Quantitative structure-activity relationship (QSAR) study of 19-nor-testosterone steroids family was performed using quantum and physicochemical molecular descriptors. The quantum-chemical descriptors were calculated using semiempirical calculations. The descriptor values were statistically correlated using multi-linear regression analysis. The QSAR study indicated that the electronic properties of these derivatives have significant relationship with observed biological activities. The found QSAR equations explain that the energy difference between the LUMO and HOMO, the total dipole moment, the chemical potential and the value of the net charge of different carbon atoms in the steroid nucleus showed key interaction of these steroids with their anabolic-androgenic receptor binding site. The calculated values predict that the 17α-cyclopropyl-17β, 3β-hydroxy-4-estrene compound presents the highest anabolic-androgenic ratio (AAR) and the 7α-methyl-17β-acetoxy-estr-4-en-3-one compound the lowest AAR. This study might be helpful in the future successful identification of real or virtual anabolic-androgenic steroids. © 2011 Elsevier Ltd. All rights reserved.

The great cost associated with the development of new anabolic-androgenic steroid (AASs) makes necessary the development of computational methods that shorten the drug discovery pipeline. Toward this end, quantum, and physicochemical molecular descriptors, plus linear discriminant analysis (LDA) were used to analyze the anabolic/androgenic activity of structurally diverse steroids and to discover novel AASs, as well as also to give a structural interpretation of their anabolic-androgenic ratio (AAR). The obtained models are able to correctly classify 91.67\% (86.27\%) of the AASs in the training (test) sets, respectively. The results of predictions on the 10\% full-out cross-validation test also evidence the robustness of the obtained model. Moreover, these classification functions are applied to an in house library of chemicals, to find novel AASs. Two new AASs are synthesized and tested for in vivo activity. Although both AASs are less active than some commercially AASs, this result leaves a door open to a virtual variational study of the structure of the two compounds, to improve their biological activity. The LDA-assisted QSAR models presented here, could significantly reduce the number of synthesized and tested AASs, as well as could increase the chance of finding new chemical entities with higher AAR. © 2007 Wiley Periodicals, Inc.

Predictive quantitative structure-activity relationship (QSAR) models of anabolic and androgenic activities for the testosterone and dihydrotestosterone steroid analogues were obtained by means of multiple linear regression using quantum and physicochemical molecular descriptors (MD) as well as a genetic algorithm for the selection of the best subset of variables. Quantitative models found for describing the anabolic (androgenic) activity are significant from a statistical point of view: R 2 of 0.84 (0.72 and 0.70). A leave-one-out cross-validation procedure revealed that the regression models had a fairly good predictability [q 2 of 0.80 (0.60 and 0.59)]. In addition, other QSAR models were developed to predict anabolic/androgenic (A/A) ratios and the best regression equation explains 68\% of the variance for the experimental values of AA ratio and has a rather adequate q 2 of 0.51. External validation, by using test sets, was also used in each experiment in order to evaluate the predictive power of the obtained models. The result shows that these QSARs have quite good predictive abilities (R 2 of 0.90, 0.72 (0.55), and 0.53) for anabolic activity, androgenic activity, and A/A ratios, respectively. Last, a Williams plot was used in order to define the domain of applicability of the models as a squared area within ±2 band for residuals and a leverage threshold of h = 0.16. No apparent outliers were detected and the models can be used with high accuracy in this applicability domain. MDs included in our QSAR models allow the structural interpretation of the biological process, evidencing the main role of the shape of molecules, hydrophobicity, and electronic properties. Attempts were made to include lipophilicity (octanol-water partition coefficient (log P)) and electronic (hardness (η)) values of the whole molecules in the multivariate relations. It was found from the study that the log P of molecules has positive contribution to the anabolic and androgenic activities and high values of η produce unfavorable effects. The found MDs can also be efficiently used in similarity studies based on cluster analysis. Our model for the anabolic/androgenic ratio (expressed by weight of levator ani muscle, LA, and seminal vesicle, SV, in mice) predicts that the 2-aminomethylene-17α-methyl-17β-hydroxy-5α-androstan-3- one (43) compound is the most potent anabolic steroid, and the 17α-methyl-2β,17β-dihydroxy-5α-androstane (31) compound is the least potent one of this series. The approach described in this report is an alternative for the discovery and optimization of leading anabolic compounds among steroids and analogues. It also gives an important role to electron exchange terms of molecular interactions to this kind of steroid activity. © 2008 Elsevier Ltd. All rights reserved.

