Najim A. Al-Masoudi

Synthesis of 5-thio-D-altrose and some of its derivatives

Abstract Acid-catalysed methanolysis of 6- O -acetyl-5- S -acetyl-1,2- O -isopropylidene-5-thio-3- O -toluene- p -sulphonyl-α- d -glucofuranose gave the methyl 5-thio-3- O -toluene- p -sulphonyl-α- and -β- d -glucopyranosides ( 5 ). Treatment of 5 with acidified 2,2-dimethoxypropane and then sodium methoxide gave the methyl 2,3-anhydro-4,6- O -isopropylidene-5-thio-α- and -β- d -allopyranosides. Epoxide opening with aqueous sodium hydroxide then gave mixtures of methyl 4,6- O -isopropylidene-5-thio-α- or -β- d -altropyranosides ( 9 ) and the corresponding gluco compounds 10 . Mild, acid hydrolysis converted 9 into the methyl 5-thio-α- and -⊙- d -altropyranosides and more vigorous hydrolysis gave 5-thio- d -altrose. Methyl 3,4- O -isopropylidene-5-thio-α- d altropyranoside was obtained when the 4,6-acetal 9a was left in acidified acetone. The methyl 2,3:4,6-di- O -isopropylidene-5-thio-α- and -β- d -glucopyranosides were quickly produced by the action of acidified 2,2-dimethoxypropane on the 4,6-acetals 10 . Methyl 2,3,4,6-tetra- O -acetyl-α- d -altropyranoside ( 17a ) was shown to exist mainly in the 4 C 1 conformation, but the β anomer 17b and 1,2,3,4,6-penta- O -acetyl-5-thio-β- d altropyranose both adopt mainly the 1 C 4 conformation.

Nucleosides, XLVI1 Syntheses and Reactions of 6- and 7-p-Chlorophenyllumazine Nucleosides

Abstract The syntheses of 6-(4) and 7-p-chlorphenyl-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-lumazine (6), was well as the debenzoylation to the corresponding free nucleosides 5 and 7, were improved. Thiation of 4 and 6 by P4S10 led in excellent yields to 4-thiolumazine nucleosides (8, 10) which could be deblocked to 9 and 11 and converted on treatment with ammonia into the isopterin-N-1- ribofuranosides 13 and 14. 2,2′-Anhydro-nucleoside formation worked well with 5 and 7 respectively to give 15 and 16, which formed on acid hydrolysis the 6- and 7-substituted 1-β-D-arabinofuranosyl-lumazines 18 and 19. The new nucleosides have been characterized by UV and 1H-NMR spectra.

Syntheses and conformations of 3-acetamido-3-deoxy-5-thio-d-xylose and 4-acetamido-4-deoxy-5-thio-l-lyxose and some derivatives thereof

Abstract In reactions with azide ions, methyl 5-thio-3- O - p -toluenesulphonyl-α- d -xylopyranoside gave methyl 3-azido-3-deoxy-5-thio-α- d -xylopyranoside, methyl 4- O -acetyl-2,3-anhydro-5-thio-α- d -ribofuranoside ( 7 ) afforded a mixture of methyl 4- O -acetyl-3-azido-3-deoxy-5-thio-α- d -xylopyranoside and the 2-azido-2-deoxy- d arabino analogue, and methyl 2- O -acetyl-3,4-anhydro-5-thio-α- d -ribopyranoside ( 8 ) afforded, after acetylation, ethyl 2,4-di- O -acetyl-3-deoxy-5-thio-α- d -xylopyranoside and methyl 2,3-di- O -acetyl-4-azido-4-deoxy-5-thio-β- l -lyxopyranoside. Treatment of 7 and 8 with methanolic ammonia gave methyl 3-amino-3-deoxy-5-thio-α- d -xylopyranoside and the 4-amino-3-deixy- l lyxo analogue, respectively, characterised as the tetra-acetates 14 and 19 , respectively. Acetolysis of 14 and 19 followed by O -deacetylation gave 3-acetamino-3-deoxy-5-thio- d -xylose and 4-acetaminado-4-deoxy-5-thio- l -lyxose, respectively.

Synthesis and Biological Activity of Some 5-Substituted-6-azauracil-N-1-Nucleosides of 2-Acetamido-2-Deoxy-D-glucose

Abstract Glycosylation of the silylated 5-bromo- and 5-benzylmercapto-6-azauracil 1 and 2, respectively, with the acylated sugar 3 afforded 1-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-s-D-glucopyranosyl)-5-bromo-6-azauracil 4 and its 5-benzylmercapto analogue 6. Deblocking of 4 and 6 gave the free nucleosides 5 and 7, respectively. Alternatively, 6 was obtained from reaction of benzylmercaptan with 4 in pyridine. Reaction of 4 with morpholine, 2,4-dichlorobenzylamine and N-methylethanolamine gave the 5-alkylamino derivatives 8, 10 and 11, respectively. Deblocking of 8 gave the nucleoside 9. All the newly synthesized compounds were characterized by their 1HNMR, U.V. and mass specta. Compounds 5, 7, 9, 10 and 11 were tested for their activity against HIV type 1 and 2, but they did not show significant biological activity and not toxic at 100 mcg/mL. The antimutagenic activity of 5 and 7 is under investigation.

