Search

Background: Spirooxindoles are privileged scaffolds in medicinal chemistry, which were identified through Wang’s pioneering work as inhibitors of MDM2-p53 interactions. Objective: To design and synthesize 2,6-diarylidenecyclohexanones and dispiro[oxindole-cyclohexanone]- pyrrolidines having potential antitumor effect. Method: Dispiro[oxindole-cyclohexanone]-pyrrolidines 6a-h were synthesized in a regioselective manner via 1,3-dipolar cycloaddition reaction of 2,6-diarylidenecyclohexanones 3a-h, isatin, and sarcocine. Compounds 6a-h were alkylated to give (7-10)a,b. All compounds were evaluated in vitro for their antitumor activity and cytotoxic selectivity against breast cancer cell lines (MCF-7 and MDA-MB-231), breast fibrosis cell line (MCF10a), and placental cancer cell line (JEG-3). Molecular modeling inside the MDM2 binding site was performed using AutoDock4.2. Results: Synthesized compounds showed antitumor activity comparable to tamoxifen and compounds 3a,b,f,g and 9a,b showed selective cytotoxicity against tumor cells but reduced toxicity toward MCF-10a cells. Molecular modelling shows that both classes of synthesized compounds are predicted to fit the deep hydrophobic cleft on the surface of MDM2 and mimic the interactions between p53 and MDM2. Conclusion: The synthesized compounds have antitumor activity against MCF-7, MDA-MB-231, and JEG-3. Few compounds showed a selective cytotoxic effect and may have the potential to inhibit MDM2 and stimulate p53. In the future, studies regarding the optimization of medicinal chemistry as well as mechanistic studies will be conducted to enhance the inhibition effect of identified compounds and elucidate their mechanism of action.

We have developed a novel method for the synthesis of benzotriazolyl alkyl esters (BAEs) from N-acylbenzotriazoles and dichloromethane (DCM) under mild conditions. This reaction is one of few examples to show the use of DCM as a C-1 surrogate in carbon–heteroatom bond formation and to highlight the versatility of using DCM as a methylene building block.

Thioacids and thioamino acids were synthesized in excellent yields from readily available acyl benzotriazoles and sodium hydrosulfide in water at room temperature. The new methodology features mild reaction conditions, high yields, short reaction times, and does not involve the use of organic solvents or bases. The reaction is eco-friendly, and the workup procedure is simple and does not require chromatographic separation.

BACKGROUND Hepatitis C virus (HCV) infection poses a considerable threat to the public health. The current standard of care treatment with pegylated interferon-alpha in combination with ribavirin (PEG-IFN- α+RBV) is associated with significant side effects, poorly tolerated, and provides limited efficacy. The development of direct-acting antiviral agents (DAAs) targeting key viral enzymes essential for viral replication represents a significant milestone in the treatment of chronic HCV infection. Given its critical role in the viral polyprotein processing and the evasion of the host innate immunity, the NS3/4A protease has emerged as a promising drug target for the development of anti-HCV therapies. Although several potent NS3/4A protease inhibitors (PIs) have been approved or are in clinical development, the majority of currently available PIs have significant limitations related to untoward adverse events and a lack of pan-genotypic activity, indicating a continuing unmet medical need for the development and optimization of novel PIs with improved efficacy and tolerability, convenient dosing schedules, and shorter treatment durations. METHODS The inhibitory efficacy of four computer-designed chemically-synthesized compounds was evaluated against in vitro-expressed NS3/4A protease from HCV genotype 4a, the most prevalent genotype in Egypt, using a fluorescence-based enzymatic assay. RESULTS We successfully identified two non-macrocyclic small molecules, BE113 (7a) and BE114 (7b), which exhibited inhibitory activity against HCV NS3/4A protease from HCV genotype 4a. CONCLUSION The two compounds presented in this study may be promising inhibitors against NS3/4A protease of HCV genotype 4a and could be novel lead compounds for developing new therapeutics for the treatment of chronic HCV infection.

