Bioactive 4-substituted-6-methyl-2-pyrones with promising cytotoxicity against A2780 and K562 cell lines

Bioactive synthetic 4-substituted-6-methyl-2-pyrones are reported. Various 4-substitutents have been incorporated using Pd-catalysed carbon–carbon bond coupling procedures. Preliminary screening of the 2-pyrones against human ovarian carcinoma (A2780) and human chronic myelogenous leukaemia (K562) cell lines show that 4-alkynyl-6-methyl-2-pyrones have excellent potential as anticancer agents. The pyrones demonstrate broad spectrum antimicrobial activities.     

Membrane-associated reactions in ubiquinone biosynthesis: 2-octaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone methyltransferase

The O-methylation of 2-octaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone, which has been previously postulated to be the final reaction in the biosynthesis of ubiquinone was demonstrated in vitro using cell extracts of Escherichia coli. $\text{S-}\text{Adenosyl}\text{-}\text{l}\text{-}\text{methionine}$ was active as the methyl donor for the reaction. The enzyme concerned, S-adenosyl-l-methionine: 2-octaprenyl-3-methyl-5-hydroxy-6-methoxy-1,4-benzoquinone-O- methyltransferase, was partially purified and shown to have a molecular weight of about 50 000 and to require a divalent metal and dithiothreitol for optimal acitivity in vitro. The methyltransferase was absent from extracts from ubiG^? mutants suggesting that the ubiG gene is the structural gene coding for the methyltransferase. The enzyme, although not firmly membrane-bound, showed some affinity for the cell membrane in broken cell preparations and could utilize the benzoquinone substrate when the latter was free or bound to the cell membrane, with about equal efficiency. It is concluded that in vivo, the methyltransferase reaction probably occurs at the internal surface of the cytoplasmic membrane.     

Design, synthesis and evaluation of new 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential Src inhibitors

Src family kinases (SFKs) are nonreceptor tyrosine kinases that are reported to be critical for cancer progression. Inhibiting the catalytic activity of these proteins has become one of the major therapeutic concepts in contemporary drug discovery. We report here the design and the synthesis of novel 6-substituted-5-benzyloxy-4-oxo-4H-pyran-2-carboxamides as potential inhibitors of Src kinase. The synthesis of these derivatives and the preliminary results of biological activity will be discussed.     

Efficient large-scale synthesis of 5'-O-dimethoxytrityl-N4-benzoyl-5-methyl-2'-deoxycytidine

An efficient process to synthesize 5'-O-dimethoxytrityl-N4-benzoyl-5-methyl-2'-deoxycytidine in high yield and quality is described. Final benzoylation was improved by developing a method to selectively hydrolyze benzoyl ester impurities. This inexpensive approach was scaled up to multikilogram quantities for routine use in oligonucleotide therapeutics.     

The synthesis of 5-substituted ring E analogs of methyllycaconitine via the Suzuki-Miyaura cross-coupling reaction

Novel 3,5-disubstituted ring E analogs of methyllycaconitine were prepared and evaluated in nicotinic acetylcholine receptor binding assays. The desired analogs were prepared through the Suzuki-Miyaura cross-coupling reaction of methyl 5-bromo-nicotinate. The Suzuki-Miyaura cross-coupling reactions of pyridines with electron withdrawing substituents have not been extensively described previously.     

An expedient synthesis of N6-substituted-5'-modified adenosines

Herein we report a short and efficient synthesis of N(6)-substituted 5'-modified adenosines, which was achieved in four steps from 2',3',5'-tris-O-(tert-butyldimethylsilyl)inosine.     

6-(Levulinyloxymethyl)-3-methoxy-2-nitrobenzoyl and 2-(levulinyloxymethyl)-5-methoxy-4-nitrobenzoyl groups as novel base-labile groups for 5'-hydroxy protection in solid-phase oligonucleotide synthesis

The 6-(levulinyloxymethyl)-3-methoxy-2-nitrobenzoyl (LMMoNBz) and 2-(levulinyloxymethyl)-5-methoxy-4-nitrobenzoyl (LMMpNBz) groups were developed as novel base-labile groups for 5'-hydroxy protection in solid-phase oligonucleotide synthesis. A comparative study of the utility of LMMoNBz, LMMpNBz, and 2-(levulinyloxymethyl)-5-nitrobenzoyl (LMNBz) groups is described.     

