combinatorial chemistry online volume 11 issue 1 january 2009

Combinatorial Chemistry - An Online Journal 11 (2009) 1–3 Contents lists available at ScienceDirect Combinatorial Chemistry - An Online Journal journal homepage: www.elsevier.com/locate/comche Combinatorial Chemistry Online Volume 11, Issue 1, January 2009 N K Terrett Ensemble Discovery Corp., Cambridge, MA 02139, USA Current literature highlights 1.1 An ephedrine receptor from a dynamic combinatorial library Dynamic combinatorial libraries are generated from a set of building blocks using solution-phase reversible reactions As all potential compounds in the library are in equilibrium, the proportion of compounds generated reflect the relative stability of each Addition of a guest molecule will enhance the stability of compounds that bind the guest and will perturb the equilibrium in favour of those library compounds A recent paper describes the formation of a dynamic combinatorial library of over 9000 compounds, and the successful identification of compounds that binds ephedrine.1 The library was prepared by the oligomerisation of equimolar amounts of eight diverse disulphide building blocks in water at pH 8.0 Results indicated that cyclic products up to tetramer in size were being generated Running the preparation for one week in both the presence and absence of mM ephedrine resulted in libraries containing different proportions of product Ephedrine was chosen for this study, as it is a member of the phenylethylamine class of compound that also includes dopamine, adrenaline and amphetamine, many of which have pharmacological activity in the CNS To identify if any compounds were amplified in the presence of ephedrine, HPLC analyses of the two libraries was undertaken seeking peaks that were enhanced for the ephedrine templated library In particular, one peak corresponding to a compound with a mass of 922.7 was highly enriched in the templated library Through LC-MS-MS experiments, this compound was identified as being a tetramer composed of two equivalents each of disulphides and Indeed it was observed that (1)2(2)2 and the close analogue (1)(2)3 were only observed when the ephedrine template was present SH COOH HOOC HS HOOC SH SH E-mail: nterrett@ensemblediscovery.com doi:10.1016/j.comche.2008.12.001 To confirm binding and identify the specific isomers that bind ephedrine, a follow-up library was prepared using only the building blocks, and It was observed that there was little selectivity in amplification between the isomers of (1)2(2)2 A similar lack of selectivity was observed with (1)(2)3, and thus no attempts were made to separate them Isothermal calorimetry demonstrated that the binding event was enthalpy driven with affinities amongst the highest reported to date for synthetic receptors for this class of molecule 1.2 Solid-phase synthesis of a library of FK228 analogues Histone deacetylases (HDACs) participate in the post-translational modification of histones by catalysing a deacetylation These result in a change of DNA conformation, resulting in epigenetic gene regulation, a process than can play a critical role in cell proliferation, differentiation and thus also in cancer Consequently, there has been a search for inhibitors of HDACs, the most fully described of which is FK228 (3), a natural product isolated from Chromobacterium violaceum O O N H S O O NH S H N HN O R3 O O HN HN O O N H O NH S S H N R1 HN O R2 O FK228 operates as a pro-drug - reduction of the disulphide bond when the compound enters cells results in the release of a thiol group that binds to a catalytic zinc cation in the HDAC active site Total synthesis of FK228 has been achieved but is a laborious process, and access to analogues has been problematic A recent publication has described a solid-phase route to the synthesis of FK228 analogues based on a modified compound (4) with isosteric substitutions.2 The modifications in the structure of allowed more rapid synthesis using readily available building blocks The trans double bond in the heptenoic acid residue of FK228 was replaced with an amide bond, and the ester bond in the