Three novel inhibitors based on 4,5,6,7-tetrahydrobenzo[b]thiophene scaffold were synthesized and characterized. The inhibitive action of the synthesized inhibitors toward carbon steel acid corrosion was investigated using weight loss and polarization techniques. It was found that the three compounds act as good corrosion inhibitor for carbon steel in the acidic medium. The inhibition efficiency was found to increase with increasing concentration and decreased with increasing temperature. The adsorption of inhibitors molecules on the carbon steel surface follows Langmuir adsorption isotherm. The correlation between the inhibitors structures and their corrosion inhibition action was studied by quantum chemical calculations.

An alternative method for the synthesis of new GFP chromophore analogous that possess good photo physical properties which can be used as efficient biomarkers. These compounds have low fluorescence most probably due to their Z–E photo isomerization. These chromophores have suitable site for complexation with transitional metals. Forming complexes with metal ions can inhibit their photo isomerization and enhance the fluorescent properties.

Global health concern regarding malaria has increased since the first report of artemisinin-resistant Plasmodium falciparum (Pf) two decades ago. The current therapies suffer various drawbacks such as low efficacy and significant side effects, alarming for an urgent need of more effective and less toxic drugs with higher patient compliance. Chemical entities with natural origins become progressively attractive as new drug leads due to their structural diversity and bio-compatibility. This study initially aimed at the targeted isolation of hydroxyquinoline derivatives following our published genomics and metabolomics study of Pantoea agglomerans (Pa). Fermentation of Pa on a pre-selected medium followed by chromatographic isolation, NMR and HRMS analyses led to the characterisation of one new hydroxyquinoline alkaloid together with another six known congeners and two known hydroxyquinolone derivatives. When screened for their antimalarial activity by high throughput screening against asexual blood-stage parasites, almost all compounds showed potent and selective sub-micromolar activities. Computational investigation was performed to identify the antiplasmodial potential targets. Ligand-based similarity search predicted the tested compounds to act as hemozoin inhibitors. Computational target identification results were further validated by competitive hemozoin inhibitory properties of hydroxyquinoline and hydroxyquinolone derivatives in vitro. The overall results suggest this natural scaffold is of potential to be developed as antimalarial drug lead.

Estrogen-related receptors (ERRs) are members of the nuclear hormone receptor (NR) superfamily. The ERR subfamily comprise three members, ERRα, ERRβ, and ERRγ. They are closely related to the estrogen receptors (ERα and ERβ), but unlike ER receptors, ERRs have constitutive activity and can function in the absence of ligands. The ERRs are orphan receptors because no natural ligands have been identified for any of the three ERR isoforms. Although ERRs are structurally related to ERs and share sequence similarity with these receptors, they do not bind with estrogens. ERRs are expressed mostly in all tissues that have been examined to date with variation of the level and type of isoform existed in a particular tissue. ERRs play an essential role in many physiological processes, and they are potential therapeutic targets in many disease areas such as Alzheimer’s disease, cancer, diabetes, and other metabolic diseases. In this chapter, we mainly focus on the structure and function of ERRs, and the medicinal chemistry efforts to design modulators of these receptors. We put great emphasis on the structure-based design of ERR modulators, which we believe is an essential tool to advance the drug discovery in this particular research area.

Estrogen Related Receptors (ERRs) are key regulators of energy homeostasis and play important role in the etiology of metabolic disorders, skeletal muscle related disorders, and neurodegenerative diseases. Among the three ERR isoforms, ERRα emerged as a potential drug target for metabolic and neurodegenerative diseases. Although ERRβ/γ selective agonist chemical tools have been identified, there are no chemical tools that effectively target ERRα agonism. We successfully engineered high affinity ERRα agonism into a chemical scaffold that displays selective ERRβ/γ agonist activity (GSK4716), providing novel ERRα/β/γ pan agonists that can be used as tools to probe the physiological roles of these nuclear receptors. We identified the structural requirements to enhance selectivity toward ERRα. Molecular modeling shows that our novel modulators have favorable binding modes in the LBP of ERRα and can induce conformational changes where Phe328 that originally occupies the pocket is dislocated to accommodate the ligands in a rather small cavity. The best agonists up-regulated the expression of target genes PGC-1α and PGC-1β, which are necessary to achieve maximal mitochondrial biogenesis. Moreover, they increased the mRNA levels of PDK4, which play an important role in energy homeostasis.

