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Biomedical subjects

Milos Budesínský

Publications and source records attributed to Milos Budesínský.

At least 19 recordsLinked to original sources
PubMed2006

Preparation of diamino pseudodisaccharide derivatives from 1,6-anhydro-beta-D-hexopyranoses via aziridine-ring cleavage.

Twelve positional isomers of diamino pseudodisaccharide derivatives with gluco-gluco configuration have been prepared using aziridine-ring cleavage of epimino derivatives of 1,6-anhydro-beta-D-hexopyranoses of the D-allo, D-manno, and D-galacto configuration by 2-, 3-, and 4-amino derivatives of 1,6-anhydro-beta-D-glucopyranose. The N-substitution of the aziridine ring by a 2-nitrobenzenesulfonyl group and ionic-liquid solvent (N-methylpyridinium tosylate) was used to obtain cleavage products in high yield (64-93%). The cleavage reactions proceeded according to the Fürst-Plattner rule and only trans-diaxial stereoisomers were formed.

Amino Sugars↗
PubMed2006

Synthesis of (+/-)-3-Methoxyestra-1,3,5(10)-trienes by the repetitive use of Negishi reagent.

[reaction: see text] The repetitive use of Cp(2)ZrBu(2) (Negishi reagent) was applied in the synthesis of three 3-methoxyestra-1,3,5(10)-trienone isomers within four steps from the advanced intermediate 11. The overall synthesis is based on three zirconium-mediated reactions: (a) oxidative addition of a benzyl ether, (b) cyclization of an allyl-ene compound, and (c) cyclocarbonylation of a diene. The presented synthesis demonstrates that complex organic compounds can be prepared by the repetitive use of one reagent.

Journal Article↗
PubMed2006

Novel isosteric, isopolar phosphonate analogs of oligonucleotides: preparation and properties.

A synthetic approach leading to novel-type modified oligothymidylates containing an isosteric, isopolar, enzyme-stable C3'-O-P-CH(2)-O-C4'' phosphonate alternative to phosphodiester internucleotide bond was elaborated. The suitable monomers were prepared from 4'-phosphonomethoxy derivatives of alpha-L-threo and beta-D-erythro-2',5'-dideoxythymidine, which were considered interesting as structurally related to nucleoside 5'-monophosphates. The phosphotriester method was applied to the automated synthesis of both homooligomeric phosphonate 15-mer chains and alternating phosphonate-phosphate constructs. The fully modified homooligomers did not hybridize while homooligomers with alternating sequences containing alpha-L-threo-configured units (but not beta-D-erythro-) showed a significant decrease in T(m) values in comparison with natural dT(15). For a comparative study, phosphodiester 4'-CH(3)-substituted oligothymidylate was synthesized and physical studies (NMR, CD, MDS modeling) were undertaken to shed more light on the changes in conformational behavior arising from the chosen structural alterations.

Circular Dichroism↗
PubMed2005

A complete set of NMR chemical shifts and spin-spin coupling constants for L-Alanyl-L-alanine zwitterion and analysis of its conformational behavior.

With the aid of labeling with stable isotopes ((15)N and (13)C) a complete set of chemical shifts and indirect spin-spin coupling constants was obtained for the zwitterionic form of L-alanyl-L-alanine in aqueous solution. Different sensitivities of the NMR parameters to the molecular geometry were discussed on the basis of comparison with ab initio (DFT) calculated values. An adiabatic two-dimensional vibrational wave function was constructed and used for determination of the main chain torsion angle dispersions and conformational averaging of the NMR shifts and coupling constants. The quantum description of the conformational dynamics based on the density functional theory and a polarizable continuum solvent model agrees reasonably with classical molecular dynamics simulations using explicit solvent. The results consistently evidence the presence of a single form in the aqueous solution with equilibrium main chain torsion angle values (psi = 147 degrees, varphi = -153 degrees), close to that one found previously in an X-ray study. Under normal temperature the torsion angles can vary by about 10 degrees around their equilibrium values, which leads, however, to minor corrections of the NMR parameters only. The main chain heavy atom chemical shifts and spin-spin coupling constants involving the alpha-carbon and hydrogen atoms appear to be most useful for the peptide structural predictions.

