Raid J. Abdel-Jalil

Synthesis and antitumor activity of 2-aryl-7-fluoro-6-(4-methyl-1-piperazinyl)-4(3H)-quinazolinones

A series of new 2-aryl-7-fluoro-6-(4-methyl-l-piperazinyl)-4(3H)-quinazolinones were prepared by the oxidative cyclization of the corresponding 2-arylidineamino-4-fluoro-5-(4-methyl-1-piperazinyl)benzamides. The new quinazolinones were evaluated for their antitumor activity.

A convenient method for the synthesis of cyclic trithiocarbonates on carbohydrate scaffolds

Abstract An efficient regio- and stereoselective method for the synthesis of cyclic trithiocarbonates on carbohydrate skeleton is described. A freshly prepared solution of sodium trithiocarbonate reacts with cis-oriented epoxytriflate pentoses 7–11 to yield the corresponding cyclic trithiocarbonates 12–16 . Structures of all new compounds are established through MS, 1H and 13C NMR techniques.

An expeditious approach to tri-substituted chiral thiazolines

A regio- and stereoselective route from the cis-oriented epoxytriflate pentoses 1 and 4 via 4-amino-4-deoxy sugars 2 and 5 to chiral thiazoline derivatives 3a–e and 6a–e in high yields is described.

A STEREOSPECIFIC SYNTHESIS OF TETRA-SUBSTITUTED CHIRAL PIPERAZINES

Abstract A one pot reaction of the epoxy triflates 1 or 2 with a variety of N , N ′-disubstituted ethylenediamines yields the corresponding chiral piperazine derivatives 3a-e and 4a-e of potential pharmacological interest in high yields.

A useful regioselective approach to episulfides via cis-oriented anhydro triflate sugars

An efficient method for the regioselective synthesis of episulfides, showing remarkable proteinase-inhibiting activity, from cis-oriented anhydro triflate sugars is decribed.

High throughput synthesis of pyrazolopyrimidines via copper- catalysed cyclization and x-ray study

A rapid and easy high-yielding synthesis of pyrazolopyrimidinones in the presensce of copper chloride is described. To fully confirm the structure of a Viagra® intermediate, the X-Ray structure of 5-(2-ethoxyphenyl)-1-methyl-3-propyl-1,6-dihydropyrazolo[4,3-d]pyrimidin-7-one (2a) was determined.

Synthesis and inhibition properties of a series of pyranose derivatives towards a Zn-metalloproteinase from Saccharomonospora canescens.

The Zn-proteinase, isolated from Saccharomonospora canescens (NPS), shares many common features with thermolysin, but considerable differences are also evident, as far as the substrate recognition site is concerned. In substrates of general structure AcylAlaAlaPhe 4NA, this neutral proteinase cleaves only the arylamide bond (non-typical activity of Zn-proteinases), while thermolysin attacks the peptide bond Ala-Phe. Phosphoramidon is a powerful tight binding inhibitor for thermolysin and significantly less specific towards NPS. The K(i)-values (65 μM for NPS vs 0.034 μM for thermolysin) differ nearly 2000-folds. This implies significant differences in the specificity of the corresponding subsites. The carbohydrate moiety is supposed to accommodate in the S₁-subsite and the series of arabinopyranosides and glucopyranosides (12 compounds), which are assayed as inhibitors in a model system: NPS with SucAlaAlaPhe4NA as a substrate could be considered as mapping the S₁-subsite of NPS. Members of the series with an additional ring (3,4-epithio, 3,4-anhydro-derivatives) turned out to be reasonably good competitive inhibitors (K(i)≈0.1-0.2 mM are of the same order as the K(i) value for phosphoramidon). The structure of these compounds (8, 9, 11 and 12) seems to fit the size of the S₁-subsite and due to an appropriately oriented OH-group in addition, to protect the active site Zn(2+).