Non-alcoholic fatty liver disease (NAFLD) affects a significant number of people worldwide and currently there are no pharmacological treatments. NAFLD often presents with obesity, insulin resistance, and in some cases cardiovascular diseases. There is a clear need for treatment options to alleviate this disease since it often progresses to much more the much more severe non-alcoholic steatohepatitis (NASH). The REV-ERB nuclear receptor is a transcriptional repressor that regulates physiological processes involved in the development of NAFLD including lipogenesis and inflammation. We hypothesized that pharmacologically activating REV-ERB would suppress the progression of fatty liver in a mouse model of NASH. Using REV-ERB agonist SR9009 in a mouse NASH model, we demonstrate the beneficial effects of REV-ERB activation that led to an overall improvement of hepatic health by suppressing hepatic fibrosis and inflammatory response.

We have developed a solvent- and catalyst-free cyclization reaction for the synthesis of 1-arylidenamino-2,4-disubstituted-2-imidazoline-5-ones under neat conditions. The new synthetic procedure is efficient and green in nature. All synthesized compounds were obtained in good yields (70–78%) and have been characterized by 1H and 13C NMR spectroscopy. The structure of compound 2d was characterized crystallographically using a single crystal X-Ray diffractometer. Compound 2d was found to crystallize in the triclinic space group P-1 with Z = 2. Moreover, the Frontier Molecular Orbitals (FMOs), the global chemical reactivity descriptors, and the molecular Electrostatic Potential (MEP) of 2d have been calculated at B3LYP/6-31G(d,p) level of theory.

Novel antibiotics are urgently needed. The troponoids [tropones, tropolones, and α-hydroxytropolones (α-HT)] can have anti-bacterial activity. We synthesized or purchased 92 troponoids and evaluated their antibacterial activities against Staphylococcus aureus, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa. Preliminary hits were assessed for minimum inhibitory concentrations (MIC80) and cytotoxicity (CC50) against human hepatoma cells. Sixteen troponoids inhibited S. aureus/E. coli/A. baumannii growth by ≥80% growth at 50 μM. Two selected tropolones (63 and 285) inhibited 18 methicillin-resistant S. aureus (MRSA) strains with similar MIC80 values as against a reference strain. Two selected thiotropolones (284 and 363) inhibited multidrug-resistant (MDR) E. coli with MIC80 ≤30 μM. One α-HT (261) inhibited MDR-A. baumannii with MIC80 ≤30 μM. This study opens new avenues for development of novel troponoid antibiotics to address the critical need to combat MDR bacterial infections.

Cancer is a multifactorial disorder involving multiplicity of interrelated signaling pathways and molecular targets. To that end, a multi-target design strategy was adopted to develop some 1,2,3-triazoles hybridized with some pharmacophoric anticancer fragments, as first-in-class simultaneous inhibitors of COX-2, 15-LOX and tumor associated carbonic anhydrase enzymes. Results revealed that compounds 5a, 5d, 8b and 8c were potent inhibitors of COX-2 and 15-LOX enzymes. COX-2 inhibitory activity was further demonstrated by the inhibition of the accumulation of 6-keto-PGF1α, a metabolite of COX-2 products in two cancer cell lines. The sulfonamide bearing derivatives 5d and 8c were effective nanomolar and submicromolar inhibitors of tumor associated hCA XII isoform, respectively. Strong to moderate inhibitory activities were observed in the in vitro antiproliferative assay on lung (A549), liver (HepG2) and breast (MCF7) cancer cell lines (IC50 2.37–28.5 μM) with high safety margins on WI-38 cells. A cytotoxic advantage of CA inhibition was observed as an increased activity against tumor cell lines expressing CA IX/XII. Further mechanistic clues for the anticancer activities of compound 5a and its sulfonamide analog 5d were derived from induction of cell cycle arrest at G2/M phase. They also triggered apoptosis via increasing expression levels of caspase-9 and Bax together with suppressing that of Bcl-2. The in vitro anti-tumor activity was reflected as reduced tumor size upon treatment with 8c in an in vivo cancer xenograft model. Docking experiments on the target enzymes supported their in vitro data and served as further molecular evidence. In silico calculations and ligand efficiency indices were promising. In light of these data, such series could offer new structural insights into the understanding and development of multi-target COX-2/15-LOX/hCA inhibitors for anticancer outcomes.

