RESUMEN
The title compounds, C28H31N2O3(+)-Cl(-)-H2O (common name rhodamine-6g), (I), and C21H17N2O3(+)-Cl(-)-3H2O (common name rhodamine-123), (II), both have planar xanthene skeletons with a formal +1 charge on the amino N atoms delocalized through the pi-electron system so that the N-Csp(2) bond distances indicate significant double-bond character. The substituted planar phenyl groups make angles of 63.29 (8) and 87.96 (11) degrees with the xanthene planes in (I) and (II), respectively. In both molecules, the carbonyl bond vectors point toward the xanthene rings. The ethylamine groups in (I) are oriented similarly with their CH2-CH3 bond vectors pointing nearly perpendicular to the xanthene plane. The chloride ions and water molecules are disordered in both structures. In (I), the chloride ion and water molecule are disordered between two sites. One water and chloride alternately occupy the same site with occupancy factors of 0.5. The other 0.5-chloride and 0.5-water occupy two distinct positions separated by 0.747 (8) A. In (II), the chloride ion is disordered between three sites and one of the waters is disordered about two other sites. Both crystal structures are stabilized by hydrogen bonds involving the chloride ions, amino groups and water molecules, as well as by pi-pi stacking between xanthene planes.
Asunto(s)
Colorantes Fluorescentes/química , Rodamina 123/química , Rodaminas/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Estructura MolecularRESUMEN
The crystal and molecular structure of methotrexate has been determined by X-ray diffraction from a highly hydrated triclinic crystal form in which the asymmetric unit contains two independent methotrexate molecules with their glutamate carboxyl groups coordinated to two strontium ions. The two methotrexates exhibit differing conformations: They are almost related to one another by a pseudocenter of symmetry. This places the C(9)-N(10) bond vectors on opposite sides of the planes of the pteridine rings. The 2,4-diaminopteridines form 2-fold symmetry-related hydrogen-bonded dimers as well as hydrogen bonds to benzoyl carbonyl oxygens and lattice water molecules. This structure provides experimental proof of the existence of pteridine conformers through rotation about the C(6)-C(9) bond. Comparison of these conformers with other free and enzyme-bound methotrexate conformations shows them all to be different and illustrates the ability of the molecule to adapt to its chemical environment. The results from this crystal structure determination are experimental proof that methotrexate has not one preferred molecular conformation but may freely rotate about several bonds. They also suggest that the dihydrofolate reductase-bound methotrexate conformation is greatly influenced by the specific binding site environment of the enzyme.
Asunto(s)
Antimetabolitos Antineoplásicos/química , Metotrexato/química , Estroncio/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Conformación Molecular , Estereoisomerismo , AguaRESUMEN
The crystal structure of the title compound contains four 2, 4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline molecules, two dimethyl sulfoxide molecules and three water molecules in the asymmetric unit, i.e. 4C(19)H(23)N(5)O(3).-2C(2)H(6)OS.3H(2)O. All four quinazoline molecules adopt trans,-gauche conformations. An extensive hydrogen-bond network involving N. N base-pairing interactions, as well as the dimethyl sulfoxide and water molecules, stabilizes the crystal structure.
Asunto(s)
Antagonistas del Ácido Fólico/química , Tetrahidrofolato Deshidrogenasa/metabolismo , Trimetrexato/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Lacticaseibacillus casei/enzimología , Modelos Moleculares , Conformación Molecular , Unión ProteicaRESUMEN
In the title compound, dimethyl(¿5-[2-(1-methylamino-2-nitroethenylamino)ethylthiometh yl]-2- furyl¿methyl)ammonium chloride, C(13)H(23)N(4)O(3)S(+).Cl(-), protonation occurs at the dimethylamino N atom. The ranitidine molecule adopts an eclipsed conformation. Bond lengths indicate extensive electron delocalization in the N,N'-dimethyl-2-nitro-1, 1-ethenediamine system of the molecule. The nitro and methylamino groups are trans across the side chain C=C double bond, while the ethylamino and nitro groups are cis. The Cl(-) ions link molecules through hydrogen bonds.