Syntheses of selected quaternary phenacylbromopyridinium compounds and their biological evaluation

The studies, presented here, deal with the synthetic modification of 5-bromonicotinic acid on its nitrogen nucleus. The synthetic transformations were carried out by reacting equimolar amounts of 5-bromonicotinic acid and phenacyl halides in acetone. A range of phenacyl halides were used with the objective of getting a variety of quaternary ammonium salts of 5- bromonicotinic acid derivatives as multipurpose biologically active compounds. Twelve quaternary ammonium salts of 5-bromonicotinic acid have been synthesized and tested for cytotoxicity, antibacterial and antifungal activities. These compounds showed promising cytotoxicity against Artemia salina. Two compounds, 3-carboxy-1-(4′-methylphenacyl)-5-bromopyridinium bromide (2) and 3-carboxy-1-(4′-nitrophenacyl)-5-bromopyridinium bromide (12), were highly active against Gram-positive and Gram-negative bacteria among all the tested compounds. All the compounds were examined for antifungal activity against fifteen fungal cultures, but none of these compounds proved to be effective against these fungi. The parent compounds and its derivatives were also examined for their effect on mean arterial blood pressure in anaesthetized rats. Compounds 7 and 8 were found to be twofold more active than the parent compound. The rest of the products showed blood pressure lowering effects comparable to the parent compound. All compounds were characterised via elemental analysis UV, IR , mass and 1H NMR spectroscopy.

The small GTPases Ras and Rheb studied by multidimensional NMR spectroscopy: Structure and function

Ras GTPases are key players in cellular signalling because they act as binary switches. These states manifest through toggling between an active (GTP-loaded) and an inactive (GDP-loaded) form. The hydrolysis and replenishing of GTP is controlled by two additional protein classes: GAP (GTPase-activating)- and GEF (Guanine nucleotide exchange factors)-proteins. The complex interplay of the proteins is known as the GTPase-cycle. Several point mutations of the Ras protein deregulate this cycle. Mutations in Ras are associated with up to one-third of human cancers. The three isoforms of Ras (H, N, K) exhibit high sequence similarity and mainly differ in a region called HVR (hypervariable region). The HVR governs the differential action and cellular distribution of the three isoforms. Rheb is a Ras-like GTPase that is conserved from yeast to mammals. Rheb is mainly involved in activation of cell growth through stimulation of mTORC1 activity. In this review, we summarise multidimensional NMR studies on Rheb and Ras carried out to characterise their structure-function relationship and explain how the activity of these small GTPases can be modulated by low molecular weight compounds. These might help to design GTPase-selective antagonists for treatment of cancer and brain disease.Abstract Ras GTPases are key players in cellular signalling because they act as binary switches. These states manifest through toggling between an active (GTP-loaded) and an inactive (GDP-loaded) form. The hydrolysis and replenishing of GTP is controlled by two additional protein classes: GAP (GTPase-activating)- and GEF (Guanine nucleotide exchange factors)-proteins. The complex interplay of the proteins is known as the GTPase-cycle. Several point mutations of the Ras protein deregulate this cycle. Mutations in Ras are associated with up to one-third of human cancers. The three isoforms of Ras (H, N, K) exhibit high sequence similarity and mainly differ in a region called HVR (hypervariable region). The HVR governs the differential action and cellular distribution of the three isoforms. Rheb is a Ras-like GTPase that is conserved from yeast to mammals. Rheb is mainly involved in activation of cell growth through stimulation of mTORC1 activity. In this review, we summarise multidimensional NMR studies on Rheb and Ras carried out to characterise their structure-function relationship and explain how the activity of these small GTPases can be modulated by low molecular weight compounds. These might help to design GTPase-selective antagonists for treatment of cancer and brain disease.

Regioselective Conversion of Anhydro Sugars into Halohydrins and X-Ray Study

A rapid, easy, regio- and stereoselective synthesis of 3-halo-3-deoxy sugars using titanium tetrahalides is described. To fully confirm the stereochemistry of the synthetic products, the X-ray structure of benzyl 3-chloro-3-deoxy-β -L-xylopyranoside was determined