically target colon cancer cells lacking p53 as well as identify a novel clinically relevant pathway to selectively induce p73 in p53-null cells...

..Continuous signals from microtubules are required to maintain the position of the cleavage furrow, and these signals control the localization of myosin II independently of other furrow components...

..The deleterious effect of replacing the 20-OH in LMD with a hydrogen was confirmed using a set of thermodynamic integration free energy simulations...

..LAM-D is the lead compound of a new promising family of antitumor agents targeting topoisomerase I and the amino acid derivatives appear to be excellent candidates for a preclinical development...

..Compounds 3-8 have all been evaluated for their anti-mitotic and cytotoxic properties and two of them, 3 and 5, display useful activities although they are less potent than combretastatin A-4...

..These observations provide a functional demonstration that the tetraploidy checkpoint does not exist in normal mammalian somatic cells...

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..Our observations indicate that myosin II ATPase is not required for the assembly of equatorial cortex during cytokinesis but is essential for its subsequent turnover and remodeling...

..Productive cell advance was a function of the second colocalized network, the lamella, where actomyosin contraction was integrated with substrate adhesion...

..We propose that Myosin 2 is a key effector of Rho-Rho kinase signaling that regulates cell-cell adhesion by determining the ability of cells to concentrate cadherins at contacts in response to homophilic ligation...

..Combined with our previous work on resveratrol, the current study further validates SIRT1 as a target for the treatment of metabolic disorders and characterizes the mechanisms underlying the therapeutic potential of SIRT1 activation...

..This study examined the effect of asenapine, a novel psychopharmacologic agent being developed for schizophrenia and bipolar disorder, on cognitive dysfunction in the rat...

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..The novel psychopharmacologic agent, asenapine, has high affinity for a range of receptors including the dopaminergic receptors...

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..Altogether, these data suggest that mitochondrial ROS generation is crucial for overriding the chemoresistance of NSCLC cells. Moreover, this study delineates the unique mechanism of action of lamellarins as potential anticancer agents...

..We believe that myosin II motors may function similarly in vivo (e.g., in the disassembly of the contractile ring by fine tuning the local concentration/activity of myosin II motors)...

..Lamellarin alpha 13,20-disulfate is a moderate inhibitor of both HIV-1 integrase and cancer cell lines. Lamellarin H is a more potent inhibitor of HIV-1 integrase but lacked the specificity required to be medicinally useful...

..In addition, these single round tests rule out action against viral assembly or budding. These findings provide a new class of compounds for potential development of clinically useful integrase inhibitors...

..Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder...

..These findings suggest that tension generated by actomyosin is essential for correct AJ assembly...

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..Our results indicate that asenapine has a unique human receptor signature, with binding affinity and antagonistic properties that differ appreciably from those of antipsychotic drugs...

..This in vitro work identifies LAM-D as a potent pro-apoptotic agent and its cytotoxic action is fully maintained in multidrug-resistant cells compared to the sensitive parental cell line...

..Collectively, the results identify LAM-D as a novel lead candidate for the development of topoisomerase I-targeted antitumor agents...

..This property may be useful in locally reversing the action of blebbistatin treatment in a cell. However, caution should be exercised as free radicals may be produced upon irradiation of blebbistatin that could result in cell damage...

..Subsequent attempts to install the C-3 methoxy group of 1-3 are also described...

..The major diastereomer is isolated, and its stereochemistry is determined by X-ray crystal structure analysis...

..The structures of the alkaloids were elucidated on the basis of spectroscopic analysis. Some alkaloids isolated in this and previous studies (1, 2, 5, and 10) were assayed for acetylcholine esterase (AChE) inhibitory activity...

..The final fragment coupling between lithiated fragment A (C1-C5) and aldehyde 40 (C6-C24) has also been successfully accomplished affording the entire carbon framework of the natural product...

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..The methodology was applied to the tyrosine-indole derivative 17 to give the EFHG-tetracyclic core of diazonamide A...

..A diastereoselective allylation and reduction of amide, nitrile, and ketone groups leads to a bicyclic alcohol, which undergoes aminocyclization through the nosyl derivative to the diazatricyclic ring...

..The IMDAF/Rh(I)-catalyzed ring opening cascade sequence was also applied to the total synthesis of (+/-)-erysotramidine as well as the lycorine type alkaloid (+/-)-epi-zephyranthine...

..A mechanism of action closely related to the DNA-interacting drugs can be supposed, although, alternative mechanisms, similar to those of the anthracyclines, can also operate...

