Dreiding Model Research Articles

Systematic naming system for Actaea triterpenes and the demand for dreiding models

The genus Actaea, recently expanded to include the now obsolete genera Cimicifuga and Souliea, has been the source of ˜200 structurally defined triterpenes (TTs). Except for a few ubiquitous TTs, all are endemic to Actaea and derivatives of the simple cycloartanol, 1. Despite this one common denominator, the TTs comprise chemically diverse substructures, formed by oxidation, ring closure and ring cleavage. Extracts of many Actaea species are ethno-medicinal and CAM products. During their discovery, the TTs were given a wide variety of names, derived haphazardly from names of the species, the traditional medicine, or occasionally from a previously described structure. Often, there is little or no chemical logic to these names. We have developed a systematic naming system based on “actanol” for 1, with all modifications following standard chemical nomenclature. The standard α and β TT stereo designation breaks down in several substructural types with spiro ring systems, and the Cahn-Ingold-Prelog system is used exclusively for defining the skeleton. In the more complex structures, this created a demand for stereo models, and the inability to purchase our favored Dreiding models, led us to establish the Dreiding Model Exchange (http://tigger.uic.edu/˜gfp/dreiding/dreidingexchange.htm), which currently has over 3,000 pieces and is currently actively buying and selling these models.

Phenylpropanoid substituted flavan-3-ols from Trichilia catigua and their in vitro antioxidative activity

The new phenylpropanoid substituted flavan-3-ol apocynin E, together with eight known compounds, epicatechin, procyanidin B2, procyanidin B4, procyanidin C1, cinchonain Ia, cinchonain Ib, cinchonain IIb, and cinchonain IIa were isolated from an acetone-H2O extract of the air-dried stem bark of Trichilia catigua. The cinchonain Ia e Ib were reevaluated to its estereochemistry. All the compounds were characterized by spectroscopic analysis including 1D and 2D nuclear magnetic resonance (NMR) and mass spectrometry (MS) of their peracetate derivatives. The absolute configuration of the phenylpropanoid moiety was determined by circular dichroism (CD) spectra and by analyzing the anisotropic effects in the Dreiding model and nuclear Overhauser effect (NOESY NMR) experiments. The nine isolated compounds showed higher radical scavenging activity and reducing power than ascorbic acid and Trolox in the free-radical 2,2-diphenyl-1-picrylhydrazyl and Fe3+-Fe2+ reduction assay systems.

Magnetizable molecular model (MMM)—behaviour of enantiomers in magnetic fields

The importance of chiral drugs is gradually increasing. Modelling is an essential tool in the research of their biological activities. The Dreiding model is a flexible tool among numerous traditional modelling methods. Our endeavours were aimed at simulating molecular behaviours under magnetic conditions, which was, however, not practicable with available molecular models. Our magnetizable molecular model (MMM) is based on elements of small strips of steel, glued to each other at their planar binding sites. Each set represents one rotation isomer, thus physical properties can be studied in a well defined configuration. Some MMMs of hydrocarbon including aromatic compounds have been presented. The antinomic bond-line representation of the Kekulé structure of benzene, as well as naphthalene, can be replaced by formulas where all aromatic carbon–carbon bonds are identical. In magnetic experiments, a few enantiomer pairs were suspended by a delicate thread attached to their chiral carbon atoms. Upon the effect of magnetic bars placed in front of each model, the enantiomers automatically turned into a mirror image position. These results may open a novel approach in stereochemistry.

