We have developed combinatorial libraries of new 2-alkylimino-1,3-thiazolines with four diversity points, consisting of more than 500 compounds, in a parallel synthetic fashion. The synthetic strategy was based on the co...We have developed combinatorial libraries of new 2-alkylimino-1,3-thiazolines with four diversity points, consisting of more than 500 compounds, in a parallel synthetic fashion. The synthetic strategy was based on the construction of a large library aimed at the discovery of new compounds with T-type calcium channel inhibitory activity through structure modifications of hit compound 2. The syntheses of the compounds of Chemset A with four diversity points were accomplished by the condensation of thioureas 5 with alpha-haloketones 6{1-66} having two diversity points each. A library of phthalimidyl 1,3-thiazolines 24 was synthesized to provide Chemset B, which allowed the introduction of other diversity points through the nucleophilic character of the amino nitrogen. A sublibrary, Chemset C, was constructed from the libraries of Chemset A and Chemset B by functionalization of the C-4 position of the 1,3-thiazoline ring. The products containing ester or acid groups at the C-4 position of the 1,3-thiazoline ring were used in amide synthesis to give a new sublibrary within Chemset C. Deprotection of the phthalimidyl moiety of 24 followed by the reaction with benzoyl chloride gave the corresponding sublibrary in Chemset C. Another sublibrary which includes secondary amino derivatives was obtained by reduction of the amide moiety or reductive amination of 23 with phenyl aldehyde. The selected compounds from the generated libraries were evaluated with respect to inhibition of T-type calcium channels, where some of them have exhibited promising activity.
A simple and efficient method for the combinatorial synthesis of highly substituted thiopyrano[3,4-b]pyridin-5(4H)-one, thiopyrano[3,4-b]quinoline-4,6(3H,5H)-dione, dithiopyrano[3,4-b:4',3'-e]pyridine-4,6(1H,3H)-dione, a...A simple and efficient method for the combinatorial synthesis of highly substituted thiopyrano[3,4-b]pyridin-5(4H)-one, thiopyrano[3,4-b]quinoline-4,6(3H,5H)-dione, dithiopyrano[3,4-b:4',3'-e]pyridine-4,6(1H,3H)-dione, and pyrazolo[3,4-b]thiopyrano[4,3-e]pyridin-5(1H)-one derivatives has been developed. The synthesis was achieved via one-pot multicomponent reaction of aromatic aldehyde, 2H-thiopyran-3,5(4H,6H)-dione and enamine (such as the derivatives of amine and 1,3-dicarbonyl compounds and 3-methyl-1-phenyl-1H-pyrazol-5-amine) in glacial acetic acid. This procedure features short reaction time, generally good to excellent yields, easily available starting materials, and operational simplicity. This chemistry provides an efficient and promising synthetic strategy to diversity-oriented construction of the thiopyrano[3,4-b]pyridine skeleton.
The first total synthesis of marine natural product, (+/-)-marinopyrrole A, has been accomplished via a nine-step synthesis in an overall yield of 30%. A small focused library based on marinopyrrole has been designed and...The first total synthesis of marine natural product, (+/-)-marinopyrrole A, has been accomplished via a nine-step synthesis in an overall yield of 30%. A small focused library based on marinopyrrole has been designed and synthesized. The scope of chemistry was investigated, and a robust chemistry suitable for library synthesis has been developed in the current study. The method that we have developed has made it possible to generate diverse analogues based on structurally novel marinopyrroles for study of potential antibiotic and anticancer activities.
An efficient method for the solution-phase parallel synthesis of 4-substituted-1,4-dihydroisoquinolin-3-ones is developed. The isoquinolinones were constructed employing an intramolecular Heck reaction, providing full re...An efficient method for the solution-phase parallel synthesis of 4-substituted-1,4-dihydroisoquinolin-3-ones is developed. The isoquinolinones were constructed employing an intramolecular Heck reaction, providing full regio- and stereoselectivity. Most of the synthesized compounds showed potent antiproliferative activities against tumor cell lines.
