Synthesis of N-[2-O-(2-acetamido-2,3-dideoxy-5-thio-d-glucopyranose-3-yl)-d-lactoyl]-l-alanyl-d-isoglutamine

N-[2-O-(2-Acetamido-2,3-dideoxy-5-thio-d-glucopyranose-3-yl)-d-lactoyl]-l-alanyl-d-isoglutamine, in which the ring-oxygen atom of the sugar moiety in N-acetylmuramoyl-l-alanyl-d-isoglutamine (MDP) has been replaced by sulfur, was synthesized from 2-acetamido-2-deoxy-5-thio-α-d-glucopyranose (1). O-Deacetylation of the acetylated acetal, derived from the methyl α-glycoside of 1 by 4,6-O-isopropylidenation and subsequent acetylation, gave methyl 2-acetamido-2-deoxy-4,6-O-isopropylidene-5-thio-α-d-glucopyranoside (4). Condensation of 4 with l-2-chloropropanoic acid, and subsequent esterification, afforded the corresponding ester, which was converted, viaO-deisopropylidenation, acetylation, and acetolysis, into 2-acetamido-1,4,6-tri-O-acetyl-2-deoxy-3-O-[d-1-(methoxycarbonyl)ethyl]-5-thio-α-d-glucopyranose (12). Coupling of the acid, formed from 12 by hydrolysis, with the methyl ester of l-alanyl-d-isoglutamine, and de-esterification, yielded the title compound.     

Total synthesis of 3-O-[2-acetamido-6-O-(N-acetyl-alpha-D-neuraminyl-2-deoxy- alpha-D-galactosyl]-L-serine and a stereoisomer

O-(5-Acetamido-3,5-dideoxy-D-glycero-alpha-D-galacto-2- nonulopyranoxylonic acid)-(2----6)-O-(2-acetamido-2-deoxy-alpha-D-galactopyranosyl)-(1----3) -L-serine, a structural unit occurring in various submaxillary mucins, was synthesized for the first time by using O-[methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-alpha-D- galacto-2-nonulopyranosyl)onate]-(2----6)-3,4-di-O-acetyl-2- azido-2-deoxy-D- galactopyranosyl trichloroacetimidate (13) and N-(benzyloxycarbonyl)-L-serine benzyl ester as the key intermediates. The trichloroacetimidate 13 was prepared by starting from two monosaccharide synthons, namely, allyl 2-azido-2-deoxy-beta-D-galactopyranoside and methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-D-glycero-beta-D- galacto-2-nonulopyranosyl chloride)onate, which were coupled in the presence of silver triflate in tetrahydrofuran to give the desired alpha-(2----6)-linked disaccharide in moderate selectivity.     

Synthesis of 2-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-5a-carba-alpha-D- mannopyranose, and 5a-carba-2-O- and 3,6-di-O-(alpha-D-mannopyranosyl)-alpha-D-mannopyranoses.

Protected derivatives of the title carba-trisaccharide 1, and carba-disaccharides 4 and 6 have been synthesised by conventional glycosylation of the precursors 8, 9, or 22 of 5a-carba-alpha-D-mannopyranose with sugar halides. These are carba-sugar analogues of the oligosaccharide chains frequently occurring as structural units in biologically important glycoconjugates, and could be utilised as the building blocks for construction of higher carba-oligosaccharides of biological interest.     

Correlation of antibacterial activity of some N-[5-(2-furanyl)-2-methyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl]-carboxamide and 3-substituted-5-(2-furanyl)-2-methyl-3H-thieno[2,3-d]pyrimidin-4-ones with topological indices using Hansch analysis

The antimicrobial activity of the N-[5-(2-furanyl)-2-methyl-4-oxo-4H-theino[2,3-d]pyrimidin-3-y1]-carboxamides and 3-substituted-5-(2-furanyl)-2-methyl-3H-thieno[2,3-d]pyrimidin-4-ones was correlated with different topological indices using Hansch analysis. Good correlations were obtained through a simple regression equation with third order molecular connectivity index (3chi). The developed QSAR models were crossvalidated by leave-one-out technique.     

Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (BMS-645737), an in vivo active potent VEGFR-2 inhibitor

We report herein a series of substituted N-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amines as inhibitors of vascular endothelial growth factor receptor-2 tyrosine kinase. Through structure–activity relationship studies, biochemical potency, pharmacokinetics, and kinase selectivity were optimized to afford BMS-645737 (13), a compound with good preclinical in vivo activity against human tumor xenograft models.     

The synthesis ofP1-[2-acetamido-2-deoxy-3-O-(β-D-glucopyranosyluronic acid)-α-D-glucopyranosyl] P2-dolichyl diphosphate (N-acetylhyalobiosyluronic dolichyl diphosphate)

Starting from 2-acetamido-4,6-di-O-acetyl-2-deoxy-3-O-(methyl 2,3,4-tri-O-acetyl-β-D-glucopyranosyluronate)-α-D-glucopyranose (20), a crystalline intermediate prepared by a conventional sequence of reactions, the total synthesis of N-acetyl-hyalobiosyluronic dolichyl diphosphate was achieved. One of the key steps involved the transformation of the disaccharide 20 into the methyloxazoline 26, which was then converted into the stable, crystalline disaccharide phosphate derivative in ～30% yield. The methyloxazoline 26 was directly prepared from the corresponding methyl α-glycoside by acetolysis. Similarly, the allyl α-glycoside was transformed into 26.     

Synthesis and SAR of 4-(3-hydroxyphenylamino)pyrrolo[2,1-f][1,2,4]triazine based VEGFR-2 kinase inhibitors

A versatile synthesis of the suitably functionalized pyrrolo[2,1-f][1,2,4]triazine nucleus is described. SAR at the C-5 and C-6 positions of the 4-(3-hydroxy-4-methylphenylamino)pyrrolo[2,1-f][1,2,4]triazine template led to compounds with good in vitro potency against VEGFR-2 kinase. Glucuronidation of the phenol group is mitigated by incorporation of a basic amino group on the C-6 side chain of the pyrrolotriazine nucleus.     

Stepwise synthesis of methyl 4-O-[3-O-(β-d-xylopyranosyl)-β-d-xylopyranosyl]-β-d-xylopyranoside

The general properties and specificity of a dextran α-(1→2)-debranching enzyme from Flavobacterium have been examined in order to apply this enzyme to the structural analysis of highly branched dextrans. The optimum pH range and temperature were pH 5.5–6.5, and 45°, respectively. The enzyme was stable up to 40° on heating for 10 min, and over a pH range of 6.5–9.0 on incubation at 4° for 24 h. The effects of various metal ions and chemical reagents have also been examined. The debranching enzyme has a strict specificity for the (1→2)-α-d-glucosidic linkage at branch points of dextrans and related branched oligosaccharides, and produces d-glucose as the only reducing sugar. The degree of hydrolysis of the dextrans by this enzyme and the K_m value (mg/mL) were as follows: B-1298 soluble, 25.2%, 0.21; B-1299 soluble, 31.5%, 0.27; and B-1397, 11.8%, 0.91. The debranching enzyme thus has a novel type of specificity as a dextranhydrolase. We have termed this enzyme as dextran α-(1→2)-debranching enzyme, and its systematic name is also discussed.     

Novel inhibitors of epidermal growth factor receptor: (4-(Arylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)(1H-indol-2-yl)methanones and (1H-indol-2-yl)(4-(phenylamino)thieno[2,3-d]pyrimidin-6-yl)methanones

Several members of the quinazoline class of known tyrosine kinase inhibitors are approved anticancer agents, often showing selectivity for receptors of the HER/ErbB-family. Combining structural elements of this class with the bisindolylmethanone-structure led to a series of novel compounds. These compounds inhibited EGFR in the nanomolar range. Moreover, inhibition of EGFR autophosphorylation in intact A431 cells was shown, with IC₅₀ values ranging form 0.3–1 μM for compound 42, and 0.1–0.3 μM for 45. In a panel of 42 human tumor cell lines the sensitivity profile of the novel compounds was shown to be similar to that of the quinazoline class of tyrosine kinase inhibitors lapatinib and erlotinib (Tarceva®).