Editorial: The Woodward‐Hoffmann Rules …︁

…︁ were recognized as ground-breaking immediately upon their formulation, and “many chemists' eyes were opened when they read the original publication by Woodward and Hoffmann in 1965 and the legendary Review in Angewandte Chemie in 1969”. These are the opinions of contemporary witnesses whom we asked for advice as to whether Angewandte Chemie should publish an article by Roald Hoffmann in which he responds to E. J. Corey's claim to have given R. B. Woodward the incentive to develop what quickly became known as the Woodward–Hoffmann rules. In his acceptance speech during the award ceremony for the Priestley Medal, the highest accolade awarded by the American Chemical Society, in Spring 2004, E. J. Corey stated that: “On May 4, 1964, I suggested to my colleague R. B. Woodward a simple explanation involving the symmetry of the perturbed (HOMO) molecular orbitals for the stereoselective cyclobutene /1,3-butadiene and 1,3,5-hexatriene/cyclohexadiene conversions that provided the basis for the further development of these ideas into what became known as the Woodward-Hoffmann rules.” (published in Chem. Eng. News 2004, 82(13), 42–44). The audience/readership was astounded: Were the Woodward–Hoffmann rules not formulated by Woodward and Hoffmann after all? Should they rather be called the Corey–Woodward–Hoffmann rules? It was well known that Havinga, Schlatmann, and especially Oosterhoff had set some very important precedents (see: J. Berson, Chemical Creativity, Wiley-VCH, Weinheim, 1999, pp. 26–31). However, Corey's name had never before been mentioned in this context. As R. B. Woodward (Figure 1) died in 1979 at the age of 62, he can no longer say whether the conversation with Corey on May 4, 1964, enlightened him, gave him a decisive impetus, or merely confirmed his already well-thought-out ideas. R. B. Woodward with a Dreiding model of cobyric acid. Copyright: Harvard University Archives. It is most fortunate for the history of science in general and for chemistry in particular that—triggered by E. J. Corey's statement—Roald Hoffmann has penned his memories of that time. Entitled “A Claim on the Development of the Frontier Orbital Explanation of Electrocyclic Reactions”, his recollections of the early days of the development of the Woodward–Hoffmann rules and the time leading up to their publication can be read on page 6586 ff. It is unfortunate, but to be respected, that E. J. Corey, whom we of course asked to respond, chose not to say any more on the subject other than reiterating: “I am sure that the statement I made in my Priestley presentation is absolutely true, and at a later time I will present the full story.” For readers who practiced and shaped chemistry in the 1960s and 1970s, Roald Hoffmann's contribution makes compelling reading. For all readers, the article is an opportunity to ponder how new theories develop and how important communication is: both personal, in the form of conversations and correspondence, and formal, from presentations to publications. And how easily the sender and receiver can interpret the same information in a completely different manner. Angewandte Chemie is a suitable forum for this contribution: The above-mentioned Review (Angew. Chem. 1969, 81, 797–869; Angew. Chem. Int. Ed. Engl. 1969, 8, 781–853), in which the detailed Woodward–Hoffmann rules were lucidly presented, was published in this journal (see Figure 2). This Review is certainly one of the most-cited publications of Angewandte Chemie and, since the launch of the electronic Backfiles, has been one of the most-often downloaded files. Furthermore, the publication of a Correspondence article in a scientific journal has a more lasting character than in a magazine. May it now and in future find many readers and spur them on to reflect carefully on their own behavior. First page of the legendary Review by R. B. Woodward and R. Hoffmann in Angewandte Chemie. Dr. Peter Gölitz Editor P.S. Another recommended read in this issue is the Essay by Amir Hoveyda, who delves into Primo Levi's literary masterpiece, The Periodic Table (page 6592 ff.).

Structures of New and Known Cyanoglucosides from a North American Plant, Purshia tridentata DC.

A new cyanoglucoside, purshianin (1), was isolated together with a known cyanoglucoside, menisdaurin (2a), from stems of Purshia tridentata DC. (Rosaceae) collected in Oregon, U.S.A. and the structure was established as (4S, 6S)-(Z)-6-(β-D-glucopyranosyloxy)-4-hydroxy-2-cyclohexene-Δ1, α-acetonitrile (1) based on chemical and spectral evidence. Notably, the absolute structure of 1 and the revised stereostructure (2), (4S, 6R)-(Z)-6-(β-D-glucopyranosyloxy)-4-hydroxy-2-cyclohexene-Δ1, α-acetonitrile for menisdaurin were decided based on combined studies of difference NOE spectra and Dreiding model inspection.

