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1.
Regul Toxicol Pharmacol ; 102: 53-64, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30562600

RESUMO

The International Council for Harmonization (ICH) M7 guideline describes a hazard assessment process for impurities that have the potential to be present in a drug substance or drug product. In the absence of adequate experimental bacterial mutagenicity data, (Q)SAR analysis may be used as a test to predict impurities' DNA reactive (mutagenic) potential. However, in certain situations, (Q)SAR software is unable to generate a positive or negative prediction either because of conflicting information or because the impurity is outside the applicability domain of the model. Such results present challenges in generating an overall mutagenicity prediction and highlight the importance of performing a thorough expert review. The following paper reviews pharmaceutical and regulatory experiences handling such situations. The paper also presents an analysis of proprietary data to help understand the likelihood of misclassifying a mutagenic impurity as non-mutagenic based on different combinations of (Q)SAR results. This information may be taken into consideration when supporting the (Q)SAR results with an expert review, especially when out-of-domain results are generated during a (Q)SAR evaluation.


Assuntos
Contaminação de Medicamentos , Guias como Assunto , Mutagênicos/classificação , Relação Quantitativa Estrutura-Atividade , Indústria Farmacêutica , Órgãos Governamentais , Mutagênicos/toxicidade , Medição de Risco
2.
Regul Toxicol Pharmacol ; 76: 79-86, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26785392

RESUMO

At the confluence of predictive and regulatory toxicologies, negative predictions may be the thin green line that prevents populations from being exposed to harm. Here, two novel approaches to making confident and robust negative in silico predictions for mutagenicity (as defined by the Ames test) have been evaluated. Analyses of 12 data sets containing >13,000 compounds, showed that negative predictivity is high (∼90%) for the best approach and features that either reduce the accuracy or certainty of negative predictions are identified as misclassified or unclassified respectively. However, negative predictivity remains high (and in excess of the prevalence of non-mutagens) even in the presence of these features, indicating that they are not flags for mutagenicity.


Assuntos
Simulação por Computador , DNA Bacteriano/efeitos dos fármacos , Modelos Moleculares , Mutagênese , Testes de Mutagenicidade/métodos , Mutação , Relação Quantitativa Estrutura-Atividade , Animais , DNA Bacteriano/genética , Reações Falso-Negativas , Humanos , Bases de Conhecimento , Reconhecimento Automatizado de Padrão , Medição de Risco
3.
Regul Toxicol Pharmacol ; 76: 7-20, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26708083

RESUMO

The relative wealth of bacterial mutagenicity data available in the public literature means that in silico quantitative/qualitative structure activity relationship (QSAR) systems can readily be built for this endpoint. A good means of evaluating the performance of such systems is to use private unpublished data sets, which generally represent a more distinct chemical space than publicly available test sets and, as a result, provide a greater challenge to the model. However, raw performance metrics should not be the only factor considered when judging this type of software since expert interpretation of the results obtained may allow for further improvements in predictivity. Enough information should be provided by a QSAR to allow the user to make general, scientifically-based arguments in order to assess and overrule predictions when necessary. With all this in mind, we sought to validate the performance of the statistics-based in vitro bacterial mutagenicity prediction system Sarah Nexus (version 1.1) against private test data sets supplied by nine different pharmaceutical companies. The results of these evaluations were then analysed in order to identify findings presented by the model which would be useful for the user to take into consideration when interpreting the results and making their final decision about the mutagenic potential of a given compound.


Assuntos
Modelos Estatísticos , Mutagênese , Testes de Mutagenicidade/estatística & dados numéricos , Mutação , Relação Quantitativa Estrutura-Atividade , Algoritmos , Animais , DNA Bacteriano/efeitos dos fármacos , DNA Bacteriano/genética , Bases de Dados Factuais , Técnicas de Apoio para a Decisão , Humanos , Reprodutibilidade dos Testes , Medição de Risco , Software
4.
Mol Pharm ; 10(8): 2962-74, 2013 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-23822517

RESUMO

In this paper we describe Zeneth, a new expert computational system for the prediction of forced degradation pathways of organic compounds. Intermolecular reactions such as dimerization, reactions between the query compound and its degradants, as well as interactions with excipients can be predicted. The program employs a knowledge base of patterns and reasoning rules to suggest the most likely transformations under various environmental conditions relevant to the pharmaceutical industry. Building the knowledge base is facilitated by data sharing between the users.


Assuntos
Sistemas Especialistas , Compostos Orgânicos/química , Bases de Dados Factuais
5.
J Org Chem ; 74(21): 8196-202, 2009 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-19807081

RESUMO

A facile route for the synthesis and isolation of 1,2,3,12b-tetrahydroimidazo[1,2-f]phenanthridines (TIPs) has been developed. The heterocycle is a reactive intermediate in the three-step cascade synthesis of 2,3-dihydro-1H-imidazo[1,2-f]phenanthridinium cations (DIPs), a biologically active DNA intercalating framework; however, the intermediate has previously only been characterized in situ. Derivatization of the structure at the imidazo-N position controls the reactivity of the intermediate with respect to electronic potential and pK(a) allowing isolation of a selection of TIP structures. Correlations between these parameters and reaction outcome have been made, and other influences such as steric and solvent effects have also been investigated.