depsipeptide macrocyclic backbone was also converted to an amide Finally, the unusual N K Terrett / Combinatorial Chemistry - An Online Journal 11 (2009) 1–3 (Z)-dehydrobutyrine amino acid in FK228 was replaced with a variable amino acid substituent, permitting further structural variation A solid-phase synthetic approach to compound was developed, using a standard N-Fmoc/tBu peptide synthesis strategy, preparing a linear pentapeptide prior to the macrocyclisation and disulphide formation From the library of analogues prepared, screening for the inhibition of T24 human bladder carcinoma cell growth revealed two compounds showing significant inhibition at 0.5 lM One of the lead compounds demonstrated significant growth inhibition against six human cancer cell lines with IC50 values between 0.18 and 0.06 lM A summary of the papers in this month’s issue 2.1 Solid-phase synthesis No papers this month 2.2 Solution-phase synthesis A library of flavonols has been made through the Algar-FlynnOyamada reaction from 20 -hydroxyacetophenones and benzaldehydes Glycosylation of these flavonols with various glycosyl donors affords a library of glycosylated flavonols which are potentially useful pharmacologically active compounds and will be studied for biological activities.3 A fast and straightforward three-component reaction to prepare 2-amino-5-alkylidene-thiazol-4-ones suitable for parallel synthesis has been reported The one-pot microwave methodology involves Knoevenagel condensation of aromatic aldehydes and rhodanine, followed by displacement of the thiocarbonyl sulphur with primary or secondary amines in the same reaction mixture.4 A practical strategy for the parallel synthesis of diazabenz[e]aceanthrylene-based heterocycles has been reported The key step in this approach was a microwave-assisted condensation and cyclisation reaction between an anthranilic acid derivative and a 20 carbomethoxy substituted N-aryl lactam The scope of the reaction has been explored as a function of both the nature and position of substituents in both components and variations in lactam ring size.5 2.3 Scaffolds and synthons for combinatorial libraries Novel multifunctional chemotypes based on a-tetralone, a-indanone, and chromanone have been synthesised by a chemo-enzymatic approach by applying an enzymatic irreversible transesterification strategy The scaffolds synthesised can be further elaborated with subsequent enzymatic as well as chemical transformations for the generation of new sets of structurally related organic molecules.6 2.4 Solid-phase supported reagents An efficient and operationally simple method for C3-alkylation of 4-hydroxycoumarins has been developed under acidic medium giving good yields of the products In the present method, a reusable AmberliteÒ IR-120 resin was used as an acid catalyst and secondary benzyl alcohols were used as alkylating agents The 3-alkylated-4-hydroxycoumarins thus obtained offered an easy access for the synthesis of 3,4-disubstituted coumarins by way of Pd-catalyzed coupling reactions.7 is based on the direct labelling with low amounts of commercially available NF31 in the presence of DMAP at room temperature, resulting in easily detectable red beads.8 A new, fluorous-tagged chiral auxiliary has been developed for the asymmetric, samarium diioide-mediated coupling of aldehydes and a,a-unsaturated esters a-Butyrolactones have been obtained in moderate to good isolated yield and in high enantiomeric excess The fluorous tag allows the auxiliary to be conveniently recovered by fluorous solid-phase extraction (FSPE) and reused.9 2.6 Library applications General, high-yielding microwave assisted organic synthesis protocols for the expedient synthesis of functionalised 3,6-disubstituted-[1,2,4]triazolo[4,3-b]pyridazines have been described This approach was amenable to an iterative analogue library synthesis strategy for the lead optimisation of an M1 antagonist screening hit.10 The affinity of nine different saccharides to a library of solidsupported pentapeptide diboronic acids was measured using a competitive binding assay, which employed alizarin as the