Conformation and structure of 2-amino-8-(beta-D-ribofuranosyl)imidazo [1,2-a]-s-triazin-4-one(5-aza-7-deaza guanosine), a potent antiviral nucleoside.

The crystal and molecular structure of one imidazo[1,2-a]-s-triazine nucleoside and its antiviral activity are described. The crystal structure of 2-amino-8-(beta-D-ribofuranosyl)imidazo[1,2-a]-s-triazin-4-one monohydroate (C10H13N5O5.H2O) was solved by X-ray counter data. The compound crystallizes in the monoclinic space group P21 with cell dimensions a = 7.353 (1), b = 6.465 (1), c = 13.701 (1) A, B = 104.64 (1) degrees. The structure was solved by direct methods and refined by full matrix least-squares technique to a final value of the conventional R-factor of 0.049 using 1998 observed intensities. The orientation of the base relative to the sugar ring defined in terms of rotating about the C(1')-N(8) glycosyl bond is anti (47.8 degrees). The ribose moiety exhibits C(2')-endo, E conformation. The conformation around C(4')-C(5') is gauche-. Molecular packing is dominated by hydrogen bonds. Base stacking occurs long the b axis. 5-Aza-7-deazaguanosine has shown a marked antiviral activity in vitro against herpes simplex virus despite the fact that N(3) is effective as the hydrogen acceptor only.

Calix

Chiral calix[4]arene derivatives with four O-(N-acetyl-PhgOMe), (1), (Phg denotes R-phenylglycine), or O-(N-acetyl-LeuOMe) (2) strands have been synthesised. Both compounds exist in chloroform in stable cone conformations with a noncovalently organised cavity at the lower rim that is formed by circular interstrand amidic hydrogen bonds. Such organisation affects both the selectivity and extraction/transport properties of 1 and 2 toward metal cations. Calix[4]arene derivatives with one OCH2COPhgOMe strand (3), two OCH2COPhgOMe strands (5) and with 1,3-OMe-2,4-(O-CH2COPhgOMe) substituents (4) at the lower rim have also been prepared. For 3, a conformation stabilised by a circular hydrogen-bond arrangement is found in chloroform, while 4 exists as a time-averaged C2 conformation with two intramolecular NH ...OCH3 hydrogen bonds. Compound 5 has a unique hydrogen-bonding motif in solution and in the solid state with two three-centred NH-.. O and two OH...O hydrogen bonds at the lower rim. This motif keeps 5 in the flattened cone conformation in chloroform. The X-ray structure analysis of 1 revealed a molecular structure with C2 symmetry; this structure is organised in infinite chains by intra- and intermolecular H bonds. The solid-state and solution structures of the [1-Na]ClO4 complex are identical, C4 symmetric cone conformations.

Synthesis and conformational analysis of muramic acid delta-lactam structures and their 4-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl) derivatives, characteristic of bacterial spore peptidoglycan.

1,6-Anhydro-4-O-benzyl-beta-muramic acid 1',2-lactam (2) was prepared by reduction of 1,6-anhydro-2-azido-4-O-benzyl-2-deoxy-3-O-[(R)-1- methoxycarbonylethyl]-beta-D-glucopyranose (1) followed by cyclisation. Debenzylation of 2 (-->3) and glycosylation of HO-4 with 3,4,6-tri-O-acetyl-2- deoxy-2-phthalimido-beta-D-glucopyranosyl chloride afforded 75% of a beta-(1-->4)-linked disaccharide derivative (7). Removal of the Phth group from 7, then acetylation, and O-deacetylation yielded 4-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-2-amino-1,6-anhydro-3-O- [(R)- 1-carboxyethyl]-2-deoxy-beta-D-glucopyranose 1',2-lactam (10) Acetolysis of the 1,6-anhydro ring in the 4-acetate (4) of 3 and the 3',4',6'-triacetate (9) of 10, with saponification of the products 5 and 11, afforded 2-amino-3-O- [(R)-1-carboxyethyl]-2-deoxy-D-glucopyranose 1',2-lactam (6) and 4-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-2-amino-3- O-[(R)-1-carboxyethyl]-2-deoxy-beta-D-glucopyranose 1',2-lactam (12), respectively. The structure of 12 corresponds to that of the disaccharide unit characteristic of the glycan chains of bacterial spore peptidoglycan. 1H NMR spectroscopy indicated that the beta-D-glucopyranose ring in the 1,6-anhydro 1',2-lactam derivatives adopts the BO,3 conformation. On cleavage of the 1,6-anhydro ring by acetolysis, the D-glucopyranose ring adopts the 4C1 conformation. X-ray analysis of 2, 4, and 5 confirmed the proposed structures. Molecular mechanics and molecular dynamics simulations were used to follow the transformation of the BO,3 conformation of the D-glucopyranose ring via transition states to the 4C1 form.