..The relative configuration of 1 was further confirmed by a single-crystal X-ray diffraction analysis. In addition, the (1)H and (13)C NMR data of the free base of daphmanidin A (4) were compared with its hydrochloric salt form...

..The structures of the new alkaloids were elucidated by spectroscopic methods. Yunnandaphnine E (6) is a novel heptacyclic yuzurimine-type alkaloid with an oxazine ring...

..Twelve new alkaloids, caldaphnidines G-R (1-12), along with 24 known ones, were isolated from the twigs of Daphniphyllum calycinum. Their structures were elucidated by spectroscopic methods, especially two-dimensional NMR techniques...

..In addition, securinine-induced intracellular calcium increment was inhibited by nimodipine (10(-6) mol. L(-1), p < 0.01), but not by 2-amino-5-phosphonovaleric acid (10(-6) mol. L(-1), p > 0.05)...

..Daphmanidins E and F showed a moderate vasorelaxant effect on rat aorta...

..X-Ray crystal structure analysis established that the quaternary centre in 64 had the same configuration as that present in diazonamide A (1)...

..2.1.0.4,8]nonane ring system, has been isolated from the leaves of Daphniphyllum calycinum (Daphniphyllaceae), and the structure and relative stereochemistry were elucidated on the basis of spectroscopic data...

..Antagonism of a 100 microM nicotine response was observed for alkaloid 1 (IC50 value of 94 +/- 8 microM) and alkaloid 2 (IC50 value of 77 +/- 19 microM)...

..Further treatment with trifluoroacetic acid afforded the tetracyclic lactam skeleton found in the alkaloid (+/-)-selaginoidine...

..The identification of an alkaloid and a sesquiterpene using this new approach is described...

..The metabolism process in rats was stereoselective. CONCLUSION: This method is simple, reliable and suitable for studying the stereoselective metabolism of securinine in rats...

..Taken together, our data indicated that evodiamine alters the balance of Bcl-2 and Bax gene expression and induces apoptosis through the caspase pathway in HeLa cells...

..The structure and relative stereochemistry was determined by spectral data interpretation and X-ray crystallography...

..It was shown that delta-carbolines selectively bind to triplex or duplex DNA (intercalation). Indirubine analogues were prepared by deprotection and lactonization of functionalized 2-alkylidene-3-iminoindoles...

..A palladium-mediated, ligand-controlled desymmetrization provided the desired bis-oxanes in greater than 98% ee. Bis-oxanes 1 and 4 represent potential synthetic intermediates for the C3-C17 subunits of phorboxazoles A and B...

..The stereochemistry of the sigma-element and not its constitution controls the outcome of the pathway selected. This work illustrates the potential of linking stereochemical control to the challenging problem of skeletal diversity...

..Both alkaloids displayed a cytotoxic profile against a panel of HCT-116 colon carcinoma cells indicative of a p53 dependent mechanism...

..Compound 3, which was probably previously regarded as bisnortoxiferine I (2), is a one-sided ring closed product of 2...

..Narcistatin (3b) and 15 salt derivatives were evaluated against a panel of human cancer cell lines, and the range (0.1-0.01) of GI(50) values in micro g/mL was found to parallel that shown by the parent narciclasine...

..The structure of 1 was determined using spectroscopic methods. All compounds were tested for their antifeedant activity against the Caribbean reef fish Thalassoma bifasciatum in an aquarium assay...

..Thus, the highest cytotoxic activity was found in dienic dilactones with ether-type substitutions on C-17, whereas the closure of the gamma-lactone ring is not critical for presenting a maximal antimicrobial activity...

..Two other known indoline alkaloids were also obtained from the heartwood, 12-hydroxy-11-methoxystrychnobrasiline 2 and strychnobrasiline 3...

..The structure of 1 was determined by the interpretation of 1D/2D NMR and MS data. Dehalogenation of perophoramidine (1) by ammonium formate catalyzed transfer hydrogenation confirmed the type and number of halogen atoms present in 1...

..collected in the Dahlak archipelago (the Red Sea), Eritrea. The structure of halichondramine was elucidated by interpretation of MS, COSY, HMQC, HMBC, TOCSY, and HSQC-TOCSY data...

..Compound 1 exhibits a selective cytotoxic activity against the HT-29 human colon carcinoma cell line...

..The relative configuration of 11 carbon stereocenters of 1 was elucidated on the basis of NOESY...

..reaction: see text] A diastereoselective total synthesis of securinine in optically pure form was achieved by employing ring-closing metathesis of the corresponding dienyne compound as a key step...

