Bahaa El-Dien M. El-Gendy

Tautomerism in drug discovery

The influence of tautomerism on the precise structure of drugs and thus of their potential to interact with biological systems is discussed from thermodynamic and kinetic aspects. The types of tautomerism encountered in the structure of drugs in current use are surveyed together with the effect of pH, solvent polarity, and temperature.

A Liver-Selective LXR Inverse Agonist That Suppresses Hepatic Steatosis

Fatty liver, which often accompanies obesity and type 2 diabetes, frequently leads to a much more debilitating hepatic disease including non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Current pharmacological therapies lack conclusive efficacy and thus treatment options are limited. Novel therapeutics that suppress either hepatic lipogenesis and/or hepatic inflammation may be useful. Here, we describe the development of the first selective synthetic LXR inverse agonist (SR9238) and demonstrate that this compound effectively suppresses hepatic lipogenesis, inflammation, and hepatic lipid accumulation in a mouse model of non-alcoholic hepatosteatosis. SR9238 displays high potency for both LXRα and LXRβ (40-200 nM IC50) and was designed to display liver specificity so as to avoid potential side effects due to suppression of LXR in the periphery. Unexpectedly, treatment of diet-induced obese mice with SR9238 suppressed plasma cholesterol levels. These data indicate that liver-selective LXR inverse agonists may hold utility in the treatment of liver disease.

Pharmacological targeting of the mammalian clock regulates sleep architecture and emotional behaviour

Synthetic drug-like molecules that directly modulate the activity of key clock proteins offer the potential to directly modulate the endogenous circadian rhythm and treat diseases associated with clock dysfunction. Here we demonstrate that synthetic ligands targeting a key component of the mammalian clock, the nuclear receptors REV-ERBα and β, regulate sleep architecture and emotional behaviour in mice. REV-ERB agonists induce wakefulness and reduce REM and slow-wave sleep. Interestingly, REV-ERB agonists also reduce anxiety-like behaviour. These data are consistent with increased anxiety-like behaviour of REV-ERBβ-null mice, in which REV-ERB agonists have no effect. These results indicate that pharmacological targeting of REV-ERB may lead to the development of novel therapeutics to treat sleep disorders and anxiety.

Pyrrolizines: Promising scaffolds for anticancer drugs.

Pyrrolizine derivatives constitute a class of heterocyclic compounds which can serve as promising scaffolds for anticancer drugs. The unique antitumor properties of mitomycin C inspired chemists to develop different pyrrolizine systems and assess their potential antitumor activities against a wide variety of cancer types. Here we review the different classes of pyrrolizines that possess anticancer potency, with an emphasis on their structure activity relationships, in an effort to pave the way for further development in this promising area of research.

NMR study of the tautomeric behavior of N-(α-aminoalkyl)tetrazoles.

N-(α-Aminoalkyl)tetrazoles exist in solution as equilibrium mixtures of N1 and N2 tautomers. The position of equilibrium depends significantly on the polarity of the solvent and the substituents in the tetrazole ring. Interconversion between individual tautomers is shown to proceed via tight ion-pair intermediates in which intramolecular recombination is faster than the intermolecular crossover since the latter probably requires solvent separation of ion-pair intermediates.

Selective synthesis and structural elucidation of S-acyl- and N-acylcysteines.

N-(Acyl)-1H-benzotriazoles 6a-f react with l-cysteine 5 at 20 degrees C to give exclusively (i) N-acyl-l-cysteines 8a-e in the presence of triethylamine in CH(3)CN-H(2)O (3:1), but (ii) S-acyl-l-cysteines 7a-e in CH(3)CN-H(2)O (5:1) in the absence of base. Structures 7b, 7d and 8b, 8d are supported by 2D NMR spectroscopic methods including gDQCOSY, gHMQC, gHMBC, and (1)H-(15)N CIGAR-gHMBC experiments. The structure of compound 8d was also supported by single-crystal X-ray diffraction.

α-Substitution effects on the ease of S→N-acyl transfer in aminothioesters.

In S‐acylcysteines and homocysteines, the efficacy and rate of S→N‐acyl transfer (5 and 6 cyclic TSs) vary with the size of S‐acyl group. Conformational and quantum chemical calculations indicate that the spatial distance, b(N‐C), between the terminal amine and the thioester carbon is shortened by α‐C(O)X (X = OH, OMe, NH2) substituents.

Antibacterial activity of diketopiperazines isolated from a marine fungus using t-butoxycarbonyl group as a simple tool for purification.

Nine diketopiperazines were characterized from the culture of marine fungal isolate MR2012 which based on DNA amplification and sequencing of the fungal internal transcribed spacer (ITS) region was identified as Aspergillus fumigatus. The isolated fungal metabolites 4-12 were unambiguously identified as a series of simple and re-arranged diketopiperazines by analysis of spectroscopic data. t-Butoxycarbonyl group (BOC) derivatization was used to separate the intractable mixture of 4 and 5. When all compounds were evaluated for antimicrobial activity against gram positive bacteria, the isolated metabolites showed moderate to weak effects, while the semisynthetic derivatives 4a and 5a displayed strong activity comparable to the positive control, tetracycline against gram positive bacteria.

Synthesis of chiral α-amino acid-derived 1H-1,2,4-triazoles and 1,2,4-triazines

Enantiopure N-(Cbz, Fmoc, Boc, or Ac)-1H-1,2,4-triazole- (8a–p, and 8f′) and previously unknown N-Cbz-1,2,4-triazine-derived α-amino acids (11a–d, 11d′, 13a,b, and 13a′) were synthesized using microwave irradiation. Reaction conditions led unexpectedly to simultaneous cyclization, deprotection and acetylation of N-Boc-aminoacylamidrazones 7m,n to afford N-acetyl-1H-1,2,4-triazoles 8o,p.

Efficient microwave-assisted synthesis of aminoxy acid conjugates

A representative set of Cbz-protected (α-aminoxyacyl)benzotriazoles was utilized as versatile building blocks for the efficient and convenient synthesis of novel α-aminoxy acid conjugates. Convenient protocols were developed for their regioselective preparation with sterically hindered nucleophiles such as sugars, terpenes, steroids and nucleosides.