New oleandomycin 9-oximes. Synthesis, characterization and biological activity.

A series of the novel oleandomycin 9-oximes has been prepared and characterized by spectroscopic data and X-ray analysis. The antibacterial in vitro activities of the oximes (6-10) were compared with that of oleandomycin (1). Among the novel derivatives the most active compound was 8(R)-methyloleandomycin-9-oxime (9) in contrast ot its 8(S)-isomer (10) which possessed only low potency. Some preliminary pharmacokinetic data of 9 confirmed its activity. Compound 9 has been advanced to further biological study.

Crystal and molecular structures of diazapyrenes and a study of pi\cdotspi interactions.

Two diazapyrenes, 5,10-dimethyl-4,9-diazapyrene (1) and novel 2,7-dimethyl-4,9-diazapyrene (2) have been synthesized. Their crystal structures are reported here and are the first representatives of diazapyrenes. Crystal data: (1) monoclinic, P2(1)/c, a = 4.0246 (5), b = 15.5147 (5), c = 9.1453 (9) Å, beta = 101.23 (1) degrees, V = 560.1 (1) Å(3), Z = 2, R = 0.043; (2) monoclinic, C2/m, a = 12.4968 (3), b = 11.4751 (4), c = 3.9615 (5) Å, beta = 96.80 (1) degrees, V = 564.09 (5) Å(3), Z = 2, R = 0.0405. The experimental bond lengths are compared with those calculated by molecular mechanics (MM3), semi-empirical methods (MOPAC6.0-PM3, AM1, MNDO) and values predicted by valence-bond and variable-electronegativity self-consistent field (VESCF) methods. pi.pi interactions in (1), (2) and seventeen other pyrene and pyrene-like molecules selected from the Cambridge Structural Database [Allen & Kennard (1993). Chem. Des. Autom. News, 8, 131-137] have been studied. The following quantitative parameters of pi.pi interactions have been calculated: the shortest crystallographic axis, the offset parameter, the interplanar angle, the interactive volume and the overlapping surfaces. They are used for the classification of crystal-packing motifs; a high predominance of beta and a few cases of gamma and sandwich-herringbone types are observed. In addition, electronegativity, the sum of partial atomic charges of the ring non-H atoms and the number of aromatic skeleton electrons are used as parameters for classification. MOPAC-PM3 was used to calculate the partial atomic charges in (1), (2) and pyrene analogues. Correlations between geometrical and electronic structure parameters reveal an analogy between the beta-type structures and the crystal structure of graphite.

Structure and molecular modelling of protected dipeptide fragment (Boc-Phe-Leu-OBzl) of enkephalin.

The conformational characteristics of a flexible totally protected C-terminal dipeptide fragment (Boc-Phe-Leu-OBzl) of enkephalin are studied using X-ray data, molecular modelling and data retrieved from the Cambridge Structural Database. The dipeptide crystallizes with seven conformers in the asymmetric unit. C(27)H(36)N(2)O(5), T = 133 K, monoclinic, P2(1), a = 13.706 (3), b = 22.800 (3), c = 30.674 (5) Å, beta = 97.15 (3) degrees, V = 9511 (3) Å(3), Z = 14, D(c) = 1.145 Mg m(-3). Six of the seven molecules exhibit folded conformations with hydrophobic groups disposed at the opposite side of the peptide backbone. The characteristic Phi(1) and Psi(1) angles of the Phe residue and Phi(2) of the Leu fragment are in the allowed region defined in the Ramachandran diagram. However, they do not belong to the family of the lowest energy conformations. In the crystal, molecules are interconnected via N-H.O hydrogen bonds of peptide groups forming an infinite sheet similar to a parallel beta-sheet. Molecular dynamics simulations performed in vacuo reproduce the conformers and rotamers detected in the solid state.

Spectroscopic evidence of beta-turn in N-glycated peptidomimetics related to leucine-enkephalin.