Conformational Features of Penicillin G in Solution as Revealed by13C-{1H} Selective Nuclear Overhauser Effects

Abstract 13C-{1H} nuclear Overhauser effects (n.O.e.) were measured for penicillin G in I 2H6 I-DMSO upon selective presaturation of proton resonances and interpreted on the basis of effective correlation times as calculated by analysis of 13C and 1H spin-lattice relaxation rates. Preferential occurrence of a compact C2 puckered conformation with folding of the benzoylamino side chain towards the methyl at C2 was given evidence. A Dreiding model of such conformation was built.

Nuclear Magnetic Resonance Investigations of Calcium Antagonist Drugs. II: Conformational and Dynamic Features of Verapamil in l2H6lDMSO

Conformational features of verapamil in i2H„lDMSO have been delineated by measuring 13C and 1H NMR parameters. Spin–lattice relaxation rates were interpreted within the frame of an extended alkane chain with segmental motions hampered by the aromatic substituents at both ends. The effective correlation times were all evaluated in the range 0.16-0.22 ns at 293 K. The aromatic rings were found to lie somewhat out-of-plane with the alkane chain. The NMR data were used to construct a Dreiding model of the most probable spatial arrangement and a molecular modeling system was utilized to represent the "preferred" conformation of verapamil in solution.

1H and13C NMR relaxation investigation of the calcium complex of β-alanyl-L-histidine (carnosine) in aqueous solution

13 C and 1H NMR chemical shifts, J couplings, and spin–lattice relaxation rates were measured for carnosine in aqueous solution at pH 7.0. A Dreiding model of the ‘most-probable’ conformation was built up, showing predominance of the g– rotamer and folding of the β-alanyl moiety towards the imidazole ring. The structural and dynamic picture was shown not to be severely changed by stepwise titration with CaII ions. Exchange of carnosine among the bulk solution, a monomer complex (Ca2+ liganded by carboxy and carbonyl oxygens) and a dimer complex (Ca2+ liganded also by imidazole nitrogen) was suggested. The formation constant was evaluated at ca. 25 dm3mol–1. A Dreiding model of the dimeric complex was also built up on the basis of measured cross-relaxation terms of proton pairs, showing occurrence of intermolecular interactions between peptide molecules mediated by CaII ions.

Cyclo(D‐Pro‐L‐Pro‐D‐Pro‐L‐Pro): Structural properties and cis/trans isomerization of the cyclotetrapeptide backbone

AbstractCombinations of L‐ and D‐proline residues are useful compounds for finding new structures and properties of cyclic peptides. This is demonstrated with one striking example, the cyclic tetrapeptide c(D‐Pro‐L‐Pro‐D‐Pro‐L‐Pro). For this molecule composed of strictly alternating D‐ and L‐configurated residues, a highly symmetrical structure is expected, which should be an optically inactive meso‐form. Cyclization of the enantiomeric pure linear precursor D‐Pro‐L‐Pro‐D‐Pro‐L‐Pro, however, yields a racemic mixture of two enantiomeric cyclotetrapeptides, both with twofold symmetry and a cis–trans–cis–trans sequence of the peptide bonds. Remarkably, this formation of a racemate was not caused by racemization, but by cis/trans isomerization of all peptide bonds in the ring. This process may occur in the linear precursor during the ring formation (cyclization of conformers with trans–cis–trans or cis–trans–cis arrangement of the amide bonds) as well as in the enantiomeric pure cyclic tetrapeptide at higher temperature. In the latter case, an all‐cis structure should exist as the intermediate, which can form a cis–trans–cis–trans sequence in two equivalent ways, leading finally to two enantiomeric cyclotetrapeptides. In the first one, the cis peptide bonds are attributed to the L‐residues and the trans peptide bonds to the D‐residues; in the second one, the cis bonds belong to the D and the trans bonds to the L‐residues. The mixture of these two enantiomers does not crystallize in the racemic form, but in enantiomeric pure separate crystals. The structural properties could be proved by 1H‐ and 13C‐nmr spectroscopy and x‐ray analysis. The cis/trans isomerization process was confirmed by optical rotation measurements and CD spectroscopy, as well as DREIDING model studies. Calorimetric measurements in the solid state suggest the existence of the expected all‐cis intermediate. The backbone conformation of the 12‐membered medium‐sized ring shows only slight deviations—up to 6° —from the planarity of the peptide bonds. On the other hand, the four pyrrolidine rings show different types of puckering of the Cγ or the Cβ atoms.