Nuclear hormone receptors represent a large family of ligand-activated transcription factors that include steroid receptors, thyroid/retinoid receptors, and orphan receptors. Among nuclear hormone receptors, the liver X receptors have emerged as very important drug targets. These receptors regulate some of the most important metabolic functions, and they were also identified as anti-inflammatory transcription factors and regulators of the immune system. The development of drugs targeting liver X receptors continues to be a challenge, but advances in our knowledge of receptor structure and function move us forward, toward achieving this goal. This review highlights the latest advances in the development of synthetic LXR modulators in the primary literature from 2013 to 2017. In this review, we place great emphasis on the structure and function of LXRs because of their essential role in the drug design process. The structure–activity relationships of the most active and promising synthetic modulators are di...

We have synthesized and separated tosylated thujaplicin isomers for the first time, and elucidated their structures using 1D, 2D-NMR techniques and X-ray crystallography. The tosylated isomers were used to synthesize 4-isopropyl–thiotropolone and 6-isopropyl–thiotropolone in a regioselective manner. 1H and 13C Chemical shifts of synthesized isomers were fully assigned using several NMR experiments, and their isotropic magnetic shielding was calculated using the GIAO (Gauge Including Atomic Orbitals) method and the B3LYP def2-TZVPP level of theory. The calculated chemical shift values were in a good agreement with the experimental results. The biological activity of all synthesized compounds was evaluated against the fungal pathogen Cryptococcus neoformans and four different bacterial strains (Staphylococcus aureus (ATCC 29213), E. coli (ATCC 35218), Acinetobacter baumannii and Pseudomonas aeruginosa (ATCC 27853)). 4-Isopropyl–thiotropolone was found to inhibit Staphylococcus aureus in a low micro molar range and exhibit good therapeutic index and ADME properties. This compound can be used for future lead optimization to design inhibitors against Staphylococcus aureus (ATCC 29213).

An efficient, economic and high yielding method was described for the synthesis of baclofen (BAC) pharmacopoeial impurities (impurity A and impurity B) which can be used for gram-scale synthesis. Furthermore, a novel ecofriendly thin-layer chromatographic TLC-densitometric method was established and validated for the determination of BAC and its synthesized impurities. The developed TLC-densitometric method is based on the chromatographic separation using TLC plates (60 F254 ) using a green mobile phase of ethyl acetate-methanol-ammonia solution, 33% (8:2:0.1, by volume) with UV scanning at 220 nm. The proposed method was validated with respect to International Conference on Harmonization guidelines. The validated method was successfully applied for determination of BAC in pure form and in its commercial dosage form. Additionally, the greenness profile of the developed method was evaluated and compared with those of the reported chromatographic methods. The developed method was found to be superior to the published methods, being environmentally benign.

Lapatinib (LAP), an oral tyrosine kinase inhibitor for the treatment of metastatic breast cancer, has been associated with idiosyncractic hepatotoxicity. Recent investigations have implicated the importance of P450 3A4/5 enzymes in the formation of an electrophilic quinone imine (LAPQI) metabolite generated through further oxidation of O-dealkylated lapatinib (OD-LAP). In the current study, hepatic stress was observed via mitochondrial impairment. OD-LAP caused a time- and concentration-dependent decrease in oxygen consumption in HepG2 cells, whereas LAP did not alter the oxygen consumption rate. Interestingly, however, HepG2 cells transfected with human P450 3A4 did exhibit mitochondrial dysfunction via P450 3A4-mediated metabolism of LAP to OD-LAP. OD-LAP-induced mitochondrial toxicity was enhanced upon depletion of intracellular GSH levels, demonstrating that cellular GSH levels are important in the protection of mitochondrial function against LAPQI. Given the nature of LAPQI and the importance of GSH levels in LAP-induced mitochondrial stress, the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) was evaluated, as this transcription factor induces the expression of NAD(P)H quinone oxidoreductase 1, glutathione S-transferase, UDP-glucuronosyltransferases, and glutathione synthetase, all of which might be expected to decrease the toxicity of LAP. Using a FRET-based target gene assay in HepG2 cells, OD-LAP was indeed found to activate Nrf2. Follow-up assays showed increased mRNA levels of Nrf2 target genes after a 4 h treatment with OD-LAP but not with LAP. LAP activation of Nrf2 was observed only when HepG2 cells were transduced with P450 3A4. The significance of Nrf2 protection was established in vivo in Nrf2-KO mice. Increased transaminase levels were found after a single LAP dose in both Nrf2-KO and control mice, indicating elevated hepatic necrosis, although transaminase levels reverted to baseline levels in the control mice upon repeat dosing. They continued to rise in Nrf2-KO mice, however, indicating the likelihood that Nrf-2 plays a significant role in combatting the hepatotoxicity triggered by LAP.

