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3 results on '"organohalogen derivative"'

1. Kinetics and toxicity of an environmentally relevant mixture of halogenated organic compounds in zebrafish embryo

Author

Lindqvist, Dennis, Wincent, E., Lindqvist, Dennis, and Wincent, E.

Abstract

Persistent and semi-persistent halogenated compounds cause health problems for the animals occupying the upper level of the food web in the Baltic Sea. Atlantic salmon (Salmo salar), being a top piscivore in the Baltic Sea, has been observed to carry a large body burden of halogenated toxins. Here, a mixture of nine halogenated compounds belonging to different groups was created, based on the observed composition of halogenated toxins in salmon serum. The toxicokinetic properties of the compounds were studied in zebrafish (Danio rerio) embryos to achieve the same proportions between the internal doses of the compounds in the zebrafish as in the salmon. Toxicity was evaluated for the compounds dosed individually as well as in a mixture. Perfluorooctanesulfonic acid (PFOS) was the dominant compound in the salmon and was observed to be the driving force for effects on swimbladder inflation caused by the mixture with a 50% effect concentration of 4.8 µM nominal dose, or 1300 µMD based on the area under the internal concentration-time curve (AUC). The driving compound for other severe effects caused by the mixture, including lethality, spinal deformity, and edemas, was the hydroxylated polybrominated diphenyl ether 6-OH-BDE47, which was observed to have a 50% lethality concentration of 93 nM, corresponding to 94 µMD based on internal dose (AUC). The individual compounds were observed to act additively on most of the documented outcomes when dosed as a mixture.

Published
2022
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2. Structural modification of ellipticine derivatives with alkyl groups of varying length is influential on their effects on human DNA topoisomerase II: a combined experimental and computational study

Author

Yavuz Ergun, Serdar Durdagi, Zeki Topcu, Á. Kulmány, M. Zaka, Kader Sahin, István Zupkó, Sevil Zencir, M. Kuskucu, V. Akyildiz, Hilmi Orhan, and Ege Üniversitesi

Subjects
Iodide, Intercalation (chemistry), cisplatin, IC50, chemistry.chemical_compound, ellipticine derivative, General Pharmacology, Toxicology and Pharmaceutics, antineoplastic agent, chemistry.chemical_classification, Ellipticine derivatives, biology, n2 hexyl n methyl 5 demethyl ellipticinium bromide, n2 ethyl n methyl 5 demethyl ellipticinium bromide, drug cytotoxicity, drug effect, quantitative structure activity relation, unclassified drug, enzyme activity, DNA topoisomerase II, n2 (3 cyanopropyl) n methyl 5 demethyl ellipticinium chloride, antiproliferative activity, Stereochemistry, In silico, tumor cell, Anticancer drugs, Article, alkyl group, drug mechanism, controlled study, human, DNA topoisomerase (ATP hydrolysing), Alkyl, cell viability, n2 cyanomethyl n methyl 5 demethyl ellipticinium iodide, catalysis, Carbazole, binding site, Topoisomerase, human cell, Organic Chemistry, molecular docking, molecular dynamics, drug structure, Enzyme, chemistry, organohalogen derivative, n2 (carboxyaminoethyl) n methyl 5 demethyl ellipticinium bromide, biology.protein, Nucleic acid, drug synthesis, computer model
Abstract

The compounds reducing tumor cell viability and disrupting DNA topoisomerase reactions have been widely used in anticancer drug development. Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) is a potent intercalating agent that interferes with nucleic acid processing through interaction with DNA topoisomerase II. Although ellipticine is a well-characterized compound, it is not a widely-accepted drug due to the adverse effects detected upon administration. We have previously reported two novel ellipticine derivatives, N-methyl-5-demethyl ellipticine (ET-1) and 2-methyl-N-methyl-5-demethyl ellipticinium iodide (ET-2) as potent compounds targeting DNA topoisomerase II. This study covers an extended synthesis, characterization, and activity data for five new salts of N-methyl 5-demetyl ellipticine (Z-1, Z-2, Z-4, Z-5 and Z-6) having several organic halides and their effects on human topoisomerase II enzymes. Moreover, combined in silico studies were conducted for better understanding of modes of action of studied molecules at the binding pocket of target. Our results showed that three of the derivatives (Z-1, Z-2, and Z-6) have considerable effect on the catalytic activity of human topoisomerase II implying the influence of alkyl groups added to the parental structure of ellipticine. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Published
2020

3. Why are organotin hydride reductions of organic halides so frequently retarded? Kinetic studies, analyses, and a few remedies

Author

Keith U. Ingold and Vincent W. Bowry

Subjects
integral equations, cyclohexane, Radical, Inorganic chemistry, Halide, propagation step, reduction, Chemical reaction, Reaction rate, reaction conditions, Delocalized electron, chemistry.chemical_compound, Computational chemistry, tin, Benzophenone, radical chain, organotin compound, organic solvents, radical, hydride reduction, Hydride, side reactions, addition reaction, model kinetic equations, Organic Chemistry, anthracene, organic halides, rate constants, Solvent, chemistry, organohalogen derivative, kinetics, chain transfer rates, repair, chains, chemical analysis, kinetic theory, chemical reaction kinetics, chemical structure, organometallics, benzophenone
Abstract

Kinetic data for reduction of organic halides (RX) by tri-n-butylstannane (SnH) reveal a serious flaw in the current view of the kinetic radical chain: the tacit but unproven assumption that the speed of reaction is determined by the slowest propagation step. Our results show this is rarely true for reductive chains and that the observed rate is in fact controlled by unseen side-reactions of propagating R• and Sn• radicals with the solvent (notably, benzene!) or solvent impurities (e.g., trace benzophenone dryness indicator in THF) or, crucially, with allylic-CH and conjugated unsaturated groups in substrates and products. Most R• and/or Sn• radicals are therefore converted into relatively inert delocalized species A• and/or B• that inhibit the chain. Retardation in the degraded chain is given by a simple sum of terms, each being the ratio of the chain-transfer rate divided by the rate of chain-return. The model kinetic equation is linear and easy to ratify, interpret, and apply: to calculate retarding rate constants, optimize reaction conditions, and identify additives or "remedies" that repair the chain and accelerate reaction. The present work is thus expected to have a helpful impact on the practice and design of SnH radical chain based (and related) syntheses. © 2014 American Chemical Society.

Published
2015

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