New approaches to the chemical synthesis of bioactive oligosaccharides.

The past year has seen some major advances in the area of carbohydrate synthesis using chemical methods. Progress in all areas of synthetic methodology, including new protecting groups and coupling methods, has been reported. A number of complex carbohydrate structures have been prepared using known, as well as new, methods. The goal to allow nonspecialists access to defined carbohydrate structures for biochemical, biophysical and biological studies has drawn closer by the introduction of two approaches towards synthesis automation. A one-pot glycosylation strategy utilized computer-assisted synthesis planning and the first solid-phase automated synthesizer was introduced very recently.     

Nucleic acid component analogues: synthesis of 2'-deoxynucleosides from 5-substituted-4-hydroxy-6(1H)-pyrimidinones

Condensation of the silylated pyrimidines 5a-c with methyl 2-deoxy-3,5-di-O-toluoyl-D-pentofuranoside 6, using trimethylsilyltriflate as catalyst gave anomeric mixtures of 2'-deoxynucleosides 7a-c, the pure alpha- and beta-anomers were separated and deprotected with sodium methoxide in methanol to give 1-(2'-deoxy-alpha-D-pentafuranosyl)-4-hydroxy-5-substituted-6(1H)-pyrimidinones 10a,b and 13a and their corresponding beta-anomers 11a,b and 13b.     

The synthesis and biological properties of some 5-substituted-2'-deoxyuridines

The reaction of various nucleophiles with 5-vinyl-2'-deoxyuridine has been studied in an attempt to explain the in vitro toxicity of the compound. Attempts to synthesise pro-drugs of 5-vinyl- and 5-ethynyl-2'-deoxyuridine are described.     

Multiple-step,one-pot synthesis of 2-substituted-3-phosphono-1-thia-4-aza-2-cyclohexene-5-carboxylates and their corresponding ethyl esters

The multiple-step, one-pot procedure for a series of 2-substituted-3-phosphono-1-thia-4-aza-2-cyclohexene-5-carboxylates, analogues of the natural, sulfur amino acid metabolite lanthionine ketimine (LK), its 5-ethyl ester (LKE) and 2-substituted LKEs is described. Initiating the synthesis with the Michaelis-Arbuzov preparation of α-ketophosphonates allows for a wide range of functional variation at the 2-position of the products. Nine new compounds were synthesized with overall yields range from 40 to 62%. In addition, the newly prepared 2-isopropyl-LK-P, 2-n-hexyl-LKE-P and 2-ethyl-LKE were shown to stimulate autophagy in cultured cells better than that of the parent compound, LKE.     

Antimicrobial activity of 3-methyl-5-furfurylidene-2-thioxo-4-thiazolidones

Substituted 3-methyl-5-furfurylidene-2-thioxo-4-thiazolidones1 –17 were tested for their action againstBacillus pumilus, B. brevis andB. megaterium and againstAspergillus flavus, A. fumigatus andA. niger. Most of the compounds possessed an activity against both bacteria and fungi. These compounds were also tested for their effectiveness as virus inhibitors employingNicotiana glutinosa as assay host against tobacco mosaic virus. Most of them exhibited potential antiviral activity bothin vitro andin vivo.     

Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-N,N-dialkyluronamides as human A3 adenosine receptor antagonists

On the basis of potent and selective A(3) adenosine receptor (AR) antagonist, 2-chloro-N(6)-(3-iodobenzyl)-4'-thioadenosine-5'-N,N-dimethyluronamide, structure-activity relationships were studied for a series of 5'-N,N-dialkyluronamide derivatives, synthesized from D-gulonic gamma-lactone. From this study, it was revealed that removal of the hydrogen bond-donating ability of the 5'-uronamide was essential for the pure A(3)AR antagonism. 5'-N,N-Dimethyluronamide derivatives exhibited higher binding affinity than larger 5'-N,N-dialkyl or 5'-N,N-cycloalkylamide derivatives, indicating that steric factors are crucial in binding to the human A(3)AR. A N(6)-(3-bromobenzyl) derivative 6c (K(i)=9.32 nM) exhibited the highest binding affinity at the human A(3)AR with very low binding affinities to other AR subtypes.     