Natural carbohydrate scaffold catalyzed diastereoselective synthesis of functionalized pyrrolidines have been developed via 1,3-dipolar cycloaddition of azomethine ylides derived from alpha-imino esters with dienes or di...Natural carbohydrate scaffold catalyzed diastereoselective synthesis of functionalized pyrrolidines have been developed via 1,3-dipolar cycloaddition of azomethine ylides derived from alpha-imino esters with dienes or dipolarophiles. Naturally most abundant carbohydrates, like cellulose and starch, were converted into their sulfuric acid derivative, which are exhibiting efficient catalytic properties, along with excellent cost effectivity and recyclability. The advantages of this methodology are diversity oriented metal free synthesis of functionalized pyrrolidines, mild reaction condition, high diasteroselectivity and yield.
We report on the commissioning experimental run of the rapid automated materials synthesis instrument (RAMSI), a combinatorial robot designed to manufacture, clean, and print libraries of nanocrystal precursor solid comp...We report on the commissioning experimental run of the rapid automated materials synthesis instrument (RAMSI), a combinatorial robot designed to manufacture, clean, and print libraries of nanocrystal precursor solid compositions. The first stage of RAMSI, parallel synthesis, uses a fully automated high throughput continuous hydrothermal (HiTCH) flow reactor for automatic metal salt precursor mixing, hydrothermal flow reaction, and sample slurry collection. The second stage of RAMSI provides integrated automated cleanup, and the third section is a ceramic printing function. Nanocrystal precursor solid ceramics were synthesized from precursor solutions and collected into 50 mL centrifuge tubes where they were cleaned by multiple centrifugation and redispersion cycles (monitored by intelligent scanning turbidimetry) and printed with an automated pipette. Eight unique compositions of a model phosphor library comprising pure nano-Y(OH)(3) and Eu(3+) doped-yttrium hydroxide, Y(OH)(3):Eu(3+) nanocrystal precursor solid were synthesized (with 2 centrifuge tubes' worth collected per composition), processed, and printed in duplicate as 75, 100, and 125 microL dots in a 21.6 ks (6 h) experiment (note: the actual time for synthesis of each sample tube was only 12 min so up to 60 compositions could easily be synthesized in 12 h if one centrifuge tube per composition was collected instead). The Y(OH)(3):Eu(3+) samples were manually placed in a furnace and heat-treated in air for 14.4 ks (4 h) in the temperature range 200-1200 at 100 degrees C intervals (giving a total of 84 samples plus one as-prepared pure Y(OH)(3) sample). The as-prepared and heat-treated ceramic samples were affixed to 4 mm wide hemispherical wells in a custom-made aluminum well-plate and analyzed using a fluorescence spectrometer. When the library was illuminated with a 254 nm light source (and digitally imaged and analyzed), the 3 mol % Eu(3+) sample heat-treated at 1200 degrees C gave the most intense fluorescence (major red peak at 612 nm); however, an identical nanocrystal precursor heat-treated at only 500 degrees C (identified as Y(2)O(3):Eu(3+) after heat treatment) was the brightest phosphor under illumination of the samples heat-treated at or below 1000 degrees C.
An efficient, economical, and convenient method was developed for the preparation of 2-substituted (N, O, C) benzothiazoles from N'-substituted-N-(2-halophenyl)thioureas, O'-substituted-N-(2-halophenyl) carbamothioates,...An efficient, economical, and convenient method was developed for the preparation of 2-substituted (N, O, C) benzothiazoles from N'-substituted-N-(2-halophenyl)thioureas, O'-substituted-N-(2-halophenyl) carbamothioates, or N-(2-halophenyl) thioamides via a base-promoted cyclization in dioxane without any transition metal. A one-pot variant combining the synthesis of the thiourea and the cyclization was also demonstrated. High yields were obtained, and a variety of functional groups were tolerated under these conditions. Transition-metal-free, mild reactive conditions, wide application scope, and shorter reaction times make this method superior to the reported methods for the synthesis of 2-substituted benzothiazoles and suitable for combinatorial format.
Rapid generation of a small library of highly functionalized indolizonones was realized by exploiting three palladium-catalyzed cross-coupling reactions of 2-iodoindolizinones which in turn were readily accessed via sequ...Rapid generation of a small library of highly functionalized indolizonones was realized by exploiting three palladium-catalyzed cross-coupling reactions of 2-iodoindolizinones which in turn were readily accessed via sequential iodine-mediated cyclization/1,2-shift reactions of propargylic alcohols.