Dipeptides↗
PubMed2005

Asymmetric synthesis of [7]helicene-like molecules.

[reaction: see text] A new approach to nonracemic [7]helicene-like molecules has been developed. Stereoselective Co(I)-mediated [2 + 2 + 2] cycloisomerization of aromatic triynes containing an asymmetric carbon atom produces [7]helicene-like scaffolds in diastereomeric ratios up to 100:0. This central-to-helical chirality transfer can be controlled by the absolute configuration at the asymmetric center and by the presence of carbon substituents.

Journal Article↗
PubMed2005

Synthesis of (R)- and (S)-3,3,3-trifluoro-2-phenylpropanoyl isocyanates and their use as reactive analogues of Mosher's acid.

The title compounds have been prepared from the respective 3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acids (MTPA) by a three-step synthesis with MTPA chloride and MTPA amide as reaction intermediates. The requested compounds were obtained in high chemical yields without any change in optical purity during the preparation. To ascertain the usefulness of this auxiliary agent in the chiral analysis, isomeric 3,3,3-trifluoro-2-phenylpropanoyl isocyanates were subjected in NMR tubes to noncatalyzed reactions with 16 different commercially available chiral alcohols. The steric arrangement of all diastereomers prepared correlated well with their NMR spectral nonequivalence data (Deltadelta), thus demonstrating the regular sign distribution of Deltadelta of particular groups according to the devised molecular model. The usefulness of the novel derivatization is discussed.

Journal Article↗
PubMed2005

Etienic etienate as synthon for the synthesis of steroid oligoester gelators.

Linear oligoesters based on etienic acid (3beta-hydroxyandrost-5-ene-17beta-carboxylic acid) containing four steroid units were prepared using a 2+2 synthetic strategy in a successful synthesis of 3beta-{[3beta-({3beta-[(3beta-hydroxyandrost-5-ene-17beta-carbonyl)oxy]androst-5-ene-17beta-carbonyl}oxy)androst-5-ene-17beta-carbonyl]oxy}androst-5-ene-17beta-carboxylic acid. The main problems with deprotection were overcome by using orthogonal groups as O-nitrates and 2-(trimethylsilyl)ethyl ethers.

Androstenes↗
PubMed2004

Chiral derivatives of 2-(1-naphthyl)-2-phenylacetic acid.

The spectral properties of diastereomeric esters and amides (1b-20b), derived from optically pure 2-(1-naphthyl)-2-phenylacetic acids (1-NPA), were systematically investigated. It was found that all compounds prepared exhibit the NMR spectral nonequivalence (Deltadelta) with regular sign distribution of particular groups according to the predicted model. Further, the analysis of data revealed that the phenyl ring is responsible for a shielding effect (upfield shift) instead of a naphthyl one. This conclusion is supported by the crystallographic analysis showing the almost ap-arrangement of the acid methine hydrogen atom and carbonyl group. In this arrangement, the phenyl ring faces toward the ester part of the molecule while the naphthyl one is orthogonal to the phenyl plane. Therefore, the mutual position of phenyl and alkyl groups with respect to the central molecule co-planarity thus determines the chemical shifts of the alcohol/amine substituents. The relative magnitude of the Deltadelta corresponds to those of Mosher's derivatives.

Journal Article↗
PubMed2004

13C and 1H nuclear magnetic resonance of methyl-substituted acetophenones and methyl benzoates: steric hindrance and inhibited conjugation.