Assuntos
Fenantridinas/síntese química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Fenantridinas/isolamento & purificação , Espectrofotometria Infravermelho
6.
Chem Commun (Camb) ; (27): 4067-9, 2009 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-19568635

RESUMO

A C-C bond forming reaction resulting from the alpha-addition of carbon based nucleophiles to N-bromoethyl phenanthridinium leads to the formation of 2,3-dihydro-12H-pyrrolo[1,2-f]phenanthridine-based derivatives which undergo reversible ring-opening/closing under pH control.

7.
Nat Chem ; 1(1): 47-52, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21378800

RESUMO

We report the spontaneous and rapid growth of micrometre-scale tubes from crystals of a metal oxide-based inorganic solid when they are immersed in an aqueous solution containing a low concentration of an organic cation. A membrane immediately forms around the crystal, and this membrane then forms micrometre-scale tubes that grow with vast aspect ratios at controllable rates along the surface on which the crystal is placed. The tubes are composed of an amorphous mixture of polyoxometalate-based anions and organic cations. It is possible for liquid to flow through the tubes, and for the direction of growth and the overall tube diameter to be controlled. We demonstrate that tube growth is driven by osmotic pressure within the membrane sack around the crystal, which ruptures to release the pressure. These robust, self-growing, micrometre-scale tubes offer opportunities in many areas, including the growth of microfluidic devices and the self-assembly of metal oxide-based semipermeable membranes for diverse applications.


Assuntos
Compostos Inorgânicos/química , Compostos de Tungstênio/química , Ânions/química , Cátions/química , Cristalização , Eletrodos , Isotiocianatos/química , Óxidos/química , Água/química
8.
J Am Chem Soc ; 130(39): 13059-65, 2008 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-18763772

RESUMO

A switchable organic system involving four distinct states that can be interconverted by use of both pH and redox chemistry as control parameters has been developed. The key molecules involved in this system are the phenanthridine-based heterocycles 1-isobutyl-1,2,3,12b-tetrahydroimidazo[1,2-f]phenanthridine (TIP) and 5-[2-(isobutylamino)ethyl]phenanthridinium (AEP). These two states are interchangeable via pH control, and in addition they can also be further manipulated by oxidation or reduction to convert them to their "pH-inert" forms: 1-isobutyl-2,3-dihydro-1H-imidazo[1,2-f]phenanthridinium (DIP) and 5-[2-(isobutylamino)ethyl]-5,6-dihydrophenanthridine (AEDP), respectively. UV and (1)H NMR experiments carried out in a biphasic dichloromethane (DCM)/water solution were used for in situ structure determination. The results showed that the pH-modulated cyclization and phase-transfer process between the TIP and AEP states was essentially quantitative and repeatable without any significant loss in activity and that reduction or oxidation could be used to lock out these states against such acid-base-induced changes.

9.
Inorg Chem ; 47(6): 1883-5, 2008 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-18271532

RESUMO

The formation of a pentanuclear palladium(II) complex with a phenanthridinonetriazine-based ligand system, which itself is formed by a metal-mediated rearrangement of a triazinephenanthridinium proligand, is described.


Assuntos
Paládio/química , Fenantridinas/química , Triazinas/química , Cristalografia por Raios X/métodos , Congelamento , Cinética , Ligantes , Espectrometria de Massas/métodos , Modelos Moleculares
10.
Chem Commun (Camb) ; (25): 2581-3, 2007 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-17579744

RESUMO

N-Heterocyclic cations are incorporated into proteins using 5-(2-bromoethyl)phenanthridinium bromide, which selectively reacts with either cysteine or lysine residues, resulting in ethylphenanthridinium (Phen) or highly stable cyclised dihydro-imidazo-phenanthridinium (DIP) adducts respectively; these modifications have been found to manipulate the observed structure of lysozyme and bovine serum albumin by AFM.


Assuntos
Compostos Heterocíclicos/química , Proteínas/química , Animais , Membrana Celular/química , Galinhas , Clara de Ovo/química , Fluoresceína-5-Isotiocianato , Microscopia de Força Atômica , Muramidase/química , Soroalbumina Bovina/química
11.
Org Lett ; 9(12): 2253-6, 2007 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-17500559

RESUMO

A very simple annulation reaction was designed, allowing an imidazole moiety to be fused onto a range of pyridine-based derivatives. The methodology consists of an activation step via the formation of a pyridinium salt to increase the electrophilicity of the pyridine ring, followed by a cascade reaction triggered by a nucleophilic attack of the iminium moiety. Depending on the pyridinium salt, it is possible to obtain functionalized imidazole moieties.