We investigated the function and expression of voltage-gated Na+ channels (VGSC) in the uteri of nonpregnant rats using organ bath techniques, intracellular [Ca2+] fluorescence measurements, and RT-PCR. In longitudinally arranged whole-tissue uterine strips, veratridine, a VGSC activator, caused the rapid appearance of phasic contractions of irregular frequency and amplitude. After 50-60 min in the continuous presence of veratridine, rhythmic contractions of very regular frequency and slightly increasing amplitude occurred and were sustained for up to 12 h. Both the early and late components of the contractile response to veratridine were inhibited in a concentration-dependent manner by tetrodotoxin (TTX). In small strips dissected from the uterine longitudinal smooth muscle layer and loaded with Fura-2, veratridine also caused rhythmic contractions, accompanied by transient increases in [Ca2+]i, which were abolished by treatment with 0.1 μM TTX. Using end-point and real-time quantitative RT-PCR, we detected the presence of the VGSC alpha subunits Scn2a1, Scn3a, Scn5a, and Scn8a in the cDNA from longitudinal muscle. The mRNAs of the auxiliary beta subunits Scbn1b, Scbn2b, Scbn4b, and traces of Scn3b were also present. These data show for the first time that Scn2a1, Scn3a, Scn5a, and Scn8a, as well as all VGSC beta subunits are expressed in the longitudinal smooth muscle layer of the rat myometrium. In addition, our data show that TTX-sensitive VGSC are able to mediate phasic contractions maintained over long periods of time in the uteri of nonpregnant rats. © 2007 by the Society for the Study of Reproduction, Inc.

Voltage-gated Na+ channels are composed of one α subunit and one or more auxiliary β subunits. A reverse transcription-polymerase chain reaction assay was used to analyse the expression of the nine known α subunits (Nav1.1-Nav1.9) in 20 different human tissues. The mRNA expression of the currently known β subunits (β1, β2, β3 and β4) was also assessed. The mRNAs of voltage-gated Na+ channel α and β subunits were found in a wide variety of human tissues assayed and were present in neuronal and non-neuronal types of cells. These data suggest that, in addition to its well-established role in skeletal muscle, cardiac cells and neurons, voltage-gated Na+ channels might play important, still undetermined local roles in the regulation of cellular functions. These channels could emerge in the next future as potential, new therapeutic targets in the treatment of visceral diseases. © 2006 Elsevier B.V. All rights reserved.

The synthesis of three new highly fluorescent compounds is reported and the basic spectroscopic properties of them described, discussed and compared with those of some structurally related fluorescent compounds usually used as fluorescent probes. The effect of the solvent on ambient temperature absorption and fluorescence spectra, and the solvatochromic properties observed for both ground and first excited states of all the probes were used to evaluate their first excited dipole moments using the solvatochromic shift method (Bakhshiev's correlation). © 2000 Elsevier Science S.A. All rights reserved.

[No abstract available]

The kinetic resolution of 2-bromo-2-cyclohexenol has been achieved through enzyme-mediated transesterification in organic solvents, using vinyl acetate as the irreversible acylating agent. The effect of the enzyme and the solvent on the velocity and the enantioselectivity of the transformation has been studied. Also the influences of the size of the carbocyclic ring and the substituent in the 2-position have been briefly examined.

Treatment of allylic alcohols with catalytic amounts of palladium catalysts in the presence of oxygen leads to the formation of α,β-unsaturated carbonyl compounds. © 1990.

Substitution of one or two triphenylphosphine ligands of Ru(CO)ClH(PPh 3 ) 3 by bidentate diphosphines Ph 2 P(CH 2 ) n PPh 2 (L-L) (n = 1, dppm; n = 2, dppe; n = 3, dppp; n = 4, dppb) or 1,1′-bis(diphenylphosphino)ferrocene (dppf) led to hydrides Ru(CO)ClH(PPh 3 ) 2 (L-L) or Ru-(CO)ClH(PPh 3 )(L-L). The hydrido complexes were characterized spectroscopically and by one X-ray structure. Hydride Ru(CO)ClH(PPh 3 )(dppf) crystallizes in the monoclinic space group P2 1 /n, with a = 17.768(1) Å, b = 25.252(2) Å, c = 11.213(1) Å, β = 92.83(1)°, Z = 4, and V = 4459.3(6) Å 3 . Reaction of Ru(CO)ClH(PPh 3 ) 3 or [Ru(CO)H(MeCN) 2 (PPh 3 ) 2 ] + PF 6 - with 2 equiv of diphosphines L-L led to [Ru(CO)H(L-L) 2 ] + A - (L-L = dppm, dppe, dppp) (A = Cl, PF 6 ). Hydrides Ru(CO)ClH(PPh 3 ) 2 (L-L) react with 1-alkynes to give alkenyl complexes Ru(CO)Cl(CH=CHR)(PPh 3 )(L-L) with a chelating diphosphine ligand. Ru(CO)ClH(PPh 3 )-(L-L) gave σ-alkynyl complexes Ru(CO)Cl(C≡CR)L(L-L) directly in their reactions with 1-alkynes. The hydride with dppb as the ligand showed the highest reactivity. The preparation of hexacoordinated alkenyl derivatives Ru(CO)Cl(CH=CHR)(PPh 3 )(L-L) with a chelating diphosphine was carried out by treatment of other alkenyl derivatives with the diphosphines. Surprisingly, reaction of alkenyls Ru(CO)Cl(CH=CHR)(Me 2 Hpz)(PPh 3 ) 2 (R = CMe 3 , p-MeC 6 H 4 ) with dppf led to complexes Ru(CO)Cl(CH=CHR)(Me 2 Hpz)(dppf) by substitution of both PPh 3 ligands instead of the dimethylpyrazole. Ruthenium alkenyls Ru-(CO)Cl(CH=CHR)L(dppf) (L = Me2Hpz, PPh 3 ) react cleanly with 1-alkynes at room temperature to give alkynyl complexes Ru(CO)Cl(C≡CR)L(dppf) in good yield. This reaction was applied to the synthesis of a bimetallic complex Ru(CO)Cl(PPh 3 )(dppf)(C≡C-p-C 6 H 4 C≡C)-Ru(CO)Cl(PPh)(dppf) as a mixture of meso and dl diastereomers. © 1994, American Chemical Society. All rights reserved.