Here we present the solution phase parallel synthesis of a combinatorial library consisting of 776 new substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines and a study of the relation of their structure with a...Here we present the solution phase parallel synthesis of a combinatorial library consisting of 776 new substituted 3-phenylsulfonyl-[1,2,3]triazolo[1,5-a]quinazolines and a study of the relation of their structure with a 5-HT(6) receptor antagonistic activity in a functional cell (HEK 293) analysis and radioligand competitive binding. We have found highly active and selective 5-HT(6)R antagonists. The most active 5-HT(6)R antagonists have IC(50) <100 nM in a functional assay, and K(i) <10 nM in a binding assay, which is 100 times higher than the activity with respect to other serotonin receptors.
A synthetic "phage-like" system was designed for screening mixtures of small molecules in live cells. The core of the system consists of 2 mum diameter cross-linked monodispersed microspheres bearing a panel of fluoresce...A synthetic "phage-like" system was designed for screening mixtures of small molecules in live cells. The core of the system consists of 2 mum diameter cross-linked monodispersed microspheres bearing a panel of fluorescent tags and peptides or small molecules either directly synthesized or covalently conjugated to the microspheres. The microsphere mixtures were screened for affinity to cell line PC-3 (prostate cancer model) by incubation with live cells, and as was with phage-display peptide methods, unbound microspheres were removed by repeated washings followed by total lysis of cells and analysis of the bound microspheres by flow-cytometry. Similar to phage-display peptide screening, this method can be applied even in the absence of prior information about the cellular targets of the candidate ligands, which makes the system especially interesting for selection of molecules with high affinity for desired cells, tissues, or tumors. The advantage of the proposed system is the possibility of screening synthetic non-natural peptides or small molecules that cannot be expressed and screened using phage display libraries. A library composed of small molecules synthesized by the Ugi reaction was screened, and a small molecule, Rak-2, which strongly binds to PC-3 cells was found. Rak-2 was then individually synthesized and validated in a complementary whole cell-based binding assay, as well as by live cell microscopy. This new system demonstrates that a mixture of molecules bound to subcellular sized microspheres can be screened on plated cells. Together with other methods using subcellular sized particles for cellular multiplexing, this method represents an important milestone toward high throughput screening of mixtures of small molecules in live cells and in vivo with potential applications in the fields of drug delivery and diagnostic imaging.
A silver triflate-catalyzed tandem reaction of N'-(2-alkynylbenzylidene)hydrazide with silyl enolate is described, which generates the unexpected H-pyrazolo[5,1-a]isoquinolines in good to excellent yields. Intramolecular...A silver triflate-catalyzed tandem reaction of N'-(2-alkynylbenzylidene)hydrazide with silyl enolate is described, which generates the unexpected H-pyrazolo[5,1-a]isoquinolines in good to excellent yields. Intramolecular cyclization, nucleophilic addition, condensation, and aromatization may be involved in the reaction process.
Tandem addition-cyclization reactions of 2-alkynylbenzenamines with isothiocyanates promoted by silica gel are described. This reaction proceeds smoothly at 80 degrees C under metal- and solvent-free conditions, which pr...Tandem addition-cyclization reactions of 2-alkynylbenzenamines with isothiocyanates promoted by silica gel are described. This reaction proceeds smoothly at 80 degrees C under metal- and solvent-free conditions, which provides an efficient and practical route for the generation of 2,4-dihydro-1H-benzo[d][1,3]thiazines. The recovered silica gel could be reused for several times.
A mild and facile method for the combinatorial synthesis of quinazolin-4-(1H)-one derivatives, containing simple 2,2-disubstituted quinazolin-4-(1H)-ones, spirocyclic quinazolin-4-(1H)-ones, spiro-heterocyclic quinazolin...A mild and facile method for the combinatorial synthesis of quinazolin-4-(1H)-one derivatives, containing simple 2,2-disubstituted quinazolin-4-(1H)-ones, spirocyclic quinazolin-4-(1H)-ones, spiro-heterocyclic quinazolin-4-(1H)-ones, and dispirocyclic quinazolin-4-(1H)-ones, is described, which results in high yields by using ionic liquids as green media. The method involves the reaction of 2-aminobenzamides with various ketones catalyzed by iodine and provides new quinazolin-4-(1H)-one library for biomedical screening.