Asunto(s)
Antagonistas de los Receptores H2 de la Histamina/química , Ranitidina/química , Cristalografía por Rayos X , Enlace de Hidrógeno , Modelos Moleculares , Conformación MolecularRESUMEN
The asymmetric unit of the title compound, C8H18N3OP, contains one bis(2,2-dimethylaziridinyl)phosphinic amide molecule. The crystal structure is characterized by hydrogen bonds from the amide-N atom, which involve both H atoms of the amino group, to the phosphinic-O atom in two different molecules, thus forming infinite double-stranded chains along the base vector [100], and by hydrophobic contacts between these chains.
Asunto(s)
Antineoplásicos/química , Aziridinas/química , Ácidos Fosfínicos/química , Cristalización , Cristalografía por Rayos X , Neoplasias Esofágicas/tratamiento farmacológico , Humanos , Estructura Molecular , Mieloma Múltiple/tratamiento farmacológicoRESUMEN
Synthesis, absolute configuration and antiviral activity of enantiomeric antiviral agents (R)-(-)- and (S)-(+)-synadenol (2 and 3a) are described.
Asunto(s)
Adenina/análogos & derivados , Antivirales/síntesis química , Antivirales/farmacología , Ciclopropanos/síntesis química , Ciclopropanos/farmacología , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Antivirales/química , Ciclopropanos/química , Virus de la Hepatitis B/efectos de los fármacos , Herpesviridae/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , EstereoisomerismoRESUMEN
In the title compound, 1-(2-deoxy-2-fluoro-beta-D-arabino-furanosyl)-5-fluoropyrimidine-2, 4(1H,3H)-dione, C9H10-F2N2O5, the furanosyl ring adopts the twisted conformation (T) with O1' endo and C1' exo. The crystal structure is characterized by a three-dimensional hydrogen-bond network involving the three H atoms bonded to heteroatoms.
Asunto(s)
Antineoplásicos/química , Antivirales/química , Arabinofuranosil Uracilo/análogos & derivados , Cristalografía por Rayos X , Arabinofuranosil Uracilo/química , Modelos MolecularesRESUMEN
The crystal structure the Schiff base contains one 4-dimethylaminomethyleneaminobenzenesulfonic acid molecule in zwitterionic form [4-(dimethylaminomethyleneammonio)benzenesulfonate], and one water molecule in the asymmetric unit (C9H12N2O3S.H2O). Protonation occurs at nitrogen atom N1, but the charge is delocalized.
Asunto(s)
Cristalografía por Rayos X , Dimetilformamida/química , Bases de Schiff/química , Ácidos Sulfanílicos/química , Modelos MolecularesRESUMEN
Synthesis of (R)-(-)- and (S)-(+)-synadenol (1a and 2a, 95-96% ee) is described. Racemic synadenol (1a + 2a) was deaminated with adenosine deaminase to give (R)-(-)-synadenol (1a) and (S)-(+)-hypoxanthine derivative 5. Acetylation of the latter compound gave acetate 6. Reaction with N, N-dimethylchloromethyleneammonium chloride led to 6-chloropurine derivative 7. Ammonolysis furnished (S)-(+)-synadenol (2a). Absolute configuration of 1a was established by two methods: (i) synthesis from (R)-methylenecyclopropanecarboxylic acid (8) and (ii) X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. Racemic methylenecyclopropanecarboxylic acid (10) was resolved by a modification of the described procedure. The R-enantiomer 8 was converted to ethyl ester 13 which was brominated to give vicinal dibromides 14. Reduction with diisobutylaluminum hydride then furnished alcohol 15 which was acetylated to the corresponding acetate 16. Alkylation-elimination procedure of adenine with 16 yielded acetates 17 and 18. Deprotection with ammonia afforded a mixture of Z- and E-isomers 1a and 19 of the R-configuration. Comparison with products 1a and 2a by chiral HPLC established the R-configuration of (-)-synadenol (1a). These results were confirmed by X-ray diffraction of a single crystal of (-)-synadenol hydrochloride. The latter forms a pseudosymmetric dimer with adenine-adenine base pairing in the lattice with the nucleobase in an anti-like conformation. Enantiomers 1a and 2a exhibit varied enantioselectivity toward different viruses. Both enantiomers are equipotent against human cytomegalovirus (HCMV) and varicella zoster virus (VZV). The S-enantiomer 2a is somewhat more effective than R-enantiomer 1a in herpes simplex virus 1 and 2 (HSV-1 and HSV-2) assays. By contrast, enantioselectivity of antiviral effect is reversed in Epstein-Barr virus (EBV) and human immunodeficiency virus type 1 (HIV-1) assays where the R-enantiomer 1a is preferred. In these assays, the S-enantiomer 2a is less effective (EBV) or devoid of activity (HIV-1).
