RESUMEN
Abstract Representations of the chemical structures of dyes and fluorochromes often are used to illustrate staining mechanisms and histochemical reactions. Unfortunately, inaccurate chemical structures sometimes are used, which results in problems for teaching and research in histochemistry. We comment here on published examples of inadequate chemical drawing and modeling. In particular, omission of hydrogen atoms can lead to misleading hydrogen-bonding interactions, and inaccurate drawing and modeling procedures result in a variety of implausible molecular structures. The examples and arguments given here are easily intelligible for non-chemists and could be used as part of a training approach to help avoid publication of misleading or puzzling dye structures and molecular models for illustrating biological staining and histochemical studies.
Asunto(s)
Investigación Biomédica/educación , Estructura Molecular , Relación Estructura-Actividad , Enseñanza/normas , Investigación Biomédica/normas , Colorantes , Histocitoquímica , Modelos Moleculares , Coloración y EtiquetadoRESUMEN
We evaluated a number of lipophilic dyes and fluorochromes, including oxazone and thiazone derivatives of oxazine and thiazine dyes, scintillator agents, a carotenoid and a metal-porphyrin complex for visualization of lipid droplets within aldehyde fixed cultured HeLa and BGC-1 cells. Observation under ultraviolet, blue or green exciting light revealed selective fluorescence of lipid droplets, particularly after treatment with aqueous solutions of Nile blue and brilliant cresyl blue oxazones, toluidine blue thiazone, or propylene glycol solutions of canthaxanthin, ethyl-BAO, and ZnTPyP. Mounting in water was required to maintain the fluorescence of lipids; the use of glycerol, Mowiol or Vectashield was not adequate. The effect of dye structure on staining intensity was assessed with the aid of numerical structure parameters modeling lipophilicity (HI and log P), overall size (MW) and the size of the conjugated system (conjugated bond number; CBN). The best stains for lipid droplets were relatively lipophilic (HI > 4.0, log P > 5.0), of small size overall (MW < 370), with small conjugated systems (CBN < 24), and not significantly amphiphilic. The two hydrophobic-hydrophilic parameters (the classic log P and the hydrophobic index, HI; values calculated by molecular modeling software) were highly correlated; however, HI was a more suitable hydrophobicity index for the dyes studied here.
Asunto(s)
Aldehídos/química , Fijadores/química , Colorantes Fluorescentes/química , Lípidos/análisis , Coloración y Etiquetado , Animales , Carotenoides/química , Bovinos , Células HeLa , Histocitoquímica/métodos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Metaloporfirinas/química , Microscopía Fluorescente/métodos , Oxazinas/química , Tiazinas/químicaRESUMEN
The biological activities of the naphthoquinones lapachol, extracted from trees of the genus Tabebuia and its cyclization products alpha and beta-lapachone, have been intensively studied. Giving continuity to the research about new derivatives obtained from the reaction of these naphthoquinones with amino-containing reagents, a series of arylhydrazones of alpha-lapachone was synthesized and their antineoplastic activity was evaluated. This new structure is based on the great electrophilicity of 1,4-quinoidal carbonyl groups towards reagents containing nitrogen as nucleophilic centers, such as arylhydrazines. The products were assayed by the National Cancer Institute (NCI, USA) and their binding to DNA, redox properties and QSAR studies were also determined.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Hidrazonas/síntesis química , Hidrazonas/farmacología , Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Algoritmos , Línea Celular Tumoral , Fenómenos Químicos , Química Física , ADN/química , Ensayos de Selección de Medicamentos Antitumorales , Electroquímica , Humanos , Modelos Moleculares , Relación Estructura-Actividad CuantitativaRESUMEN
A CoMFA study of benzo- and benzothienothiadiazines derivatives as phosphodiesterase 7 inhibitors has been carried out in order to determine the factors required for the activity of these compounds and also for the selectivity versus other phosphodiesterase isoenzymes. This methodology is employed to gain clues on the design of new fused thiadiazines with improved activity and selectivity on phosphodiesterase 7. Using the information achieved from the three CoMFA models, new structures have been designed in silico and their inhibitory activity on phosphodiesterase 7 was predicted.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Isoenzimas/antagonistas & inhibidores , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Relación Estructura-Actividad Cuantitativa , Tiadiazinas/química , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7 , Diseño de Fármacos , Análisis de los Mínimos Cuadrados , Modelos Moleculares , Programas Informáticos , Tiadiazinas/farmacologíaRESUMEN
The benzothiadiazine dioxide (BTD) derivatives are potent nonnucleoside human cytomegalovirus (HCMV) inhibitors. As part of our comprehensive structure-activity relationship study of these compounds, we have now synthesized N,N- and N,O-dibenzyl derivatives with different para-substituents (alkyl, phenyl, electron-donating, electron-withdrawing) in the phenyl ring of the benzyl moieties. The antiviral activity against HCMV (AD-169 strain) was also experimentally measured showing IC(50) values between 2.5 and 50 microM. Comparative molecular field analysis (CoMFA) was employed to generate a model, based upon 32 diverse BTD derivatives, to delineate structural and electrostatic features important for enhanced activity against HCMV. The steric (van der Waals) interactions with the receptor majoritary describes the variation in antiviral activity among the inhibitors. Finally, the CoMFA model was used to design two sets of novel BTD derivatives. Synthesis and subsequent anti-HCMV evaluation of these compounds enabled us to maintain the activity of this new kind of HCMV inhibitors.