Assuntos
Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Imidazóis/química , Piridinas/síntese química , Estrutura Molecular , Piridinas/química , Estereoisomerismo
12.
Biophys Chem ; 126(1-3): 117-23, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16750289

RESUMO

Isothermal titration (ITC) and differential scanning calorimetry (DSC) have been used to screen the binding thermodynamics of a family of DNA intercalators based on the dihydro-imidazo-phenanthridinium (DIP) framework. All members of this DIP-based ligand family bind to both genomic (calf thymus and/or salmon testes) and a synthetic dodecamer d(CGCGAATTCGCG) duplex DNA with broadly similar affinities regardless of side chain size or functionality. Viscosity measurements confirm that binding satisfies standard criteria for intercalation. Binding is exothermic but with an additional favourable positive entropy contribution in most cases at 25 degrees C, although a significant negative heat capacity effect (DeltaC(p)) means that both DeltaH(0) and DeltaS(0) decrease with increasing temperature. DIP-ligand binding to DNA also shows significant entropy-enthalpy compensation effects that are now almost standard in such situations, probably reflecting the conformational flexibility of macromolecular systems involving a multiplicity of weak non-covalent interactions. This ability to vary side chain functionality without compromising DNA binding suggests that the DIP framework should be a promising basis for more adventurous chemistry at the DNA level.


Assuntos
DNA/química , Imidazóis/química , Substâncias Intercalantes/química , Fenantridinas/química , Termodinâmica , Calorimetria , Varredura Diferencial de Calorimetria , Ligantes , Viscosidade
13.
Chembiochem ; 7(11): 1757-63, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17031882

RESUMO

We have synthesised a library of dihydroimidazophenanthridinium cations (DIPs) with large structural diversity (1-29) using a "one-pot" approach. The DNA binding constants of DIPs range from 2x10(4) to 1.3x10(5) M(-1), and the free energies for binding range from -5.9 to -6.40 kcal mol(-1). Viscosity measurements demonstrated that the binding of the compounds caused DNA lengthening, thus signifying binding by intercalation. The cytotoxicities of the compounds were determined by tetrazolium dye-based microtitration assays and showed a large range of values (0.09-11.7 microM). Preliminary molecular modelling studies of the DNA-DIP interactions suggested that the DIP moieties can interact with DNA by intercalation, and some R groups might facilitate binding by minor-groove binding. The results provide insight into how to design biologically active DNA binding agents that can interact in these ways.


Assuntos
DNA/química , Fenantridinas/química , Fenantridinas/toxicidade , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Estrutura Molecular
15.
Chem Commun (Camb) ; (11): 1194-6, 2006 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-16518488

RESUMO

A new class of heterocyclic aromatic cation with novel physical properties has been constructed by an unprecedented reaction pathway that proceeds via five spontaneous steps to yield a 'synthon' that can be further derivatised by a final nucleophilic substitution step.


Assuntos
Compostos Heterocíclicos , Imidazóis , Fenantridinas , DNA/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Fenantridinas/síntese química , Fenantridinas/química , Relação Estrutura-Atividade
16.
J Med Chem ; 48(14): 4504-6, 2005 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-15999988

RESUMO

A new class of cytotoxic heteroaromatic cations is presented, based on the dihydro-imidazo-phenanthridinium framework (DIP), that have affinity for DNA and cytotoxicity toward cancerous cells. The DIP framework is particularly tunable due to the flexible synthetic methodology. Furthermore, the central moiety has proved to be very stable to hydrolysis and reduction compared to other phenanthridinium-based agents.


Assuntos
Antineoplásicos/síntese química , DNA/metabolismo , Substâncias Intercalantes/síntese química , Fenantridinas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Substâncias Intercalantes/química , Substâncias Intercalantes/farmacologia , Fenantridinas/química , Fenantridinas/farmacologia , Relação Estrutura-Atividade
17.
J Org Chem ; 69(18): 5934-46, 2004 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-15373478

RESUMO

A new class of phenanthridinium derivative has been isolated from the reaction of 2-bromoethyl-phenanthridinium bromide with a range of primary amines in excellent yields. The reaction pathway is unprecedented and proceeds via three cascade steps: nucleophilic attack of a primary amine on the iminium moiety of a heteroaromatic ring system and cyclization to form a five-membered ring, followed by hydride loss to yield a rearomatized dihydro-1H-imidazo[1,2-f]phenanthridinium derivative. A range of NMR phase transfer experiments were carried out to elucidate the mechanistic pathway, and the methodology has been further developed by means of a biphasic system using N-bromosuccinimide as a co-oxidizing agent. The method has also been extended to other N-heterocyclic cation derivatives such as quinolinium and quinazolinium.

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