chromophoric indicator Considerable variation in carbohydrate binding strengths was observed and the remarkably selective binding characteristics of these boronic acid-peptide hybrids suggest their potential use in carbohydrate sensors and cell-specific diagnostics and therapeutics.11 3,5-Diaryl carbothioamide pyrazolines designed as mycobactin analogues have been reported to be potent antitubercular agents under iron limiting conditions These compounds were evaluated for their MAO-inhibitory activity against rat liver MAO-A and MAO-B The thirty-two compounds analysed have shown a spectrum of activity from selective to nonselective against these two isoforms.12 Inspired by polyhydroxylated pyrrolidine alkaloid natural products, a 18-membered library of 2-aryl polyhydroxylated pyrrolidines has been efficiently prepared in two or three synthetic steps from known chiral cyclic nitrones The inhibitory activity of all these compounds against various glycosidase enzymes was evaluated.13 A small library of HI-236 derivatives substituted at the C-2 phenolic oxygen have been synthesised and evaluated as HIV non-nucleoside reverse transcriptase inhibitors (NNRTI) A number of them have superior antiviral activity to HI-236 as evaluated in both cell culture and in an RT inhibition assay.14 References 10 11 12 13 14 Ludlow, R F.; Otto, S J Am Chem Soc 2008, 130 (37), 12218-12219 Di Maro, S et al J Med Chem 2008, 51 (21), 6639-6641 Li, Z et al Tetrahedron Letters 2008, 49 (51), 7243-7245 Anderluh, M et al Tetrahedron, 2009, 65 (1), 344-350 Jones, A M et al Tetrahedron, 2009, 65 (2), 563-578 Mahapatra, T et al Tetrahedron: Asymmetry 2008, 19 (21), 2497-2507 Reddy, C R et al Tetrahedron, 2008, 64 (51), 11666-11672 Caroen, J.; Van der Eycken, J Tetrahedron Lett 2009, 50 (1), 41-44 Vogel, J C et al Tetrahedron, 2008, 64 (52), 11876-11883 Aldrich, L N et al Tetrahedron Lett 2009, 50 (2), 212-215 Duggan, P J.; Oermann, D A Tetrahedron 2009, 65 (1), 109-114 Jayaprakash, V et al Bioorg Med Chem Lett 2008, 18 (24), 6362-6368 Tsou, E -L et al Bioorg Med Chem 2008, 16 (24), 10198-10204 Hunter, R et al Bioorg Med Chem 2008, 16 (24), 10270-10280 Further Reading Papers on combinatorial chemistry or solid-phase synthesis from other journals 2.5 Novel resins, linkers and techniques A new sensitive and practical colorimetric test for solid-supported hydroxyl and thiol groups has been described The assay Betts, H M.; Barnard, P J.; Bayly, S R.; Dilworth, J R.; Gee, A D.; Holland, J P Controlled axial coordination: solid-phase synthesis and purification of metalloradiopharmaceuticals Angewandte Chemie, International Edition 2008, 47 (44), 8416-8419 N K Terrett / Combinatorial Chemistry - An Online Journal 11 (2009) 1–3 Roof, R A.; Sobczyk-Kojiro, K.; Turbiak, A J.; Roman, D L.; Pogozheva, I D.; Blazer, L L.; Neubig, R R.; Mosberg, H I Novel peptide ligands of RGS4 from a focused one-bead, one-compound library Chemical Biology & Drug Design 2008, 72 (2), 111–119 Kwon, Y -U.; Kodadek, T Encoded combinatorial libraries for the construction of cyclic peptoid microarrays Chemical Communications (Cambridge, United Kingdom) 2008, (44), 5704-5706 Caballero, E.; Figueroa, J.; Puebla, P.; Pelaez, R.; Tome, F.; Medarde, M Imino-DielsAlder reactions of 1-aryl-3-(trialkylsiloxy)-1,3-butadienes in solution and the solid phase European Journal of Organic Chemistry 2008, (23), 4004-4014 Gareiss, P C.; Sobczak, K.; McNaughton, B R.; Palde, P B.; Thornton, C A.; Miller, B L Dynamic combinatorial selection of molecules capable of inhibiting the (CUG) repeat RNA-MBNL1 interaction in vitro: discovery of lead compounds targeting myotonic dystrophy (DM1) Journal of the American Chemical Society 2008, 130 (48), 16254-16261 Lee, J T.; Mah, H.; Nam, K D.; Shin, D.; Ha, D -C.; Hahn, H -G Syntheses of 1,3-imidazolin2-ones and 1,3-imidazolin-2-thiones from new building blocks, c-aminoacetoacetanilides Journal of Combinatorial Chemistry 2008, 10 (6), 803-806 Lee, S S.; Lim, J.; Cha, J.; Tan, S.; Heath, J R Rapid microwave-assisted CNBr cleavage of bead-bound peptides Journal of Combinatorial Chemistry 2008, 10 (6), 807-809 Albada, H