101,957 research outputs found
Direct deconvolution techniques for pool libraries of small organic molecules
No full textA review with 99 refs. on techniques for linking the structures of library components with specific parts of the library (wells, pools, single beads, etc.)
Encoding techniques for pool libraries of small organic molecules
No full textA review with 92 refs. The aim of this chapter is to provide helpful information to decide if, when, and how to apply any of the encoding techniques to the synthesis of libraries of any format. The complementarity, rather than mutual exclusion, of the different methods is often highlighted
Trialkylsilyl cyanide, polymer-supported
No full textA review. A handbook chapter. This chapter reviewed polymer-supported trialkylsilyl cyanide reagent for a safer replacement for liq. TMS-CN, loading ca. 1 mmol/g
Preparation of indolylpropenylideneheterocycles for treatment of osteoporosis
No full textTitle compds. [I; R2-R4 = H, alkyl, (substituted) aryl; R5 = H, alkyl, (substituted) aryl; R6, R7 = H, OH, amino, alkoxy, (substituted) aryloxy, benzyloxy, alkylamino, dialkylamino, halo, CF3, OCF3, NO2, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl; R6R7 = methylenedioxy, carbonyldioxy, carbonyldiamino; R8 = = H, OH, alkanoyl, alkyl, aminoalkyl, hydroxyalkyl, carboxyalkyl, carbalkoxyalkyl, carbamoyl, aminosulfonyl; Z1Z2C = heterocyclic group], were prepd. Thus, Et [(2-ethenecarbonyloxy)ethoxy]diethoxyphosphorylacetate (prepn. given), tetramethylguanidine, and (E)-3-(5,6-dichloro-1H-indol-2-yl)prop-2-enal (prepn. given) in PhMe were heated at 100° overnight to give 6.9% (2Z,4E)-3-[3-(5,6-dichloro-1H-indol-2-yl)-2-propenylidene]-1,4-dioxan-2-one. The latter inhibited bafilomycin-sensitive chicken osteoclast ATPase with IC50 = 8.5 μM
Stereoselective alkenylation of aldehydes with phosphorus carbanions : preparation of E- and Z-2-alkoxy- and 2-aryloxy-2-alkenoates
No full textEighteen phosphorus-based alkerrylation reagents 1a-6c were synthesized and condensed with n-butyraldehyde 7a and benzaldehyde 7f. They were condensed with the aldehydes 7b-e,g-n to produce 2-methoxy-2-alkenoates 8a-n and 2-phenoxy-2-alkenoates 9a-n. A discussion on different selectivities for the alkerrylation reagents under different experimental conditions (base, soh em, temperature), the influence of the aldehydes on the geometrical outcome (electron rich or poor substituents steric hindrance) and the selection of the most E-and Z-selective reaction conditions for each class of aldehydes are reported Namely, triphenyl phosphonium salt la at RT in THF with DBU was better for Z-selectivity while trifluoroethylphosphonates 5b, 6b and 6c at -78 degrees in THF with KN(SiMe3)(2) were better for E-selectivity
Synthesis of dual action Smac/Zinc-Chelator conjugates as putative proapoptotic agents
No full textApoptosis, or programmed cell death, is a critical cell process in normal development and homeostasis of multicellular organisms. It is now recognized that dysfunction of the apoptosis machinery is a hallmark of cancer. Accordingly, targeting critical apoptosis regulators is an attractive approach for the development of new classes of therapies for the treatment of cancer and other human diseases.
The X-linked inhibitor of apoptosis protein (XIAP) is a member of IAP proteins that potently inhibit apoptosis[1]. XIAP contains three baculovirus IAP repeat (BIR) domains. The mechanism of action of XIAP entails its binding with initiator and effector caspases through its BIR domains. In cells, the anti-apoptotic function of XIAP is antagonized by Smac/DIABLO (second mitochondria-derived activator of caspases or direct IAP binding protein with low pI). Despite the rather complex structure of Smac, its short N-terminal AVPI sequence is sufficient to trigger the inactivation of anti-apoptotic XIAP[2]. Our research group has shown how small monomeric, AVPI-inspired Smac mimics can bind XIAP on its BIR3 domain with sub-micromolar potency[3,4]. Executioner caspase-3, -6 and -7 exist within the cytosol as inactive zymogens (procaspases) activated by limited proteolysis within their inter-domain linker, carried out by an initiator caspaseThe essential executioner caspase-3 is proteolytically activated by either caspase-8 or -9. Zinc ions co-localize with procaspase-3/caspase-3 and inhibit its enzymatic activity in the cell by direct interaction with an Asp-Asp-Asp (DDD) “safety catch” region[5]. Thus, in this work we coupled a zinc chelator moiety based on di(picolylamide)amine (DPA) and its N,N-bis(pyridin-2-ylmethyl)ethane-1,2-diamine (BPEN) derivative to pro-apoptotic Smac mimetics, synthesized starting from known intermediates 1 and 2.
Dual action Smac mimetic-zinc chelators 3 and 4 were prepared from compounds 1 and 2 as shown in Scheme 1 and characterized in vitro, using cell-free and cellular assays[6,7]. Their ability to bind XIAP BIR3 domain, to process pro-caspase-3 to caspase-3 and their cytotoxicity have been experimentally determined, and favorably compared with those of a potent Smac mimic compound, especially for the most potent, tribasic dual action compound 4. Furthermore, the Zinc affinity for both compounds was confirmed by fluorescence measurements.