On the basis of the idea of equilateral ingredient triangle, a material library of the TiO(2)/WO(3)/MnO(2) composite material system was designed, which consisted of 66 ingredient points. Each point in the library corres...On the basis of the idea of equilateral ingredient triangle, a material library of the TiO(2)/WO(3)/MnO(2) composite material system was designed, which consisted of 66 ingredient points. Each point in the library corresponded with a device. To fabricate the device, the technology of screen printing was used. The pastes which were suitable for this technology were prepared by ball milling. After we printed the pastes onto the alumina substrate which had been preprinted with Au interdigital electrodes, these printed samples were sintered at 550 degrees C for 2 h in air. The photocurrent of each device under different light sources was measured respectively using a high-throughput screening system. The largest photocurrent was observed when the mole ratio of TiO(2)/WO(3) was 2/8 in the composite system. X-ray diffraction (XRD) was used to investigate the phase structure of the powder which had excellent photoelectric response.
A combinatorial approach has been carried out to systematically investigate visible-light responsiveness of Fe-Ti-M (M: various metal elements) oxides for photoelectrochemical water splitting. Among the 25 elements teste...A combinatorial approach has been carried out to systematically investigate visible-light responsiveness of Fe-Ti-M (M: various metal elements) oxides for photoelectrochemical water splitting. Among the 25 elements tested, strontium was the most effective. A ternary metal oxide with the composition Fe(86.1)Ti(9.6)Sr(4.3)O(x) has been identified as a new lead structure for a visible-light responsive, n-type semiconductor. We have conducted various kinds of characterization of the Fe-Ti-Sr oxide semiconductor and discussed the reason why Sr in the Fe-Ti oxide gave the highest photocurrent.
J Comb Chem
· 2010 May · PMID 20218730
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An efficient approach toward the parallel solid-phase synthesis of highly diversified chiral polyaminothiazoles employing Hantzsc’s thiazole synthesis is presented. The treatment of resin-bound chiral polyamines with Fmo...An efficient approach toward the parallel solid-phase synthesis of highly diversified chiral polyaminothiazoles employing Hantzsc’s thiazole synthesis is presented. The treatment of resin-bound chiral polyamines with Fmoc-isothiocyanates generated polythioureas which were further reacted with a variety of α-halogenoketones to afford following cleavage from the solid support the desired chiral polyaminothiazoles in good yield and purity.
J Comb Chem
· 2010 May · PMID 20218627
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A mild and efficient protocol for the synthesis of a 2,6-disubstituted pyrimidine-5-carboxylate library via a Morita-Baylis-Hillman (MBH) adduct is described. Herein, the three step methodology involves the use of substi...A mild and efficient protocol for the synthesis of a 2,6-disubstituted pyrimidine-5-carboxylate library via a Morita-Baylis-Hillman (MBH) adduct is described. Herein, the three step methodology involves the use of substituted alpha-iodomethylene beta-keto ester intermediates obtained after oxidation of the MBH adducts, which are condensed with various types of amidine or guanidine derivatives, to generate the 2, 6-disubstituted pyrimidines-5-carboxylate libraries.
Cyclic peptides and their cyclic analogs have received a great deal of attention because of their numerous interesting biological activities and their challenging chemical synthesis. It has also been hypothesized that th...Cyclic peptides and their cyclic analogs have received a great deal of attention because of their numerous interesting biological activities and their challenging chemical synthesis. It has also been hypothesized that they might improve the cell permeability compared to linear molecules by providing internal hydrogen bonding and generally decreasing the conformational flexibility. In this study, a series of cyclic and linear peptoid-dexamethasone conjugates were rationally designed and efficiently synthesized on solid-phase for systematic cell permeability studies using reporter gene-based assays. These model compounds should be used to reveal how the cell permeability of cyclic molecules is affected by several physicochemical properties, especially, the reduced conformational flexibility and the ring size. In addition, the synthetic strategy that was adopted in this study can also provide a robust platform for postchemical modifications of various molecular scaffolds in solid-phase or solution-phase syntheses.