A novel anil compounds, 1-{(Z)-[(3,5dimethylphenyl)imino]methyl}naphthalen-2-ol (HNMA) and 5- (diethylamino) -2- {(Z)- [(3,5-dimethylphenyl)imino] methyl} phenol (DMSMA), were prepared and characterized on the basis of elemental analyses, X-ray, 1H NMR, 13C NMR, UV–Vis and IR spectral data. Their inhibiting performance for mild steel in 0.5 M H2SO4 solution was evaluated by a series of techniques including potentiodynamic polarization, electrochemical impedance spectroscopy, scanning electronic microscope (SEM), energy-dispersive X-ray spectroscopy (EDX) and theoretical calculations. Findings show that HNMA and DMSMA act as good inhibitors, and their inhibition efficiency increases with increasing their concentration. Polarization data suggested that the Schiff bases molecules used as mixed type inhibitors. Impedance measurements indicating that the corrosion reaction is controlled by charge transfer process. The adsorption of HNMA and DMSMA on the metal surface was found to obey Langmuir adsorption isotherm. Furthermore, theoretical study gives insightful explanations of the inhibition mechanism.

Three novel peptidomimetic cationic surfactants were synthesized in good yields. The chemical configurations of these surfactants were clarified using 1H, 13C NMR and FT-IR spectroscopy. The inhibition capacity and adsorption performance of these compounds on C-steel were studied by electrochemical techniques (Electrochemical impedance spectroscopy (EIS) and Potentiodynamic polarization (PDP) methods). The prepared compounds demonstrated outstanding protection power for the erosion of C-steel in 0.5 M HCl at 323 K. The PDP studies demonstrated that the novel surfactants behaved as mixed-type additives. The protection capacity rises with an increasing surfactant dose, with values ranging from 93.10 to 98.25% at 100 ppm. The adsorption of additives on the electrode interface follows the Langmuir model and contains chemisorption modes. The Monte Carlo (MD) simulations and density functional theory (DFT) calculations support the experimental findings and provide insight into the understanding of the adsorption features and protection performance mechanisms of the examined surfactants.

Herein, we describe the design and synthesis of new benzenesulfonamide derivatives as selective COX-2 inhibitors based on bumetanide scaffold. Benzenesulfonamides bearing both the pyrazole 6b and the triazoles 9a, 9c were good inhibitors of COX-2 with IC50 values of 0.32, 0.28 and 0.17 µM, respectively. These benzenesulfonamides 6b, 9a and 9c exhibited a higher selectivity index than the reference drug celecoxib. Molecular modeling study showed that incorporation of bumetanide led to a unique binding mode that is most likely the reason for the observed significant COX-2 selectivity. The anti-inflammatory activity of synthesized compounds revealed that triazoles 9a and 9c demonstrated higher efficacy than celecoxib upon using in vivo carrageenan-induced rat paw edema model. Most of the prepared compounds possess low ulcerogenic potential when administered orally. Therefore, these compounds have a great potential to be developed as safe therapeutics for inflammation, pain, and other diseases where COX-2 plays important role in their pathophysiology.

Liver X Receptor (LXR) agonists have been reported as a potential treatment for atherosclerosis, Alzheimer’s disease and hepatitis C virus (HCV) infection. We have designed and synthesized a series of potent compounds based on a 1,2,4-triazole scaffold as novel LXR modulators. In cell-based cotransfection assays these compounds generally functioned as LXR agonists and we observed compounds with selectivity towards LXRα (7-fold) and LXRβ (7-fold) in terms of potency. Assessment of the effects of selected compounds on LXR target gene expression in HepG2 cells revealed that compounds 6a-b and 8a-b behaved as inverse agonists on FASN expression even though they were agonists in the LXRα and LXRβ cotransfection assays. Interestingly, these compounds had no effect on the expression of SREBP-1c confirming a unique LXR modulator pharmacology. Molecular docking studies and evaluation of ADME properties in-silico show that active compounds possess favorable binding modes and ADME profiles. Thus, these compounds may be useful for in vivo characterization of LXR modulators with unique profiles and determination of their potential clinical utility.