The 1H and 13C NMR spectra of 14 methyl-substituted acetophenones and 14 methyl-substituted methyl benzoates were assigned and interpreted with respect to the conformation of the C(ar)-C(O) bond. The substituent effects are proportional in the two series and can be divided into polar and steric: each has different effects on the 13C SCS of the individual atoms. In the case of C atoms C(O), C(1) and CH3(CO), the steric effects were quantitatively separated by comparing SCS in the ortho and para positions. The steric effects are proportional for the individual C atoms and also to steric effects estimated from other physical quantities. However, they do not depend simply on the angle of torsion phi of the functional group as anticipated hitherto. A better description distinguishes two classes of compounds: sterically not hindered or slightly hindered planar molecules and strongly sterically hindered, markedly non-planar. In order to confirm this reasoning without empirical correlations, the J(C,C) coupling constants were measured for three acetophenone derivatives labeled with 13C in the acetyl methyl group. The constants confirm unambiguously the conformation of 2-methylacetophenone; their zero values are in accord with the conformation of 2,6-dimethylacetophenone. The zero values in the unsubstituted acetophenone are at variance with previous erroneous report but all J(C,C) values are in accord with calculations at the B3LYP/6-311++G(2d,2p)//B3LYP/6-311+G(d,p) level.

Acetophenones↗
PubMed2004

Synthesis of [19- 2H3]-analogs of dehydroepiandrosterone and pregnenolone and their sulfates.

Deuterated analogs of pregnenolone and pregnenolone sulfate with three atoms of deuterium in position 19 were prepared. The synthetic approach was developed on derivatives of dehydroepiandrosterone, where initial intermediates were well characterized, and then applied to the pregnenolone series. Starting 19-hydroxy compounds were transformed into 3alpha,5-cycloderivatives to simplify the Jones oxidation into the corresponding 19-oic acids. After oxidation, rearrangement to 3-hydroxy-5-enes, and suitable protection, two deuterium atoms were introduced by lithium aluminum deuteride reduction. Mesylate exchange by iodide in the presence of zinc and deuterium oxide added third deuterium atom. Deprotection gave title analogs with about 93-95% content of d3-derivative, the rest was mainly not fully deuterated d2-analogue as followed from the mass spectra analysis. Thus, 3beta-hydroxy[19-2H3]androst-5-en-17-one was prepared in 14 steps from 19-hydroxy-17-oxoandrost-5-en-3beta-yl acetate in 8.9% yield, the analogous sequence in the pregnenolone series gave 3beta-hydroxy[19-2H3]pregn-5-en-20-one in 7.3% yield. Corresponding sulfates were prepared via pyridinium salts in 53 and 57% yields, respectively. Fully assigned NMR data of selected pregnenolone derivatives were given.

Androstanes↗
PubMed2004

Synthesis of 3-methyl-3-hydroxy-6-oxo-androstane derivatives.

3alpha,17beta-Dihydroxy-3beta-methyl-5alpha-androstan-6-one (1) and 3beta,17beta-dihydroxy-3alpha-methyl-5alpha-androstan-6-one (13) were prepared by the reaction of methylmagnesium bromide with the 3-ketosteroids. Structures and configurations in position 3 were determined by NMR spectra. Substitution in the position 6 influences the ratio of the products.

Androstane-3,17-diol↗
PubMed2003

Utilization of nosylepimines of 1,6-anhydro-beta-D-hexopyranoses for the preparation of halogenated aminosaccharides.

The aziridine ring cleavage of N-nosylepimines 3 and 7 having D-allo and D-manno configurations with halides led regioselectively to N-o-nitrobenzenesulfonylated 2-halo-3-amino- and 3-halo-2-amino-2,3-dideoxy derivatives of 1,6-anhydro-beta-D-glucopyranose 8-14 in 59-81% yields. Removal of o-nitrobenzenesulfonyl protecting group with benzenethiol afforded aminosaccharides, which were converted into more stable hydrochlorides 15-18.

Amino Sugars↗
PubMed2003

(S)-2-chloro-2-fluoroethanoyl isocyanate, a chiral derivative of trichloroacetyl isocyanate.