The conformational differences caused by N-glycation of the amide bond in endogenous opioid pentapeptide leucine-enkephalin (Tyr-Gly-Gly-Phe-Leu) have been explored in solution using FTIR spectroscopy, NMR and molecular modelling. The compounds studied include protected and unprotected enkephalin analogues N-alkylated at the second (Gly2) amino acid residue with a 6-deoxy-D-galactose moiety (1-3). Comparison of the amide I component bands in the FTIR spectra, measured in trifluoroethanol (TFE), CHCl3 and DMSO, revealed significant differences in the intensity as well as shifts in component band frequencies for glycopeptides 1-3. We found that only the FTIR spectrum of the fully protected compound 1 indicated the presence of a higher population of beta-turns, while the spectra of the partially protected and unprotected glycopeptides 2 and 3 reflected the dominance of unordered or open structures, with some low population of turns. The observed NOE connectivities in CDCl3 for both isomers of the fully protected compound 1, the all-trans one and another with Tyr1-Gly2 peptide bond in cis conformation, indicate the presence of a beta-like turn conformation. Molecular dynamics simulations of the glycopeptide 1 obtained by unconstrained energy minimization of trans- and cis-1 shows that one of trans form conformations is consistent with beta-turn whereas cis isomer has revealed less-compact turn.

1H-Pyrrolo[2,3-b]pyridine-3-acetic acid as a molecular probe for use in auxin physiology.

The structural characterization of 1H-pyrrolo[2, 3-b]pyridine-3-acetic acid (alternative name: 7-azaindole-3-acetic acid), C(9)H(8)N(2)O(2), reveals similar molecular geometry, i.e. with the side chain perpendicular to the 7-azaindole ring, to that of the natural plant growth hormone indole-3-acetic acid (auxin) and its alkylated and halogenated derivatives.

Benzdiamidine.

The molecule of benzene-1,4-dicarboxamidine or benzdiamidine, C(8)H(10)N(4), reveals C(i) symmetry. Hydrogen bonds utilize the amino groups as double donors, whereas the imino groups act as double acceptors. The network formed is similar to that observed in the crystal packing of terephthalamide.

Correlation of structural and physico-chemical parameters with the bioactivity of alkylated derivatives of indole-3-acetic acid, a phytohormone (auxin).

As part of molecular recognition studies on the phytohormone indole-3-acetic acid (IAA) a series of alkylated IAAs has been examined. Phenyl-ring substitution (alkyl = methyl and ethyl) at positions 4-, 6- or 7- as well as pyrrole substitution at the 2-site resulted in the six compounds which are analyzed: 2-Me-IAA, 4-Me-IAA, 6-Me-IAA, 7-Me-IAA, 4-Et-IAA and 6-Et-IAA. The structure-activity relationships investigated include those between the geometrical parameters of the molecular structures determined by X-ray analysis, the growth-promoting activities in the Avena coleoptile straight-growth bioassay and relative lipophilicities calculated from retention times on a reversed-phase HPLC column and from R(F) values in reversed-phase TLC. Lipophilicities are correlated with the moments of inertia, average polarizability, molecular mass, and the van der Waals radii of the ring substituents. The influence of substitution on the electronic properties of the indole ring and its geometry is discussed on the basis of the UV and 1H NMR spectra.

meso-N,N'-oxalyldivaline.

The title compound, 2,2'-(oxalyldiimino)bis(3-methylbutanoic acid), C12H20N2O6, possesses a centre of symmetry. In the crystal, molecules are connected by hydrogen bonds between oxamide and carboxyl groups, similar to the pattern of the monoclinic forms of HO-Gly-CO-CO-Gly-OH and HO-Aib-CO-CO-Aib-OH (Gly is glycine and Aib is 2-aminoisobutyric acid). The characteristic torsion angles in the title compound are close to those in peptide alpha-helices.

Classification of auxin plant hormones by interaction property similarity indices.