Nuclear hormone receptors represent a large family of ligand-activated transcription factors that include steroid receptors, thyroid/retinoid receptors, and orphan receptors. Among nuclear hormone receptors, the liver X receptors have emerged as very important drug targets. These receptors regulate some of the most important metabolic functions, and they were also identified as anti-inflammatory transcription factors and regulators of the immune system. The development of drugs targeting liver X receptors continues to be a challenge, but advances in our knowledge of receptor structure and function move us forward, toward achieving this goal. This review highlights the latest advances in the development of synthetic LXR modulators in the primary literature from 2013 to 2017. In this review, we place great emphasis on the structure and function of LXRs because of their essential role in the drug design process. The structure-activity relationships of the most active and promising synthetic modulators are discussed.

SummaryMalignant cells exhibit aerobic glycolysis (the Warburg effect) and become dependent on de novo lipogenesis, which sustains rapid proliferation and resistance to cellular stress. The nuclear receptor liver-X-receptor (LXR) directly regulates expression of key glycolytic and lipogenic genes. To disrupt these oncogenic metabolism pathways, we designed an LXR inverse agonist SR9243 that induces LXR-corepressor interaction. In cancer cells, SR9243 significantly inhibited the Warburg effect and lipogenesis by reducing glycolytic and lipogenic gene expression. SR9243 induced apoptosis in tumors without inducing weight loss, hepatotoxicity, or inflammation. Our results suggest that LXR inverse agonists may be an effective cancer treatment approach.

3-(2,4-Dichlorophenyl)-7-[(2,4-dichlorophenyl)methylidene]-11-methyl-4-phenyl-4,5,11-triazatricyclo[6.2.1.0*2,6*]undec-5-ene (3) was synthesized in a stereoselective manner. Single crystal X-ray study of 3 revealed that the structure belongs to the triclinic system with space group . The structure is further stabilized by an intermolecular CH…π interaction. Molecular mechanics force field (MM+), followed by either semi-empirical AM1 or PM3, was used to calculate the optimized geometrical parameters of 3. The determined theoretical geometry parameters were found to be in good agreement with the parameters obtained by a single-crystal study. Vibrational frequencies and gauge-independent atomic orbital, 1H-NMR and 13C-NMR chemical shifts were computed at B3LYP/6-31G(d) level of theory. Moreover, the molecular electrostatic potential of 3 has been calculated exhibiting that the most electrophilic site of 3 is the N-3 atom; however, the nucleophilic site is distributed on the H atoms of dichlorophenyl groups. The frontier molecular orbitals of 3 have been determined by the same technique.

In this work, two dispiro[3H-indole-3,2′-pyrrolidine-3′,3″-piperidines], C31H29Cl2N3O3 (4a) and C32H31Cl2N3O3 (4b), have been synthesized and characterized by IR, 1H NMR, 13C NMR, 1H 1H COSY, 1H 13C HSQC and single crystal X-ray diffraction. Both compounds were found to be crystallized in the triclinic space group P 1 ¯ with Z = 2. Molecules of the crystalline structure of 4a are linked with intermolecular C H⋯O and N H⋯O hydrogen bonding. Meanwhile, an intermolecular N H⋯O hydrogen bonding was recognized in the crystalline structure of 4b. Molecular mechanics force field (MM+), followed by either semi-empirical AM1 or PM3, has been used to calculate the optimized geometrical parameters for the two compounds. The determined theoretical geometry parameters were found to be in a good agreement with the parameters obtained using X-ray studies. Moreover, the Molecular Electrostatic Potential (MEP) of both compounds have been calculated at B3LYP/6-31G(d,p) level of theory exhibiting that, the most electrophilic site of the synthesized compounds, is the piperidone O3 atom however, the most nucleophilic site is the indolyl N2. Additionally, the Frontier Molecular Orbitals (FMOs) 4a and 4b have been determined by the same technique exhibiting large energy gap between HOMO and LUMO orbitals (3.40, 3.43 eV for 4a and 4b, respectively), inferring good stability, high excitation energies and large chemical hardness of these molecules.

