Molecular Docking Studies, Synthesis and Biological Evaluation of Substituted Pyrimidine-2,4-diamines as Inhibitors of Plasmodium falciparum Dihydrofolate Reductase.

A series of 5-[(phenethylamino)methyl]pyrimidine-2,4-diamines were assessed in silico as potential inhibitors of Plasmodium falciparum dihydrofolate reductase (PfDHFR), synthesised and tested for inhibitory activity against PfDHFR in vitro. The compounds displayed promising inhibitory activity against both wild-type (K 1.3-243 nM) and quadruple mutant (K 13-208 nM) PfDHFR in the biochemical enzyme assay, but were less potent in the whole-cell P.

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones.

A wide range of -(ethoxycarbonylmethyl)enaminones, prepared by the Eschenmoser sulfide contraction between -(ethoxycarbonylmethyl)pyrrolidine-2-thione and various bromomethyl aryl and heteroaryl ketones, underwent cyclization in the presence of silica gel to give ethyl 6-(hetero)aryl-2,3-dihydro-1-pyrrolizine-5-carboxylates within minutes upon microwave heating in xylene at 150 °C. Instead of functioning as a nucleophile, the enaminone acted as an electrophile at its carbonyl group during the cyclization. Yields of the bicyclic products were generally above 75%.

Copper-imidazo[1,2-a]pyridines differentially modulate pro- and anti-apoptotic protein and gene expression in HL-60 and K562 leukaemic cells to cause apoptotic cell death.

Despite the availability of a myriad targeted treatments, resistance and treatment failures remains common in cancer treatment. Moreover, the high cost of targeted antibodies excludes a large cohort of patients from their benefits. In this context, copper-imidazo[1,2-a]pyridines were evaluated as alternative drug candidates against two common leukaemias, represented by HL-60 and K562 cells.

Synthesis of phenanthridines via a novel photochemically-mediated cyclization and application to the synthesis of triphaeridine.

Readily synthesized biphenyl-2-carbaldehyde -acetyl oximes were exposed to UV radiation affording phenanthridines. The scope and limitations of this novel reaction were explored. For example, exposure of 2',3'-dimethoxy-[1,1'-biphenyl]-2-carbaldehyde -acetyl oxime to UV radiation afforded 4-methoxyphenanthridine in 54% yield.

Biosynthesis, synthetic studies, and biological activities of the jadomycin alkaloids and related analogues.

The jadomycins are an expanding class of compounds produced from Streptomyces venezuelae, by diverting the normal biosynthesis which provides the antibiotic chloramphenicol. In the presence of amino acids, and either by heat shock, supplementation with ethanol, or when phage SV1 is added to the culture, the formation of substituted jadomycins and benzo[b]phenanthridines can be achieved. The first part of this review provides details of intermediates involved in the biosynthesis of the jadomycins and the related benzo[b]phenanthridines.

Analysis of the Combinatory Effects of Novel Aminonaphthoquinone Derivatives and Curcumin on Breast Cancer Progression.

Background/aim: We previously reported the potential of aminonaphthoquinone derivatives as therapeutic agents against breast and other oestrogen-responsive tumours when combined with curcumin. This study aimed at screening of novel aminonaphthoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) combined with curcumin for cytotoxic, anti-angiogenic and anti-metastatic effects on MCF-7 and MDA-MB-231 breast cancer cells.

Materials And Methods: Cytotoxic and anti-angiogenic effects were analysed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and enzyme-linked immunosorbent assay; while anti-metastatic effects were measured using adhesion assay, Boyden chambers and Matrigel.

Demethylative Lactonization Provides a Shortcut to High-Yielding Syntheses of Lamellarins.

Modular gram-scale syntheses of the trimethyl ethers of lamellarins G () and D () were achieved from readily accessible precursors in the highest overall yields reported to date (, six steps, 82%; , seven steps, 86%). A novel demethylative lactonization between an aryl methyl ether and a neighboring carboxylic acid was developed for creating the chromenone unit of the targets to avoid the need for additional protection and deprotection steps. The central pyrrole core was constructed in a late-stage [4 + 1] condensation between ethyl bromoacetate and an enaminone possessing the remaining components of the lamellarin skeleton.

Identification and characterisation of a fluorinase from Actinopolyspora mzabensis.