References
1. Q. L. Deveraux, J. C. Reed. Genes & Dev. 1999, 13, 239-252
2. J. Chai, C. Du, J. W. Wu, S. Kyin, X. Wang, Y.Shi. Nature 2000, 406, 855-862
3. P. Seneci, A. Bianchi, C. Battaglia, L. Belvisi, M. Bolognesi, A. Caprini, F. Cossu, E. de Franco, M. de, D.
Delia, C. Drago, A. Khaled, D. Lecis, L. Manzoni, M. Marizzoni, E. Mastrangelo, M. Milani,I. Motto, E.
Moroni, D. Potenza, V. Rizzo, F. Servida, E. Turlizzi, M. Varrone, F. Vasile, C. Scolastico. Bioorg. Med.
Chem. 2009, 17, 5834–5856.
4. L. Manzoni, D. Arosio, L. Belvisi, A. Bracci, M. Colombo, D. Invernizzi, C. Scolastico. J. Org. Chem. 2005, 70,
4124-4132.
5. K. S. Putt, G. W. Chen, J. M. Pearson, J. S Sandhorst, M. S. Hoagland, J. Kwon, S. Hwang, H. Jin, M. I.
Churchwell, M. Cho, D. R. Doerge, W. G. Helferich, P. J. Hergenrother. Nat. Chem. Biol. 2006, 2, 543, 550
6. Z. Nikolovska-Coleska, R. Wang, X. Fang, H. Pan, Y. Tomita, P. Li, P.P. Roller, K. Krajewski, N.G. Saito, J.A.
Stuckey, S. Wang, Anal. Biochem. 2004, 332, 261-273.
7. Z. Nikolovska-Coleska, J.L. Meagher, S. Jiang, S.A. Kawamoto, W. Gao, H. Yi, D. Qin, P.P. Roller, J.A.
Stuckey, S. Wang, Anal. Biochem. 2008, 374, 87-98
Concepts of combinatorial chemistry and combinatorial technologies
No full textA survey of basic concepts of combinatorial chemistry and combinatorial technologies and a great impact of this new approach on the traditional chemistry is presented. The main fields of application of CC/CT are reviewed and the reasons why CC/CT is so strongly needed and demanded are given. Besides obvious utilization of CC/CT in drug discovery, agro-chemical research and research and development of new materials and catalysts also gain from this approach. The paper describes the origins and development of the technique, formed on the basis of probabilistic justifications. The applicability of combinatorial technologies and main combinatorial tools are described together with computer-assisted combinatorial chemistry, molecular design and biological methods of CC/CT. A list of important Web resources relevant to the topic is also presented
Preparation of 5-(indol-2-yl)-2,4-pentadienoates as inhibitors of bone resorption.
No full textTitle compds. [I; R1 = H, alkyl, halo, N3, alkylthio, PhS, PhCH2S, alkoxyalkyloxy, amino; R2-R4 = H, alkyl, (substituted) aryl; R5, R6 = H,, OH, amino, alkoxy, (substituted) aryloxy, PhCH2O, amino, halo, CF3, OCF3, NO2, alkyl, carboxy, carbalkoxy, carbamoyl, alkylcarbamoyl; R5R6 = methylenedioxy, carbonyldioxy, carbonyldiamino; X = OH, (substituted) alkoxy, amino, heterocyclyl], were prepd. Thus, (E,E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methyl-2,4-pentadienoic acid (prepn. given) and 3-diethylamino-1-propylamine, HOBT, and DCC were refluxed in MeCN/THF to give 36.4% (E,E)-5-(5,6-dichloro-1H-indol-2-yl)-N-[3-(diethylamino)propyl]-2-methyl-2,4-pentadienamide. The latter inhibited chicken osteoclast bafilomycin-sensitive ATPase with IC50 = 1.2 μM
Solid supported chiral auxiliaries in asymmetric synthesis. Part 2: Catalysis of 1,3-dipolar cycloadditions by Mg(II) cation
No full text1,3-Dipolar cycloadditions of supported Evans' chiral auxiliary with nitrile oxides and nitrones in the presence of Mg(II) cation as catalyst were evaluated. The presence of acetonitrile as co-solvent was found to be fundamental for the Lewis acid catalysis on solid-phase. The regio- and stereochemical outcome of nitrile oxide cycloadditions is influenced by nearly stoichiometric quantities of the cation, whilst catalytic amounts of Mg(II) influence both the reactivity and the stereoselectivity of the nitrone cycloadditions. The results obtained support a reaction mechanism involving the coordination of the Mg(II) to the dicarbonyl fragment of the chiral auxiliary
The effects of combinatorial chemistry and technologies on drug discovery and biotechnology : A mini review
No full textThe review will focus on the aspects of combinatorial chemistry and technologies that are more relevant in the modern pharmaceutical process. An historical, critical introduction is followed by three chapters, dealing with the use of combinatorial chemistry/high throughput synthesis in medicinal chemistry; the rational design of combinatorial libraries using computer-assisted combinatorial drug design; and the use of combinatorial technologies in biotechnology. The impact of "combinatorial thinking" in drug discovery in general, and in the examples reported in details, is critically discussed. Finally, an expert opinion on current and future trends in combinatorial chemistry and combinatorial technologies is provided
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