Carbamate diastereomers 3b-18b were prepared from easily accessible (S)-2-chloro-2-fluoroethanoyl isocyanate (1) and various secondary chiral alcohols. Compound 1 as a chiral analog of trichloroacetyl isocyanate undergoes the reaction with alcohols very fast, thus blocking the hydroxyl group for the purposes of NMR investigation. Moreover, the correlation of stereochemistry of 3b-18b with their (1)H NMR spectra revealed that the constitution as well as configuration influences regularly the values of chemical shift difference (deltadelta = delta(R) - delta(S)) except for those diastereomers bearing simple alkyl groups in the molecule. Spectral as well as crystallographic data manifest the predominant planar conformation of the central part of the molecule. Due to the good accessibility and high reactivity in particular, the acylisocyanate 1 might be considered, to some extent, an alternative for TAI giving additional information on a compound's spatial structure.

Journal Article↗
PubMed2002

Analogues of androgen hormones with inverted configuration at carbons 5, 9, and 10.

On catalytic hydrogenation of Delta(9)-steroids (e.g. 3beta-hydroxy-5-methyl-19-nor-5beta-androst-9-en-17-one), four isomers were formed: 9alpha,10alpha-, 9alpha,10beta-, 9beta,10alpha- and 9beta,10beta-adducts. The product distribution was affected by the nature of the C-3 substituent. A chair conformation of A, B, and C rings was found in all of the products with the exception of the 9alpha,10alpha-adduct whose B ring adopts a twist boat conformation. The products were utilized for the synthesis of dihydrotestosterone analogues.

Androgens↗
PubMed2002

Photochemical transformation of 20-hydroxyecdysone: production of monomeric and dimeric ecdysteroid analogues.

Structural modification of 20-hydroxyecdysone (20E) based on photochemical transformation yielded dimeric ecdysteroid 7alphaH,7'alphaH-bis-[(20R,22R)-2beta,3beta,20,22,25-pentahydroxy-5beta-cholest-8(14)-en-6-one-7-yl] as a main product. Its structure was determined by detailed NMR analysis. Furthermore, two new monomeric analogues: 14-epi-20-hydroxyecdysone and 14-deoxy-14,18-cyclo-20-hydroxyecdysone were identified in addition to the earlier described 14-deoxy and 14-hydroperoxy derivatives of 20E. Formation of the specific and so far unique ecdysteroid dimer has not been observed in earlier photo-transformation studies. The transformed dimeric analogue of 20-hydroxyecdysone retained the high agonistic activity on the ecdysone receptor in the B(II)-bioassay compared with the original 20E.

Animals↗
PubMed1999

Conformation and Steric Effects in Mono- and Dimethoxybenzoic Acids.

The conformation of mono- and dimethoxybenzoic acids in solution was determined from their IR spectra and (13)C and (1)H NMR spectra. The main feature is a strong intramolecular hydrogen bond in all 2-methoxy derivatives that persists even in polar aprotic solvents but not in methanol. The methyl groups are mostly coplanar with the ring plane, the two planar conformations are almost equally abundant, and their conformation is not responsible for some enhanced values of the enthalpy of formation. The hydrogen bond (and possibly dimerization) is the reason for differences in the relative acidities (deltapK = pK - pK(H)) measured either in dimethyl sulfoxide or in methanol and also for the differences between deltapK values of methoxybenzoic acids and corresponding methylbenzoic acids. Nevertheless, it was possible to separate with good approximation the polar and steric effects on the acidity. The steric effects in methanol are then parallel for methyl- and methoxybenzoic acids despite variable conformation of the latter. Steric effects in dimethyl sulfoxide are smaller and less regular. The acidity enhancement by ortho substituents is better described as electrostatic induction in the anion rather than a steric hindrance.

Journal Article↗
PubMedDate not supplied

Oligomerization aiming at phosphonate analogues of oligoadenylates.

This work deals with isopolar, phosphonate-based nucleotide analogues containing a bridging P-C bond instead of the ester P-O linkage. Specifically, starting from activated derivatives 1, 2, and 3, a simple process for preparation of mixtures of short oligomers and their analyses were elaborated.

Adenine Nucleotides↗