Asunto(s)
Adenina/análogos & derivados , Antivirales/síntesis química , Ciclopropanos/síntesis química , Adenina/síntesis química , Adenina/química , Adenina/farmacología , Animales , Antivirales/química , Antivirales/farmacología , Células Cultivadas , Chlorocebus aethiops , Cromatografía Líquida de Alta Presión , Dicroismo Circular , Cristalografía por Rayos X , Ciclopropanos/química , Ciclopropanos/farmacología , Citomegalovirus/efectos de los fármacos , Citomegalovirus/crecimiento & desarrollo , Fibroblastos , VIH-1/efectos de los fármacos , VIH-1/crecimiento & desarrollo , Virus de la Hepatitis B/efectos de los fármacos , Virus de la Hepatitis B/crecimiento & desarrollo , Herpesvirus Humano 3/efectos de los fármacos , Herpesvirus Humano 3/crecimiento & desarrollo , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/crecimiento & desarrollo , Humanos , Concentración 50 Inhibidora , Ratones , Conformación Molecular , Simplexvirus/efectos de los fármacos , Simplexvirus/crecimiento & desarrollo , Estereoisomerismo , Células Vero , Ensayo de Placa ViralRESUMEN
Paclitaxel (formerly called taxol), an important anticancer drug, inhibits cell replication by binding to and stabilizing microtubule polymers. As drug-receptor interactions are governed by the three-dimensional stereochemistries of both participants, we have determined the crystal structure of paclitaxel to identify its conformational preferences that may be related to biological activity. The monoclinic crystals contain two independent paclitaxel molecules in the asymmetric unit plus several water and dioxane solvent molecules. Taxane ring conformation is very similar in both paclitaxel molecules and is similar to the taxane ring conformation found in the crystal structure of the paclitaxel analogue docetaxel (formerly called taxotere). The two paclitaxel molecules have carbon-13 side-chain conformations that differ from each other and from that of the corresponding side chain in the docetaxel crystal structure. The carbon-13 side-chain conformation of one paclitaxel molecule is similar to what was proposed from NMR studies done in polar solvents, while that of the other paclitaxel molecule is different and hitherto unobserved. The paclitaxel molecules interact with each other and with solvent atoms through an extensive network of hydrogen bonds. Analysis of the hydrogen-bonding network together with structure-activity studies may suggest which atoms of paclitaxel are important for binding to microtubule receptors.
