ABSTRACT
The first general protocol for the preparation of symmetric triarylmethanes bearing secondary anilines by ytterbium-catalyzed Friedel-Crafts reaction of hetero(aryl) aldehydes and secondary anilines is reported. Mechanistic studies indicated that the iminium ion intermediate is the electrophilic partner. The reaction is greatly accelerated by high pressure (9 kbar) and showed a broad substrate scope on the hetero(aryl) aldehyde. The new triarylmethanes exhibited activity against HT-29 cancer cell lines, with the best result scoring an IC50 of 1.74 µM.
ABSTRACT
Iminoboronates have been utilized to successfully install azide and alkyne bioorthogonal functions on proteins, which may then be further reacted with their bioorthogonal counterparts. These constructs were also used to add polyethylene glycol (PEG) to insulin, a modification which has been shown to be reversible in the presence of fructose. Finally, iminoboronates were used to assemble a folic acid/paclitaxel small-molecule/drug conjugate in situ with an IC50 â value of 20.7â nM against NCI-H460 cancer cells and negligible cytotoxicity against the CRL-1502 noncancer cells.
Subject(s)
Boronic Acids/chemistry , Lysine/chemistry , Proteins/chemistry , Alkynes/chemistry , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Azides/chemistry , Cell Line , Cell Line, Tumor , Folic Acid/chemistry , Humans , Imines/chemistry , Insulin/chemistry , Models, Molecular , Muramidase/chemistry , Neoplasms/drug therapy , Paclitaxel/chemistry , Paclitaxel/pharmacology , Polyethylene Glycols/chemistryABSTRACT
A diversity-oriented library of s-triazine-based hybrids was screened for activity against the chloroquine-resistant Plasmodium falciparum W2 strain. The most striking result was sub-micromolar activity against cultured erythrocytic-stage parasites of hybrid molecules containing one or two 8-aminoquinoline moieties. These compounds were not clearly toxic to human cells. The most effective blood-schizontocidal s-triazine derivatives were then screened for activity against the liver stage of malaria parasites. The s-triazine hybrid containing two 8-aminoquinoline moieties and one chlorine atom emerged as the most potent against P.â berghei liver-stage infection, active in the low nanomolar region, combined with good metabolic stability in rat liver microsomes. These results indicate that s-triazine-8-aminoquinoline-based hybrids are excellent starting points for lead optimization as dual-stage antimalarials.
Subject(s)
Antimalarials/pharmacology , Erythrocytes/parasitology , Liver/parasitology , Malaria/drug therapy , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Triazines/pharmacology , Animals , Antimalarials/chemistry , CHO Cells , Cell Line, Tumor , Cell Proliferation , Cricetinae , Cricetulus , Dose-Response Relationship, Drug , Humans , Malaria/parasitology , Parasitic Sensitivity Tests , Rats , Structure-Activity Relationship , Triazines/chemistryABSTRACT
Sophorolipids (SLs) are glycolipid biosurfactants, produced as a mixture of several compounds by some nonpathogenic yeast. In the current study, separation of individual SLs from mixtures with further evaluation of their surface properties and biologic activity on MDA-MB-321 breast cancer cell line were investigated. SLs were biosynthesized by Starmerella bombicola in a culture media supplemented with borage oil. A reverse-phase flash chromatography method with an automated system coupled with a prepacked cartridge was used to separate and purify the main SLs. Compositional analysis of SLs was performed by high-performance liquid chromatography with electrospray ionization mass spectrometry and tandem mass spectrometry. The following diacetylated lactonic SLs were isolated and purified: C18:0, C18:1, C18:2, and C18:3. The critical micelle concentration (CMC) and surface tension at CMC (γCMC ) of the purified SLs showed an increase with the number of double bonds. High cytotoxic effect against MDA-MB-231 cells was observed with C18:0 and C18:1 lactonic SLs. The cytotoxic effects of C18:3 lactonic SL on cancerous cells were for the first time studied. This cytotoxic effect was considerably higher than the promoted by acidic SLs; however, it induced a lower effect than the previously mentioned SLs, C18:0 and C18:1. To our knowledge, for the first time, C18:1 lactonic SL, in selected concentrations, proved to be able to inhibit MDA-MB-231 cell migration without compromising cell viability and to increase intracellular reactive oxygen species.