Conformational dynamics of cytochalasin B in solution as detected by 13C and 1H NMR relaxation rates.

13C and 1H NMR spin-lattice relaxation rates have been measured for cytochalasin B in [2H]6DMSO. Motional features have been interpreted in terms of nearly isotropic reorientation of the whole molecule with few additional internal motions. The 'isotropic' reorientational correlation time was evaluated at 0.21 ns at room temperature. By using selective and double-selective excitation techniques, relevant cross-relaxation terms have been obtained wherefrom proton-proton distances have been calculated. A Dreiding model of the 'preferred' conformation in solution has been built, yielding evidence of a strong similarity between solution and solid state structures of cytochalasin B.

1H and 13C NMR conformational analysis in solution of isoproterenol a pure β‐agonist drug

Abstract13C and 1H NMR parameters were measured for isoproterenol in solution. Spin‐lattice relaxation rates were considered and C‐H and H‐H J couplings were determined. The t rotamer was shown to occur in a much greater abundance than the two g rotamers. Dynamics in solution were interpreted in terms of a nearly isotropic motion of the α‐hydroxyphenethyl moiety and of a high degree of flexibility of the isopropyl moiety, Relevant distances and dipolar connectivities were measured and used to build up a Dreiding model of the most probable conformation.

Nuclear magnetic resonance investigations of calcium-antagonist drugs. Part 1. Conformational and dynamic features of nimodipine {3-[(2-methoxyethoxy)carbonyl]-5-(isopropoxycarbonyl)-4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine} in [2H6]dimethyl sulphoxide

Conformational and dynamic features of nimodipine in [2H6]DMSO solution were investigated by 1D and 2D n.m.r. techniques. 1H and 13C n.m.r. relaxation rates, 13C-{1H} n.O.e.s, and 2D n.O.e. proton spectra were used to build up a Dreiding model of the preferred conformation. Folding of the two side-chains in opposite directions was indicated. Complete anisotropic motion was assumed wherefrom internal reorientational times within the phenyl ring and the side-chains were evaluated. Folding of the isopropoxycarbonyl side-chain was also demonstrated by motional constraints undergone by carbon atoms within it.

Crystal and molecular structure of BN 52021, a PAF-acether antagonist. Comparison with the conformation of Kadsurenone and related compounds

BN52021 (Ginkgolide B) monohydrate C 20H 24O 10 · H 2O crystallizes in the triclinic space group P1 with two independent molecules in the unit cell of which parameters are a = 7.627(2), b = 11.514(3), c = 12.941(3)Å, α = 97.05(2), β = 90.27(2) and γ = 108.71(2)°, V = 1067.06Å 3. Calculated density D x = 1.320g.cm −3. The crystal structure was solved by Patterson methods starting from dreiding model data. The final reliability index R = 0.099 for 3848 observed reflections collected with a four-circle diffractometer. Anti-PAF activities of Kadsurenone, Kadsurin-A, Kadsurin-B and Piperenone, molecular structure of MIRANDIN-A, related compounds and BN52021 suggest that a distance O-O of about 6.6Å observed in Kadsurenone and in BN52021 could be favourable to anti-PAF activity.