Asunto(s)
Paclitaxel/química , Taxoides , Cristalografía por Rayos X , Docetaxel , Enlace de Hidrógeno , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Paclitaxel/análogos & derivados , Relación Estructura-ActividadRESUMEN
High-resolution structures of the glucosidase inhibitors deoxynojirimycin (dNM) and castanospermine (CAST) have been determined by X-ray diffraction. The crystal parameters are a = 10.751(3) and 8.788(3) A, b = 9.263(3) and 8.172(3) A, c = 7.719(2) and 6.507(2) A, and space group P2(1)2(1)2(1) and P2(1) for dNM and CAST, respectively. (beta = 105.44(8) degrees for CAST.) The absolute configuration of CAST has also been established. Stereochemical comparisons with natural glucosidase substrates such as maltose and methyl glucoside show great similarities in the positioning of functional groups, and indicate the basis for enzyme inhibition. Conformational comparison between dNM and CAST suggests the greater activity of CAST may be due to the fixed axial positioning of the O6 atom; the results have implications for the design of analogues for potential anti-HIV and other antiviral therapies.
Asunto(s)
1-Desoxinojirimicina/farmacología , Glucosidasas/antagonistas & inhibidores , Indolizinas/farmacología , 1-Desoxinojirimicina/química , Cristalografía , Indolizinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The tripeptide L-alanyl-L-alanyl-L-alanine has been crystallized from a water/dimethylformamide solution in an unhydrated form, with cell dimensions a = 11.849, b = 10.004, c = 9.862 A, beta = 101.30 degrees, monoclinic space group P21 with 4 molecules per cell (2 independent molecules in the asymmetric unit). The structure was determined by direct methods and refined to a discrepancy index R = 0.057. The tri-L-alanine molecules are packed in a parallel pleated sheet arrangement with unusually long amide nitrogen-carbonyl oxygen contacts within sheets. Comparisons are made with the antiparallel pleated sheet structure of tri-L-alanine hemihydrate, previously crystallized from the same solvent system.
Asunto(s)
Oligopéptidos/química , Conformación Proteica , Secuencia de Aminoácidos , Dimetilformamida/química , Enlace de Hidrógeno , Sustancias Macromoleculares , Datos de Secuencia Molecular , Agua/química , Difracción de Rayos XRESUMEN
The crystal and molecular structures of the anti-human immunodeficiency virus agent 3'-fluoro-3'-deoxythymidine have been determined by x-ray diffraction and stereochemical comparisons with thymidine have been made. Atomic charge distributions have been calculated by the complete neglect of differential overlap method for thymidine and antiretrovirally active and inactive C3'-substituted analogues. The structural and electronic results suggest that antiviral activity in these analogues may be correlated with the presence of an electronegative atom attached to C3'.
Asunto(s)
Antivirales , Didesoxinucleósidos , VIH/efectos de los fármacos , Timidina/análogos & derivados , Didesoxinucleósidos/farmacología , Enlace de Hidrógeno , Conformación Molecular , Estructura MolecularRESUMEN
The crystal and molecular structures of alpha and beta isomers of the antineoplastic alkylating agent 1,3,5-triglycidyl-s-triazinetrione (TGT) have been determined by X-ray diffraction. Although the isomers differ chemically only in the order of a carbon and an oxygen atom in one of the glycidyl epoxide rings, the molecular conformations and crystal packing arrangements are very different. The different physical and biological properties of the two stereoisomers can be explained on the basis of the structures. The sample of alpha-TGT was found to be a mixture of alpha and beta forms, and it is suggested that use of pure alpha-TGT may lead to better therapeutic results.