Subject(s)
Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Glycolipids/biosynthesis , Glycolipids/pharmacology , Saccharomycetales/physiology , Cell Line, Tumor , Cell Movement/drug effects , Chromatography, Liquid/methods , Culture Media/chemistry , Female , Humans , Plant Oils/pharmacology , Reactive Oxygen Species/metabolism , Spectrometry, Mass, Electrospray Ionization , Tandem Mass Spectrometry , gamma-Linolenic Acid/pharmacologyABSTRACT
Folic acid targeting by functionalization of the terminal γ-carboxylic acid is one of the most important strategies to selectively deliver chemotherapeutics and dyes to cancer cells which overexpress folate receptors. However, conjugation of folic acid is limited by its unique solubility and by selectivity issues imposing the need for expensive preparative reverse-phase chromatographic purification to isolate γ-folate conjugates. Herein is provided a novel synthetic tool for the synthesis of new folic acid conjugates with excellent γ-purity based on strain-promoted alkyne-azide cycloadditions with a γ-folate-cyclooctyne conjugate 3. To demonstrate the potential of this methodology several new folate conjugates were synthesized with high γ-purity and without using any type of chromatographic purification by reacting conjugate 3 with several fluorescent probes, polymers and siliceous materials bearing azide. In addition, the cycloaddition reaction between conjugate 3 and an azido-derived fluorescent dye was successfully performed in cellular media leading to an increase of fluorescence in the cells which overexpress folate receptors (NCI-H460).
Subject(s)
Click Chemistry/methods , Folic Acid/chemistry , Chromatography, High Pressure Liquid , Chromatography, Reverse-Phase , Ethanolamine/chemistry , HEK293 Cells , Humans , Microscopy, Confocal , Spectrometry, FluorescenceABSTRACT
Herein we present the synthesis of fluorescent 2-acetylbenzeneboronic acids that undergo B-N promoted conjugation with lysozyme and N-(2-aminoethyl) folic acid (EDA-FA), generating conjugates that are selectively recognized and internalized by cancer cells that over-express folic acid receptors.
Subject(s)
Benzene Derivatives/metabolism , Boronic Acids/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Fluorescent Dyes/metabolism , Folate Receptor 1/metabolism , Folic Acid/metabolism , Muramidase/metabolism , Benzene Derivatives/chemistry , Boronic Acids/chemistry , Endocytosis , Fluorescent Dyes/chemistry , Folic Acid/chemistry , Humans , Lung Neoplasms/metabolism , Molecular Structure , Tumor Cells, CulturedABSTRACT
Magnetic ionic liquids (MILs) are new solvents with an interesting broad of applications however their toxicity is still an open issue. In this paper we report the toxicity of [C(8)MIM] and [Choline-C(n)] based magnetic ionic liquids assessed in two human cell lines: normal skin fibroblasts (CRL-1502) and colorectal adenocarcinoma cells (CaCo-2), acquiring this last characteristics of human enterocytes after differentiation. The results showed that [CoCl(4)] and [MnCl(4)] are more prone to generate cytotoxicity.
Subject(s)
Environmental Pollutants/toxicity , Ionic Liquids/toxicity , Magnetics , Caco-2 Cells , Cell Line , Cell Survival/drug effects , Chlorides/chemistry , Chlorides/toxicity , Cobalt/chemistry , Cobalt/toxicity , Environmental Pollutants/chemistry , Humans , Ionic Liquids/chemical synthesis , Ionic Liquids/chemistry , Manganese Compounds/chemistry , Models, Chemical , Solvents/chemistrySubject(s)
Diterpenes/chemistry , Abietanes/chemistry , Abietanes/isolation & purification , Abietanes/pharmacokinetics , Biotransformation , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacokinetics , Diterpenes/isolation & purification , Diterpenes/pharmacokinetics , Furans/chemistry , Furans/pharmacokinetics , Naphthalenes/chemistry , Naphthalenes/pharmacokinetics , Polycyclic Sesquiterpenes , Terpenes/chemistry , Terpenes/pharmacokinetics , Tetrahydronaphthalenes/chemistry , Tetrahydronaphthalenes/pharmacokineticsABSTRACT
A novel dirhodium complex (Rh(2)(L-PheAla)(2)(OAc)(2) is reported with strong activity towards human colon adenocarcinoma cells. Its effect was not accompanied by generation of reactive oxygen species (ROS) neither by activation of caspase-3.
Subject(s)
Adenocarcinoma/pathology , Colorectal Neoplasms/pathology , Rhodium/pharmacology , Adenocarcinoma/enzymology , Adenocarcinoma/metabolism , Caspase 3/metabolism , Colorectal Neoplasms/enzymology , Colorectal Neoplasms/metabolism , Enzyme Activation , Humans , Reactive Oxygen Species/metabolismABSTRACT
The isolation, identification and total synthesis of two plant-derived inhibitors of the NF-κB signaling pathway from the iso-seco-tanapartholide family of natural products is described. A key step in the efficient reaction sequence is a late-stage oxidative cleavage reaction that was carried out in the absence of protecting groups to give the natural products directly. A detailed comparison of the synthetic material with samples of the natural products proved informative. Biological studies on synthetic material confirmed that these compounds act late in the NF-κB signaling pathway. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009).