..Their structures were determined by spectroscopic data analysis. DPPH (2,2-diphenyl-1-picrylhydrazyl) radicals were scavenged by compounds 1 and 2, but with weak activity...

..The synthetic sequence also produced four biologically active naturally occurring drimanic sesquiterpenes, (+)-drimane-8alpha,11-diol (34), (-)-drimenol (38), (+)-albicanol (39), and (-)-albicanal (31) as intermediates...

..aureus strains, and antimycobacterial activity against Mycobacterium tuberculosis H37Rv...

..The facility of the cycloaddition is critically dependent on conformational factors in the transition state...

..The configuration of the exo-cyclic alkene group in 4 is tentively assigned as E on the basis of mechanistic considerations...

..It appears the two compounds are slow reacting and do not reach steady state conditions within the standard half an hour time frame but only seemed to have reached steady state conditions after 4 h...

..We report the stereoselective total synthesis of norzoanthamine in 41 steps, with an overall yield of 3.5% (an average of 92% yield each step)...

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..The strategy is demonstrated by accomplishing the formal total synthesis of (+/-)-pancracine. [reaction: see text]..

..1beta-Dehydroxybaccatin VI (7) remained unreacted under the same condition...

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..An unprecedented tandem 1,7-hydrogen shift, 8pi-electrocyclization is proposed to explain the formation of this ring-expanded species...

..CONCLUSION: All of four compounds were isolated from S. suffruticosa for the first time and were the enantiomers isolated from this plant before...

..The trans-anti-trans relative configuration of the ABC framework of 4 was installed via a sequence of reactions that included a hydroboration and a modified Robinson annulation...

..All the compounds were evaluated for in vitro cytotoxic activity against 12 distinct human cancer cell lines. They all exhibit cytotoxic activity with IC(50) values at least of micromolar order...

..Primary bioassays showed that compound 1 had medium cytotoxic activity against HEp-2 and HepG2 Cells, with IC(50) of 23.337 microM and 29.4497 microM, respectively...

..1'S)-Hydroxystemofoline (10) and a number of related analogues were also prepared. In a TLC bioautographic assay, 9 was found to be the most active acetylcholinesterase inhibitor, but it was not as active as galanthamine...

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..The application of the chemistry is demonstrated by synthesizing (+/-)-maritidine...

..This novel model for recruitment and restraint of MP provides a means to effect a rapid cytoskeletal reorganization at the cell cortex upon demand...

..5 % (an average of 92 % yield each step) and that of zoanthamine (2) in 43 steps with an overall yield of 2.2 % (an average of 91 % yield each step) starting from (R)-5-methylcyclohexenone (3), respectively...

..We present a physical model for fluid pressure and flow in moving cells that quantitatively accounts for our experimental data...

..The theoretically computed energetic properties of the title compound (3) indicated the superior performance in comparison to tetranitrodibenzo tetraazapentalene (TACOT) and hexanitrostilbene (HNS) in terms of velocity of detonation...

..Importantly, the cellular activity translates to potent inhibition of tumor growth in vivo. An oral dose of 5 mg/kg QD is well tolerated and results in near stasis (92% TGI) in an HCT116 mouse xenograft model...

..abstract_text> ..

..The design of new and possibly more effective agents should then be feasible. ..

..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. ..

..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. ..

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

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

..abstract_text> ..

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

..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 ..

..To this end, new synthetic chemistry will be developed that will have utility not only for this program, but also be of general value to the academic and pharmaceutical communities engaged in Cancer Biology. ..

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..We believe that this philosophy of "unified synthetic strategies" will be further developed by this proposal...

..Once such features are identified the design of new and possibly more effective antitumor drugs should be feasible...

..Thus, as we develop an approach to each target structure, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships. ..

..Once such features are identified, the design of new and possibly more effective antitumor drugs should be feasible...

..Expected findings should lead to novel compounds that can be developed as much needed innovative non-stimulant treatments for ADHD and other major neuropsychiatric disorders. ..

..adult rats, and should evolve new principles for improved treatments for childhood-onset schizophrenia and other major pediatric psychiatric disorders. ..

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..Expected findings should evolve new principles and lead to novel compounds that can be used as much-needed innovative treatments for ADHD and other major neuropsychiatric disorders. ..

..Thus, as we develop an approach to each target structure, we will also prepare model compounds designed to permit the elucidation of structure-activity relationships. ..

..abstract_text> ..

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

..abstract_text> ..

..This philosophy of "unified synthetic strategies" will be further developed in this proposal. ..

..The design of new and possibly more effective agents should then be feasible...