Synthesis of some novel 1-(5-thio-β-D-xylopyranosyl)-lumazine and -pyrimidine nucleosides

Abstract 1,2,3,4-Tetra-O-acetyl-5-thio-D-xylopyranose (1) reacts with the silylated lumazine bases (2–5) under trimethylsilyl trifluoromethylsulfonate catalysis to give the nucleosides 6, 8, 10, and 12 respectively, which face deblocking with potassium carbonate in dry methanol to yield the free nucleosides 17, 9, 11, and 13 respectively. The synthesis of 1-(2,3,4-tri-O-acetyl-5-thio-β-xylopyranosyl)-thymine (17) and its free nucleoside 18 have been improved and in a similar manner reacted the silylated pyrimidine bases 15 and 16 to the 5-iodo- (19) and 5-fluoro- (21) analogues. Deacylation afforded the free nucleosides 20 and 22, respectively.

Synthesis of some novel acyclolumazine N-1 nucleosides

Abstract Reactjon of (2-acetoxyethoxy)methyl bromide with the silylated lumazine bases (1-6) in the presence of n-Bu4NI leads to the formation of the nucleosides 8, 10, 12, 14, 16 and 18 respectively. Deacetylation with methanolic ammonia afforded the free nucleosides 9, 11, 13, 15, 17 and 19, respectively, in good yields. Structural proofs of the newly synthesized compounds are based on elemental analyses, UV and 1H-NMR spactra. None of the acyclic nucleosides exhibited antiviral activity against HSV-1 in vitro.

New CYP17 Hydroxylase Inhibitors: Synthesis, Biological Evaluation, QSAR, and Molecular Docking Study of New Pregnenolone Analogs

A new series of pregnenonlone analogs were synthesized and evaluated for their inhibitory activity against cytochrome P450 (CYP17 hydroxylase enzyme). In general, the 5‐aryl‐1,3,4‐thiadiazol‐2‐yl)‐imino‐pregnenolone derivatives 11–15 were more active than the sulfonate 24–31 and the ester 37–41 analogs. Derivative 12 showed optimal activity in this series, with IC50 values of 2.5 µM compared with the standard abiraterone (IC50 = 0.07 µM). However, the analogs 11 and 25 showed a better selectivity profile (81.5 and 82.7% inhibition of hydroxylase, respectively), which may be a useful lead in CYP17 inhibition studies. Molecular docking studies demonstrated quite similar binding patterns of all new pregnenolone derivatives at the active site of CYP17 through hydrogen bonding and hydrophobic interaction.

Synthesis of Some Novel 1-(5-Thio-ß-D-glucopyranosyl)-6-azauracil Derivatives - Thiosugar Nucleosides

Abstract The chemical syntheses of 1-(2,3,4,6-tetra-0-acety]-5-thio-β-D-glucopyranosyl)-6-azauracil (4) and the 5-bromo analogue 6 are described. Deblocking of 4 and 6 with sodium methoxide afforded the free nucleosides 5 and 7, respetively. Treatment of 6 with benzylmercaptan in basic medium led to the formation of 6-benzylthio-1-((2,3,4,6-tetra-0-acetyl-5-thio-β-D-glucopyranosyl)-6-azauracil (8), in good yield, which was deblocked to 9 on treatment with sodium methoxide. Reaction of 6 with benzlamine gave 5-benzylamino-1-(5-thio-β-D-glucopyranosyl)-6-azauracil (10).

Synthesis, crystal structure, anti-HIV, and antiproliferative activity of new pyrazolylthiazole derivatives

The development of new HIV-1 non-nucleoside reverse transcriptase inhibitors offers the possibility of generating novel structures of increased potency. Based on the bioisosteric principle, new series of N′-benzylidene-2-(5-(4-chlorophenyl)-3-phenyl-4,5-dihydropyrazol-1-yl)thiazole-4-carbohydrazide schiff bases 5a–x containing 1,3-thiazole clubbed with 2-pyrazoline was synthesized and characterized by spectroscopic techniques. The structure of the synthesized compounds was unambiguously confirmed by single-crystal X-ray diffraction analysis of compound 5k. All the new analogs were evaluated in vitro for antiviral activity against the replication of HIV-1 and HIV-2 in MT4 cells using MTT assay. The results showed that only compounds 5n, and 5r possess potent activity against HIV-1 replication (IC50 = 0.50, 0.45 μM, SI = 3 and 5), respectively. None of the compounds are active against HIV-2. Furthermore, compounds 5a, 5i, 5n, and 5r were evaluated for their antiproliferative activity against two solid tumor-derived cell lines consisting MCF-7 (breast cancer) and Hep-G2 (human hepatocarcinoma).

New biaryl-chalcone derivatives of pregnenolone via Suzuki-Miyaura cross-coupling reaction. Synthesis, CYP17 hydroxylase inhibition activity, QSAR, and molecular docking study.

A new class of steroids is being synthesized for its ability to prevent intratumoral androgen production by inhibiting the activity of CYP17 hydroxylase enzyme. The scheme involved the synthesis of chalcone derivative of pregnenolone 5 which was further modified to the corresponding biaryl-chalcone pregnenolone analogs 16-25 using Suzuki-Miyaura cross-coupling reaction. The synthesized compounds were tested for activity using human CYP17α hydroxylase expressed in Escherichia coli. Compounds 21 was the most active inhibitor in this series, with IC50 values of 0.61μM and selectivity profile of 88.7% inhibition of hydroxylase enzyme. Molecular docking study of 21 was performed and showed the hydrogen bonds and hydrophobic interaction with the amino acid residues of the active site of CYP17.