Bauke; Liskamp, Rob, M J TAC-scaolded tripeptides as artificial hydrolytic receptors: a combinatorial approach toward esterase mimics Journal of Combinatorial Chemistry 2008, 10 (6), 814-824 Gobin, O C.; Schueth, F On the suitability of dierent representations of solid catalysts for combinatorial library design by genetic algorithms Journal of Combinatorial Chemistry 2008, 10 (6), 835-846 Baxendale, I R.; Ley, S V.; Smith, C D.; Tamborini, L.; Voica, A -F A bifurcated pathway to thiazoles and imidazoles using a modular flow microreactor Journal of Combinatorial Chemistry 2008, 10 (6), 851-857 Bogolubsky, A V.; Ryabukhin, S V.; Plaskon, A S.; Stetsenko, S V.; Volochnyuk, D M.; Tolmachev, A A Dry HCl in parallel synthesis of fused pyrimidin-4-ones Journal of Combinatorial Chemistry 2008, 10 (6), 858-862 Verdie, P.; Subra, G.; Averland-Petit, M -C.; Amblard, M.; Martinez, J Solid-phase synthesis of 4-methylcarboxy-1,4-benzodiazepine-2,5-diones Journal of Combinatorial Chemistry 2008, 10 (6), 869-874 Chen, Y -Y.; He, W -Y.; Wu, Y.; Niu, C -Q.; Liu, G Dynamic selection of novel vancomycin N-terminal derivatives by resin-bound reversed D-Ala-D-Ala Journal of Combinatorial Chemistry 2008, 10 (6), 914-922 Fraczyk, J.; Kaminski, Z J Design, synthesis, and application of a library of supramolecular structures formed by N-lipidated peptides immobilized on cellulose Journal of Combinatorial Chemistry 2008, 10 (6), 934-940 Cho, C -H.; Neuenswander, B.; Lushington, G H.; Larock, R C Parallel synthesis of a multi-substituted benzo[b]furan library Journal of Combinatorial Chemistry 2008, 10 (6), 941-947 Shortridge, M D.; Hage, D S.; Harbison, G S.; Powers, R Estimating protein-ligand binding affinity using high-throughput screening by NMR Journal of Combinatorial Chemistry 2008, 10 (6), 948-958 Roskov, K E.; Epps, T H., III; Berry, B C.; Hudson, S D.; Tureau, M S.; Fasolka, M J Preparation of combinatorial arrays of polymer thin films for transmission electron microscopy analysis Journal of Combinatorial Chemistry 2008, 10 (6), 966973 Messeguer, J.; Cortes, N.; Garcia-Sanz, N.; Navarro-Vendrell, G.; Ferrer-Montiel, A.; Messeguer, A Synthesis of a positional scanning library of pentamers of Nalkylglycines assisted by microwave activation and validation via the identification of trypsin inhibitors Journal of Combinatorial Chemistry 2008, 10 (6), 974-980 McIntee, J W.; Sundararajan, C.; Donovan, A C.; Kovacs, M S.; Capretta, A.; Valliant, J F A convenient method for the preparation of fluorous tin derivatives for the fluorous labeling strategy Journal of Organic Chemistry 2008, 73 (21), 8236-8243 Ziach K.; Jurczak J Controlling and measuring the equilibration of dynamic combinatorial libraries of imines Organic Letters 2008, 10 (22), 5159-5162 O’Keefe B M.; Simmons N.; Martin S F Carbonylative cross-coupling of orthodisubstituted aryl iodides Convenient synthesis of sterically hindered aryl ketones Organic Letters 2008, 10 (22), 5301-5304 Duschmale, J J.; Woltering, T J.; Bleicher, K H A highly efficient synthesis route for the rapid generation of 1,2,5,6-tetrasubstituted benzimidazoles Synlett 2008, (10), 1467-1470 Jeon, M -K.; Kwon, J -J.; Kim, M -S.; Gong, Y -D A novel solid-phase synthetic method for 1,4-benzodiazepine-2,5-dione derivatives Synlett 2008, (11), 16511656 Tsukamoto, H.; Suzuki, R.; Kondo, Y Traceless solid-phase synthesis of mappicine ketone library via multiple chemoselective palladium-catalyzed reactions on benzenesulfonate linker Synlett 2008, (13), 2005-2010 Fu, G -Y.; Sheng, S -R.; Liu, X -L.; Cai, M -Z.; Huang, X Solid-phase organic synthesis of vinyl-substituted 1,3,4-oxadiazoles using polymer-bound a-selenopropionic acid Synthetic Communications 2008, 38 (23), 4240-4249 Liu, Z.; Mu, Y.; Lin, J.; Chen, Y Traceless solid-phase synthesis of 1,2,3thiadiazole derivatives from resin-bound acylhydrazine Synthetic Communications 2008, 38 (24), 4407-4414 Vogel, P Combinatorial synthesis of linearly condensed polycyclic compounds, including anthracyclinones, through tandem Diels-Alder additions Topics in Current Chemistry 2008, 282(Anthracycline Chemistry and Biology I), 187-214