Computer methods for molecular design

The computational design and simulation of the properties of proteins requires powerful computers, colour graphics and interactive software. A brief description of such a system will be presented. One of the key requirements in the design of novel proteins is the ability to construct a three-dimensional model of the target protein from a knowledge of its amino-acid sequence and the X-ray crystal structure of a homologous protein. Most of the models constructed in this fashion have used the computer as an electronic Dreiding model; where the inserted, deleted, and substituted amino acids are placed in three-dimensional space by subjective, visually oriented procedures (R. J. Read, G. D. Brayer, L. Jurasek & M. N. G. James, Biochemistry 23, 6570 (1984)). An objective computational procedure has been developed whereby the insertions, deletions, and substitutions are performed automatically by making use of a list of rules and a hierarchical energy minimization scheme. The procedure is highly interactive and all of the options are invoked by pointing to the appropriate amino acid residues displayed on the graphics screen. Applications of the procedure and the use of the finished models in enzyme-substrate docking studies for drug design are described.

ポリ（リボウリジル酸）とＭｎ｀２＋´の相互作用の核磁気緩和による研究

T1s of protons of poly(ribouridylic acid) (poly(U)) were reduced by an addition of Mn2+. This phenomenon is considered to be caused by the dipole-dipole interaction between the proton and the electron spin of Mn2+. T1 minima were obtained from the temperature dependence of T1 of the complex, and the apparent distances between Mn2+ and the protons of poly(U) wer e estimated by substituting 1.59×10-9 s of which value is estimated from the relation that τc equals ωI-1. But if Mn2+ is assumed to bind to N(3), these estimated distances are longer than those which are estimated from Mn2+-proton distances presumed from the Dreiding model by the Bloembergen equation. The reason for this result is considered that a part of Mn2+ which binds to phosphate group chelates to N(3). It was found that O.28 of Mn2+binds to N(3) from the ratio of T1 estimated from the Dreiding model to T1 observed.τc of Mn2+-poly(U) complex at each temperature was eatimated from the: ratio of T1 at each temperature to T1 minimum. The comparison of these values with the τc of poly(U), which is obtained in the absence of Mn2+, indicates that the motion of poly(U) becomes slower in the presence of Mn2+ than in the absence of Mn2+.

The “Normalizing Factor” for the Tomato Mutant chloronerva. XXIII. Deaminonicotianamine and 2‐Decarboxynicotianamine

AbstractDeaminonicotianamine (8) and 2‐decarboxynicotianamine (11) were synthesized by stepwise reductive alkylation of (S)‐2‐ethoxycarbonylazetidine (3) or azetidine (9) with ethyl (S)‐4‐oxo‐2‐(trifluoroacetylamino)butanoate (4) and ethyl 4‐ oxobutanoate (7), respectively. The amino acids 8 or 11 as well as the intermediates, (2S,αS)‐α‐amino‐2‐carboxy‐1‐azetidinebutanoic acid (6) and (S)‐α‐amino‐1‐azetidinebutanoic acid (10) did not show biological activity with regard to chlorophyll synthesis in chlorotic leaflets of the tomato mutant chloronerva. The compound 11 promoted the normally inhibited root growth of the mutant.Nicotianamine (1) has been identified as the “normalizing factor” which restores chlorophyll synthesis, growth and development of the auxotroph mutant chloronerva of Lycopersicon esculentum Mill. [2]. Nicotianamine proved to be widespread in the plant kingdom ([1], cf. [3]). Biochemical experiments revealed a disturbed iron metabolism of the mutant, leading to an excessive iron absorption by the roots on the one hand and an irregular iron distribution within young leaves on the other [4, 5]. Nicotianamine (1) forms stable 1:1 complexes with iron (II) and other bivalent metal ions [6] with high stability constants in comparison with those of bidentate amino acids; e.g. the stability constants for the 1:1 copper complexes of nicotianamine and α‐alanine are 1018.6 [6] and 108.5 [7], respectively. As is evident from a Dreiding model, nicotianamine has an optimal molecular structure for complex formation with metal ions. Not only are six functional groups present, necessary for octahedral coordination, but the distances between the groups are also optimal for the formation of chelate rings: three 5‐membered rings formed by the α‐amino acid residues and two 6‐membered rings formed by the 1,3‐diaminopropane moieties [2, 3]. In order to study whether strong complex formation is important for the biological activity of nicotianamine, a series of synthetic analogues were prepared. The antipode of nicotianamine [8] and the proline analogue [9] were biologically active, further analogues, e.g. homologues with 1,4‐diaminobutane moieties [10], peptides [11] or quadridentate ligands [2, 8, 10] proved to be inactive. The hitherto existing results indicate that a partial structure 2 (or enantiomeric) is essential for the biological activity and that nicotianamine plays an important role in the cellular iron transport and/or metabolism in plants.