The incorporation of fluorine has been shown to improve the biophysical and bioactive properties of several organic compounds. However, sustainable strategies of fluorination are needed. Fluorinases have the unique ability to catalyse a C-F bond, hence, have vast potential to be applied as biocatalysts in the preparation of fine chemicals.

A Xylochemically Inspired Synthesis of Lamellarin G Trimethyl Ether via an Enaminone Intermediate.

A concise high yielding synthesis of lamellarin G trimethyl ether has been achieved from precursors and solvents that can in principle be derived from xylochemical (woody biomass) sources. The route is comparatively green in that some reactions are performed without solvent or with relatively benign solvents. In addition, chromatographic purification of products is avoided, and only a single aqueous workup is performed.

Preparation and antiplasmodial activity of 3',4'-dihydro-1'H-spiro(indoline-3,2'-quinolin)-2-ones.

A series of 3',4'-dihydro-1'H-spiro(indoline-3,2'-quinolin)-2-ones were prepared by the inverse-electron-demand aza-Diels-Alder reaction (Povarov reaction) of imines derived from isatin and substituted anilines, and the electron-rich alkenes trans-isoeugenol and 3,4-dihydro-2H-pyran. These compounds were assessed for in vitro antiplasmodial activity against drug-sensitive and drug-resistant forms of the P. falciparum parasite.

Copper-imidazo[1,2-a]pyridines induce intrinsic apoptosis and modulate the expression of mutated p53, haem-oxygenase-1 and apoptotic inhibitory proteins in HT-29 colorectal cancer cells.

Metastatic colorectal cancer responds poorly to treatment and is a leading cause of cancer related deaths. Worldwide, chemotherapy of metastatic colorectal cancer remains plagued by poor efficacy, development of resistance and serious adverse effects. Copper-imidazo[1,2-a]pyridines were previously shown by our group to be selectively active against several cancer cell lines, with three complexes, JD46(27), JD47(29), and JD88(21), showing IC values between 0.

Ceric Ammonium Sulfate (CAS) Mediated Oxidations of Benzophenones Possessing a Phenolic Substituent for the Synthesis of Xanthones and Related Products.

Work previously published by our group described novel methodology for the synthesis of xanthones and related products from phenolic benzophenones in a reaction mediated by ceric ammonium sulfate (CAS). In this paper we further explore this novel reaction by subjecting an additional set of phenolic benzophenones to CAS to afford a range of compounds, including xanthones, 9 H-xanthen-2,9(4a H)-diones, 3 H-spiro[benzofuran-2,1'-cyclohexa[2,5]diene]-3,4'-diones, and biaryl compounds. A comparison of these reactions with the more commonly used oxidant ceric ammonium nitrate (CAN) was also conducted.

A modern and practical laccase-catalysed route suitable for the synthesis of 2-arylbenzimidazoles and 2-arylbenzothiazoles.

Heterocyclic aromatic compounds containing an imine (C[double bond, length as m-dash]N) bond such as benzimidazoles and benzothiazoles are important active pharmaceutical ingredients. The synthesis of 2-aryl-1-benzimidazoles and 2-arylbenzothiazoles in good to excellent yields was achieved by reacting 2-aminoaromatics with various benzaldehyde derivatives catalysed by the commercial laccases Novoprime and Suberase® at room temperature and in the presence of atmospheric oxygen.

Evaluation of the Effects of Aminonaphthoquinone Derivatives in Combination with Curcumin Against ER-positive Breast Cancer and Related Tumours.

Background/aim: Combination therapies are often explored to treat cancer. The use of curcumin as an adjuvant to current chemotherapies has been reported, whilst aminonaphthoquinones have shown potential as anticancer agents in various tumour cell lines. This study aimed at screening synthetic aminonathoquinone derivatives (Rau 008, Rau 010, Rau 015 and Rau 018) alone and in combination with curcumin for anti-breast cancer activity.

Characterization of and seed oils: two melon seed oils from Namibia used in food and cosmetics applications.

The physicochemical characteristics, fatty acid, tocopherol, stigmasterol, β-sitosterol, and H NMR profiles of and melon seed oils were determined and compared among different extraction methods (cold pressing, traditional, and Soxhlet). The oil content was 40.2 ± 3.

New syntheses of (±)-tashiromine and (±)-epitashiromine via enaminone intermediates.