The development of a general strategy for the construction of anthracyclinones based on a Diels-Alder reaction of substituted derivatives of 10-amino-9-hydroxy-1,4-anthraquinone is described. The key stages are (i) formation of N,O,O-triacyl derivatives of 1,4-dihydroxy-9,10-anthraquinone monoimines in a tautomer specific fashion, (ii) transacylation into N,N,O-triacyl derivatives of the corresponding 10-amino-9-hydroxy-1,4-anthraquinone, and (iii) Diels-Alder reaction with an appropriately substituted 1,3-diene regiocontrolled by steric factors. This strategy has been applied to the total synthesis of (±)-5-iminodaunomycinone (4) and (±)-4-demethoxy-5-iminodaunomycinone (3) and to a novel and short synthesis of (±)-daunomycinone (5). © 1993, American Chemical Society. All rights reserved.

1,4-Dihydroxy-9,10-anthraquinone monoimine and differently substituted derivatives thereof (6a-i) have been prepared by ammonolysis of the corresponding 1,4-dihydroxy-9,10-anthraquinones. 1H- and 13C-n.m.r. studies show the existence of a rapid tautomeric equilibrium in quinone imines of type 6. Diels-Alder reaction with the 1,4-anthraquinonoid tautomer of quinone monoimines 6a,e affords ABCD tetracyclic systems related to those existing in anthracyclinones. © 1992.

The total synthesis of (±)-5-iminodaunomycinone (4a) and (±)-4-demethoxy-5-iminodaunomycinone (4b) has been achieved from the readily available 5-methoxy-1,4-dihydroxy-9,10-anthraquinone (5a) and 1,4-dihydroxy-9,10-anthraquinone (5b), respectively. A short and convenient synthesis of (±)-daunomycinone (4c) has also been achieved by acid hydrolysis of 4a. Short syntheses of 4a (R = OMe, X = NH), 4b (R = H, X = NH) and 4c (R = OMe, X = O) are reported. © 1991.

The palladium-catalyzed coupling of hydroxyanthraquinone triflates with stannanes provides an efficient entry into substituted anthraquinones under neutral conditions. © 1990.

Reactions of [Ru(CO)H(MeCN)2(PPh3)2]A with mono- and di-substituted acetylenes give the alkenyl derivatives [Ru(CO)(RCCHR′)(MeCN)2(PPh3)2]A (A ClO4, R H; R′ C3H7, CMe3, Ph, COOMe; R R′ COOMe; A PF6, R R′ Ph) resulting from a cis-insertion of the alkyne into the RuH bond. The reaction of the perchlorate complex with diphenylacetylene yields alkenyl chlororuthenium derivatives resulting from the unexpected reduction of the perchlorate anion to chloride. The crystal structure of [Ru(CO)(MeOOCCCHCOOMe)(MeCN)2(PPh3)2]ClO4 has been determined by X-ray crystallography (orthorhombic, P212121, a 14.498(1), b 15.080(1), c 22.677(2) Å). In this cationic complex both phosphine and acetonitrile molecules and, consequently, the carbonyl and alkenyl ligands are mutually trans, whereas in the other complexes only the phosphine ligands are in trans disposition, as inferred from 1H NMR spectroscopic data. © 1989.

Multivariate analysis methods (principal component analysis, discriminant analysis, and SIMCA) have been applied to the 1H n.m.r. parameters of acyclic 2-hetero-substituted sulphoxides, in order to establish their relative configurations, with satisfactory results. These methods are quicker and probably also more accurate than previous methods based on a complex conformational study. The results indicate that chemical shifts can be accurately correlated with the relative configurations of the substrates; however this relationship is not overt and is impossible to derive directly.