Asunto(s)
Triazinas , Fenómenos Químicos , Química , Cristalografía , Modelos Moleculares , Conformación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
The 4-(m-OH-phenyl)piperidines are a flexible fragment of the morphine/benzomorphan fused-ring opioids. Analogs in this family were synthesized with varying 4-alkyl substituents increasing in bulk from H through methyl, n-propyl, to t-butyl, each with the three N-substituents methyl, allyl, and phenethyl. These twelve compounds were evaluated for analgetic agonism in mice using two different models for antinociceptive activity, acetic acid writhing and tail-flick, the latter by both subcutaneous and intracerebroventricular routes of administration. Antagonism to morphine analgesia was also measured by the mouse tail-flick procedure. Binding affinities of these new analogs to different opioid receptor subtypes were determined. Energy conformational calculations on these compounds were also carried out using the empirical energy program called MOLMEC, in order to better understand how the 4-R substituents modulate receptor binding affinities and efficacies. The results obtained show that, in general, the compounds studied are mu-selective and vary in agonist potency from weak to morphine-like. Significant differences in rank order of analgetic potencies and their relationship to receptor affinities were obtained from the results of subcutaneous and intracerebroventricular administration. Results of energy-conformational calculations for twelve N-methyl compounds indicate that those with 4-alkyl substituents favor a common, non-morphine-like phenyl axial conformation. The 4-t-butyl compounds are, in fact, the first simple mono-alkyl-substituted 4-phenyl-piperidines predicted to definitely exist in a phenyl axial conformation, as confirmed by X-ray analysis. On the basis of this common phenyl axial conformation, the observed variation in mu receptor affinities and efficacies of the 4-methyl, 4-n-propyl, and 4-t-butyl compounds could be understood and the behavior of 4-ethyl and 4-isopropyl analogs predicted. Two equatorial conformers (rotamers) were found to be the preferred forms of the analogs with 4-R being H or an ester group, or with a 3-methyl group added trans (beta) to the 4-R group. Taking into account the rotational flexibility of these analogs, these two conformers could be used to understand differences in high and low efficacy compounds observed among analogs with preferred phenyl equatorial conformations. None of the analogs exhibit a fused-ring-like N-substituent modulation of efficacy. This result can, perhaps, be understood by their inability in any proposed conformer to totally mimic key receptor interactions of both the phenol-OH and N-substituent portions of the fused compounds.
Asunto(s)
Morfina/farmacología , Analgésicos/farmacología , Animales , Técnicas In Vitro , Inyecciones Intraventriculares , Conformación Molecular , Morfina/administración & dosificación , Morfina/metabolismo , Piperidinas/metabolismo , Ratas , Ratas Endogámicas , Receptores Opioides/metabolismo , Receptores Opioides delta , Receptores Opioides kappa , Receptores Opioides mu , Relación Estructura-ActividadRESUMEN
The structure of the non-classical quinazoline antifolate trimetrexate (TMQ) has been determined in two crystal forms, TMQ acetate monohydrate, and hydrated TMQ free base. Trimetrexate has an extended conformation in both structures, and the quinazoline and phenyl rings are mutually perpendicular. Protonation occurs at N1 in the acetate salt. The TMQ conformation is similar to corresponding parts of quinespar, the only other quinazoline antifolate structurally determined, and the hydrated strontium salt of methotrexate.
Asunto(s)
Antineoplásicos , Quinazolinas , Cristalización , Modelos Moleculares , Conformación Molecular , TrimetrexatoRESUMEN
The crystal and molecular structures of the anti-acquired immunodeficiency syndrome agent 3'-azido-3'-deoxythymidine (AZT) have been determined by x-ray diffraction. There are two crystallographically independent AZT molecules in the crystal asymmetric unit; they have similar conformations and differ primarily in the glycosyl torsion angle. Comparisons with a hydrated thymidylate structure indicate that the azido group does not significantly affect the gross conformational preference of the molecule. The comparisons also suggest possible functional roles for the azido group in enzyme binding.
Asunto(s)
Timidina/análogos & derivados , Cristalografía , Modelos Moleculares , ADN Polimerasa Dirigida por ARN/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , ZidovudinaRESUMEN
The structure of a new crystal form of leucine-enkephalin has been determined by X-ray diffraction. There are two independent molecules in the asymmetric unit and both have extended peptide backbone conformations with side-chains arranged alternately above and below the backbone planes. The two pentapeptides are hydrogen-bonded to each other and to other molecules forming an extended antiparallel beta-pleated sheet. The structure differs from that in similar crystals of methionine enkephalin primarily in side-chain orientations and inter-sheet interactions.