The syntheses of the naturally occurring indolizidine alkaloid (±)-tashiromine and its unnatural epimer (±)-epitashiromine are demonstrated through the use of enaminone chemistry. The impact of various electron-withdrawing substituents at the C-8 position of the indolizidine core on the preparation of the bicyclic system is described.

PEGylation potentiates hepatoma cell targeted liposome-mediated in vitro gene delivery via the asialoglycoprotein receptor.

Hepatocellular carcinoma is a burgeoning health issue in sub-Saharan Africa and East Asia where it is most prevalent. The search for gene medicine treatment modalities for this condition represents a novel departure from current treatment options and is gaining momentum. Here we report on nonPEGylated and on sterically stabilized PEGylated cationic liposomes decorated with D-galacto moieties linked to 24.

A one-pot laccase-catalysed synthesis of coumestan derivatives and their anticancer activity.

Suberase®, a commercial laccase from Novozymes, was used to catalyse the synthesis of coumestans. The yields, in some cases, were similar to or better than that obtained by other enzymatic, chemical or electrochemical syntheses. The compounds were screened against renal TK10, melanoma UACC62 and breast MCF7 cancer cell-lines and the GI, TGI and LC values determined.

Synthesis of copper and zinc 2-(pyridin-2-yl)imidazo[1,2-a]pyridine complexes and their potential anticancer activity.

A small library of novel copper and zinc imidazo[1,2-a]pyridine complexes have been synthesized. Their structures were confirmed by X-ray diffraction crystallography and a selection of these compounds was tested against five cancer cell lines originating from breast cancer (MCF-7 and MDA-MB-231), leukemia (K562 and HL-60) and colorectal cancer (HT-29). The imidazo[1,2-a]pyridines and their zinc complexes showed poor anticancer activity, while the copper complexes were active against the cancer cell lines with IC values comparable to and lower than camptothecin.

Spacer Length: A Determining Factor in the Design of Galactosyl Ligands for Hepatoma Cell-Specific Liposomal Gene Delivery.

Background: Use of nucleic acids to treat acquired or inherited hepatic diseases has considerable potential. Although recombinant viruses are popular vectors, interest in cheaper, often less immunogenic, non-viral modalities, is increasing. Thus hepatotropic, galactosylated lipoplexes directed to the hepatic asialoglycoprotein receptor (ASGP-R) are promising candidates.

Double Sonogashira reactions on dihalogenated aminopyridines for the assembly of an array of 7-azaindoles bearing triazole and quinoxaline substituents at C-5: Inhibitory bioactivity against Giardia duodenalis trophozoites.

The synthesis of 2,3,5-trisubstituted 7-azaindoles as well as 2,5-disubstituted 7-azaindoles from 3,5-dihalogenated 2-aminopyridines is outlined. Using a double Sonogashira coupling reaction on 2-amino-3,5-diiodopyridine followed by the Cacchi reaction the synthesis of 2,3,5-trisubstituted 7-azaindoles was accomplished. In addition, using two sequential Sonogashira coupling reactions on 2-amino-5-bromo-3-iodopyridine and a potassium t-butoxide mediated ring closure reaction resulted in the assembly of 2,5-disubstituted 7-azaindoles.

Stealth lipoplex decorated with triazole-tethered galactosyl moieties: a strong hepatotropic gene vector.

Mono-antennary galacto derivatives of cholesterol are being actively developed to direct lipoplexes to the asialoglycoprotein receptor (ASGP-R) on hepatocytes. Here we report on a novel ASGP-R ligand cholest-5-en-3-yl [1-(β-D-galactopyranosyl)-1H-1,2,3-triazol-4-yl]methylcarbamate (4), assembled by a copper(I)-catalyzed azide-alkyne cycloaddition (click chemistry), and compare it with cholest-5-en-3-yl-β-D-galactopyranoside (2) and cholest-5-en-3-yl [1-(β-D-galactopyranosyl-1'-oxy)phen-4-yl]carbamate (3), in liposome formulations with or without 5 mol% distearoylphosphatidylethanolamine poly(ethylene glycol)2000, intended for DNA delivery to ASGP-R-positive hepatocyte-derived HepG2 cells and the ASGP-R-negative embryo kidney cell line HEK293. Transfection levels attained with lipoplex 4 were 100 and 300% greater than those for lipoplexes 2 and 3 respectively in HepG2 cells, while competition assays reduced transfection levels by up to 98%.