Although auxins were the first type of plant hormone to be identified, little is known about the molecular mechanism of this important class of plant hormones. We present a classification of a set of about 50 compounds with measured auxin activities, according to their interaction properties. Four classes of compounds were defined: strongly active, weakly active with weak antiauxin behaviour, inactive and inhibitory. All compounds were modeled in two low-energy conformations, 'P' and 'T', so as to obtain the best match to the 'planar' and 'tilted' conformations, respectively, of indole 3-acetic acid. Each set of conformers was superimposed separately using several different alignment schemes. Molecular interaction energy fields were computed for each molecule with five different chemical probes and then compared by computing similarity indices. Similarity analysis showed that the classes are on average distinguishable, with better differentiation achieved for the T conformers than the P conformers. This indicates that the T conformation might be the active one. Further, a screening was developed which could distinguish compounds with auxin activity from inactive compounds and most antiauxins using the T conformers. The classifications rationalize ambiguities in activity data found in the literature and should be of value in predicting the activities of new plant growth substances and herbicides.

Intermolecular contacts in the crystal packing of 2,2'-(N,N'-oxalyldiimino)bis(3-phenylpropanamide) dimethyl sulfoxide solvate.

In the title compound, C20H22N4O4*C2H6OS, two distinct hydrogen-bond systems connect oxalamide groups in one pattern and primary amide groups in the other to form a two-dimensional network perpendicular to the c axis. These hydrophilic layers are joined to the three-dimensional structure through C--H...pi interactions. The hydrogen-bonded waved layers shape holes which are occupied by disordered dimethyl sulfoxide solvent molecules.

Bis(amino acid) oxalyl amides as ambidextrous gelators of water and organic solvents: supramolecular gels with temperature dependent assembly/dissolution equilibrium.

Bis(LeuOH) (1a), bis-(ValOH) (2a) and bis(PhgOH) (5a) (Phg denotes (R)-phenylglycine) oxalyl amides are efficient low molecular weight organic gelators of various organic solvents and their mixtures as well as water, water/DMSO, and water/DMF mixtures. The organisational motifs in aqueous gels are dominated primarily by lipophilic interactions while those in organic solvents are formed by intermolecular hydrogen bonding. Most of the gels are thermoreversible and stable for many months. However, 2a forms unstable gels with organic solvents which upon ageing transform into variety of crystalline shapes. For some 1a/alcohol gels, a linear correlation between alcohol dielectric constants (epsilon) and gel melting temperatures (Tg) was found. The 1H NMR and FTIR spectroscopic investigations of selected gels reveal the existence of temperature dependent network assembly/dissolution equilibrium. In the 1H NMR spectra of gels only the molecules dissolved in entrapped solvent could be observed. By using an internal standard, the concentration of dissolved gelator molecules could be determined. In FTIR spectra, the bands corresponding to network assembled and dissolved gelator molecules are simultaneously present. This enabled determination of the Kgel values by using both methods. From the plots of InKgel versus 1/T, the deltaHgel values of selected gels have been determined (-deltaHgel in 10-36 kJ mol(-1) range) and found to be strongly solvent dependent. The deltaHgel values determined by 1H NMR and FTIR spectroscopy are in excellent agreement. Crystal structures of 2a and rac-5a show the presence of organisational motifs and intermolecular interactions in agreement with those in gel fibres elucidated by spectroscopic methods.

Physicochemical Properties of Dodecylammonium Picrate.

A novel surfactant, dodecylammonium picrate (DDAP), was synthesized and its crystal structure was determined by X-ray diffraction analysis. DDAP's physicochemical properties were examined by spectral (infrared and nuclear magnetic resonance), thermal, microscopic, and conductometric studies. The results revealed the influence of counterion specificity on thermal solid-state transitions and solution properties: the Krafft point, the aqueous solubility, the critical micelle concentration, the degree of counterion binding, and thermodynamic parameters of micellization. Copyright 2000 Academic Press.

Complex of Burkholderia cepacia lipase with transition state analogue of 1-phenoxy-2-acetoxybutane: biocatalytic, structural and modelling study.

In a series of four racemic phenoxyalkyl-alkyl carbinols, 1-phenoxy-2-hydroxybutane (1) is enantioselectively acetylated by Burkholderia cepacia (formerly Pseudomonas cepacia) lipase with an E value > or = 200, whereas for the other three racemates E was found to be < or = 4. To explain the high preference of B. cepacia lipase for (R)-(+)-1, a precursor of its transition state analogue with a tetrahedral P-atom, (R(P),S(P))-O-(2R)-(1-phenoxybut-2-yl)methylphosphonic acid chloride was prepared and crystallized in complex with B. cepacia lipase. The X-ray structure of the complex was determined, allowing to compare the conformation of the inhibitor with results of molecular modelling.