Discovery of 5-substituted 2-amino-4-chloro-8-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7,8-dihydropteridin-6(5H)-ones as potent and selective Hsp90 inhibitors

A new series of compounds, 5-substituted 2-amino-4-chloro-8-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7,8-dihydropteridin-6(5H)-ones, have been designed and identified as potent and selective inhibitors of Hsp90. These compounds demonstrated nanomolar potency toward both Hsp90-regulated Her2 degradation and the growth of a panel of human tumor cell lines in cell-based assays. High selectivity of these compounds toward Hsp90 was evident given that they did not inhibit a panel of 34 kinases at 10 μM. The structure–activity relationship (SAR) of this series is reported here.     

Synthesis and cytotoxicity of 8-cyano-3-substitutedalkyl-5-methyl-4-methylene-7-methoxy-3,4-dihydropyrido[4,3-d]pyrimidines

Synthesis and cytotoxicity of 11 4-methylene pyrido[4,3-d]pyrimidines 5a-k were described. Cytotoxicity assay results showed that some compounds had much stronger antitumor activity than Fluorouracil against KB cell lines. The most active compound 5i exhibited high potency against KB, CNE2, MGC-803 cell lines with IC(50) values of 0.48, 0.15, 0.59 μM, respectively. The preliminary structure-activity relationships indicated that the introduction of benzyl groups bearing electron-donating function groups is favorable for the activity.     

A library synthesis of 4-hydroxy-3-methyl-6-phenylbenzofuran-2-carboxylic acid ethyl ester derivatives as anti-tumor agents

As a result of a hit-to-lead program using a technique of solution-phase parallel synthesis, a highly potent (2,4-dimethoxyphenyl)-[6-(3-fluorophenyl)-4-hydroxy-3-methylbenzofuran-2-yl]methanone (15b) was synthesized as an optimized derivative of 4-hydroxy-3-methyl-6-phenylbenzofuran-2-carboxylic acid ethyl ester (1), which was discovered as a screening hit from small-molecule libraries and exhibited selective cytotoxicity against a tumorigenic cell line.     

Tautomerism and conformation of the promutagenic analogue N6-methoxy-2'',3'',5''-tri-O-methyladenosine

N6-Methoxy-2',3',5'-tri-O-methyladenosine crystallizes in space group P2(1)2(1)2(1) with cell dimensions a = 4.693, b = 11.412, c = 31.741 A. Least-squares refinement of diffractometer data converged at R = 0.038. The location of a hydrogen atom at N1 and the observed bond lengths and bond angles indicate unequivocally the imino tautomer of the adenine moiety. The N6-methoxy group is oriented syn to N1 and the glycosidic torsion angle XCN is -3.6 degrees, i.e. in the anti range. The furanose ring has a C2'-exo/C3'- endo pucker (P = 0.9 degrees) and is unusually flattened (tau m = 30.0 degrees). The conformations of the O-methyl groups of the ribose ring are compared with those of monomethylated nucleosides, including the biologically important 2'-O-methyl nucleosides. Evidence is presented for the existence of C-H ... N intermolecular hydrogen bonds between adenine moieties. Bearing in mind that N6-methoxyadenosine is a promutagenic analogue, the results are compared with those for the corresponding promutagenic N4-methoxycytidine. They are also discussed in relation to the tautomerism, the conformation of the N6-methoxy group, and the associated base-pairing abilities in the absence and presence of polymerases.     

Discovery and SAR of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of mGlu5

A high-throughput cell-based screen identified a series of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of metabotropic glutamate receptor 5 (mGlu₅). This Letter describes the SAR of this series and the profile of selected compounds in selectivity and radioligand binding assays.