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.

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.

The structure–activity relationship study of a diphenylpropanamide series of ROR-γ selective modulators is reported. Compounds were screened using chimeric receptor Gal4 DNA-binding domain (DBD)-NR ligand binding domain cotransfection assay in a two-step format. Three different regions of the scaffold were modified to assess the effects on repression of ROR-γ transcriptional activity and potency. The lead compound 1 exhibits modest mouse pharmacokinetics and an acceptable in vitro profile which makes it a suitable in vivo probe to interrogate the functions of ROR-γ in animal models of disease.

ANRORC Rearrangements of 1,2,4-Oxadiazoles Bog an Draghici,a Bahaa El-Dien M. El-Gendy,a,b Alan R. Katritzky*a,c a Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA b Department of Chemistry, Faculty of Science, Benha University, Benha, Egypt c Department of Chemistry, King Abdulaziz University, Jeddah 21589, Saudi Arabia Fax +1(352)3929199; E-mail: katritzky@chem.ufl.edu Received 20 October 2011; revised 5 December 2011

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.

1H, 13C, and 15N NMR chemical shifts for pyridazines 4–22 were measured using 1D and 2D NMR spectroscopic methods including 1H1H gDQCOSY, 1H13C gHMQC, 1H13C gHMBC, and 1H15N CIGAR–HMBC experiments. Copyright © 2010 John Wiley & Sons, Ltd.

Reactions of readily available and stable 1-(α-alkoxyalkyl)benzotriazoles type 9a,b and 10a–d with a variety of silyl enol ethers 11 or 1,3-dicarbonyl compounds 13 give the expected ketones 12a–l (60–92%), β-keto esters 14a,b (62–67%), and malonates 14c,d (79–88%) in which a tetrahydrofuran or tetrahydropyran moiety has been introduced at the α position. 1-(Benzotriazol-1-yl)alkyl esters 7 are converted by cyanide anion into cyanohydrin esters 15a–i (55–98%).

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.

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.

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.

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.

1,2,4-Oxadiazoles bearing an aryl group with a nucleophilic substituent at the ortho-position react with BuLi via addition reaction, ring opening, and ring closing to give the title heterocycles in moderate yields.

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.

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.

N-(Acyl)-1H-benzotriazoles 6a−f react with l-cysteine 5 at 20 °C to give exclusively (i) N-acyl-l-cysteines 8a−e in the presence of triethylamine in CH3CN−H2O (3:1), but (ii) S-acyl-l-cysteines 7a−e in CH3CN−H2O (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 1H−15N CIGAR-gHMBC experiments. The structure of compound 8d was also supported by single-crystal X-ray diffraction.

2-Hydrazono-3-phenylquinazolin-4(3H)-ones 11a-i are shown by (15)N NMR to exist in DMSO solution predominantly as the imino tautomers B and not the amino tautomers A. 2-Hydrazino-benzimidazole derivative 12 and 2-hydrazino-4,6-dimethylpyrimidine derivative 13 were found to exist predominantly as the amino tautomers.

N-Protected-(aminoacyl)benzotriazoles 1a-e, g, i, j, 1a'-c' convert heterocyclic amines of the following series: thiazoles (3a and 3a'), benzothiazoles (3b and 3b'), benzimidazoles (3c and 3c'), thiadiazoles (3d), pyrimidones (9a, b, a'), pyrazoles (11a, b), and pyridines (13a-g, 13d') under microwave irradiation, into N-substituted amides in yields of 40-98% (average 76%). N-Protected peptidoylbenzotriazoles 6a, b similarly afforded C-terminal N-protected dipeptidoyl amides 7a, b (52-60%).

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 behavior in mice. REV-ERB agonists induce wakefulness and reduce REM and slow-wave sleep. Interestingly, REV-ERB agonists also reduce anxiety-like behavior. These data are consistent with increased anxiety-like behavior of REV-ERBβ null mice, in which REV-ERB agonists have no effect Also consistent with these effects being mediated by REV-ERB, the effect of the agonist on sleep and anxiety was suppressed by lithium treatment. These results indicate that pharmacological targeting of REVERB may lead to the development of novel therapeutics to treat sleep disorders and anxiety.

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.