ABSTRACT
Fluocinolone acetonide topical is used to treat skin discomforts such as swelling, itching and redness by activating the natural substances in the skin. Several process-related impurities and degradation products are identified and reported. But hydroperoxide impurities in Fluocinolone acetonide topical solution are not reported anywhere. In this study, we identify two potential genotoxic isomeric hydroperoxide impurities in Fluocinolone acetonide topical solution by Liquid Chromatography Mass Spectrometry analysis. A possible mechanism for the formation of these two novel hydroperoxide impurities is based on the neighboring group participation effect of adjacent hydroxyl group (Internal SN2) which results in the loss of fluorine atom and formation of epoxide intermediate followed by the addition of the HOOH group. Since most of the hydroperoxide impurities are genotoxic in nature, one should eliminate these impurities from Active Pharmaceutical Ingredient (API) or protect the formulation product from these oxidative impurities.
ABSTRACT
A series of new diaryl ether linked pyrrolobenzodiazepine (PBD) conjugates (4a-i, 5a-i and 6a-f) was synthesized and evaluated for their anticancer activity against a panel of 11 human cancer cell lines. These conjugates exhibited significant anticancer activity with GI50 values in the range of 0.1-3.88 µM. Some of the potent conjugates (4b, 4h, 5h, 6b, 6c and 6e) were further investigated on cell cycle distribution. FACS analysis showed the accumulation of cells in G0 phase indicating the apoptosis inducing nature of these conjugates. Moreover, compound 6b caused a decrease in the mitochondrial membrane potential, which indicates the apoptotic nature of the compound through mitochondrial mediated pathway. Further conjugates 4b, 4h and 6b induce the activation of caspase and PARP proteins, followed by apoptotic cell death in MCF7 cell line.
Subject(s)
Antineoplastic Agents/pharmacology , Benzodiazepines/pharmacology , Epithelial Cells/drug effects , Gene Expression Regulation, Neoplastic , Mitochondria/drug effects , Pyrroles/pharmacology , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Benzodiazepines/chemical synthesis , Caspase 3/genetics , Caspase 3/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Epithelial Cells/metabolism , Epithelial Cells/pathology , Ethers , Female , Humans , Inhibitory Concentration 50 , Mammary Glands, Human/drug effects , Mammary Glands, Human/metabolism , Mammary Glands, Human/pathology , Membrane Potential, Mitochondrial/drug effects , Mitochondria/metabolism , Molecular Structure , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/metabolism , Pyrroles/chemical synthesis , Resting Phase, Cell Cycle/drug effects , Signal Transduction , Structure-Activity RelationshipABSTRACT
A series of combretastatin-amidobenzothiazole conjugates have been synthesized and evaluated for their anticancer activity. All these compounds exhibited significant anticancer activity and the most potent compound (11a) showed GI(50) values ranging 0.019-11 µM. Biological studies such as cell cycle distribution, effect on tubulin polymerization and effect on ERK signalling pathway have been examined in MCF-7 cell line. FACS analysis revealed that these compounds induced cell cycle arrest at G2/M phase. Compound 11a showed significant effect on tubulin polymerization and affected the ERK signalling pathway that result in the decreased levels of ERK1/2, p-ERK and c-Jun proteins. Docking experiments have shown that the active molecules interact and bind well in the ATP binding pocket of ERK protein.
Subject(s)
Antimitotic Agents/pharmacology , Benzothiazoles/pharmacology , Bibenzyls/pharmacology , Antimitotic Agents/chemical synthesis , Antimitotic Agents/chemistry , Benzothiazoles/chemistry , Bibenzyls/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Models, Molecular , Molecular Dynamics Simulation , Molecular Structure , Polymerization , Structure-Activity Relationship , Tubulin/metabolism , Tumor Cells, CulturedABSTRACT
In this letter, we describe the first synthesis of two recently isolated flavones 5-carbomethoxymethyl-7-hydroxy-2-pentylchromone (3a), 5-carboethoxymethyl-4',7-dihydroxyflavone (3b) and their derivatives (3c-t), evaluated for their antimicrobial, antioxidant and anticancer activities. Most of the synthesized compounds exhibited antimicrobial activity against the tested microbial strains and some of these compounds were found to be more potent as compared to the standard drugs like neomycin and luteolin. Interestingly, some of these synthesized compounds also showed moderate antioxidant property.