Catalytic reduction of carbon dioxide at carbon electrodes modified with cobalt phthalocyanine

(1 1) There may be a question that the bad interactions depicted in 9 and 16 can be avoided by rotating the carbon so that the hydrogen is in the position of the methyl in 9 and the phenyl in 16. Inspection with a Dreiding model clearly indicates that such conformations are destabilized by the steric repulsion between the 9-BBN ring and the phenyl group in 9 and between the 9-BBN ring and the methyl group in 16. (12) (a) For addition of allylboronates to Schiff bases, see: Hoffmann, R. W.; Eichler, G.; Endesfelder, A. Liebigs Ann. Chem. 1983,2000. (b) When alkylorganometallics, such as BuCu-BF, and Bu2CuLi.BF,, were utilized, the Cram/anti-Cram selectivity was low (-4:l). This is reasonable since the six-membered cyclic transition state is not involved in this reaction. For the reaction of imines with RCuaBF,, see: Wada, M.; Sakurai, Y. ; Akiba, K . Tetrahedron Lett. 1984, 25, 1079. If (13) An oxonium salt of aldehydes may take a trans geometry (17).

Synthesis and Characterization of Imidazolate-bridged Copper(II) Complexes of Triangular Skeleton

Abstract New polynuclear copper(II) complexes of the composition [CuL(im)]X (L=N,N,N′,N′-tetramethylethylenediamine (tmen), bip, phen; X=ClO4, PF6, BF4; im= imidazolate ion) have been prepared. Cryomagnetic measurements have indicated that the complexes involve a trianglar-trinuclear skeleton and an antiferromagnetic spin-exchange interaction operates between copper(II) ions; exchange integrals being evaluated at −37–−45 cm−1.Based on the Dreiding model consideration of the complexes and the crystal structure of [Cu(tmen)(imH)2](ClO4)2, a trinuclear structure of the triangular skeleton with imidazolate bridges, (Remark: Graphics omitted.), was supposed for the complexes.

Studies on the structure-activity relationships of adrenergic beta-mimetic benzylamine derivatives. V. 9-Aryl-1H-2,3,7,8,9,10-hexahydrobenzo[d,e]quinolines.

The synthesis and adrenergic β-mimetic activities of stereoisomeric 9-aryl-5, 6-dihydroxy-1 H-2, 3, 7, 8, 9, 10-hexahydrobenzo [d, e] quinolines (5), which should be regarded as constrained analogs of the benzylamine (2), the tetrahydronaphthalenes (3) and trimetoquinol (TMQ, 1), are presented. Structure-activity relationships of these compounds were explained in terms of various spatial orientations of the functional groups in these molecules suggested by inspection of Dreiding model. The conformations of 3b-trans and 5b-trans, both of which are potent tracheal relaxants, are the type A orientation of the functional groups where the catechol and trimethoxyphenyl groups are approximately anti to each other. 5b-cis which can not hold the type A orientation was only 1/130 as active as 5b-trans. The spatial orientation of the functional groups in TMQ in the crystalline state was found to be the type A. These results may suggest that the conformation of TMQ required for manifesting its β2-stimulating activity in the biophase is probably similar to that in the crystalline state. Contrary to the previous finding that 2 and 3b-trans were active in both β2 and β1 adrenoceptors, 5b-trans was found to possess high selectivity for β2-adrenoceptors.

Aminoethylation. III. Stereochemical configuration of 2-oxo-3-ethoxycarbonyl-trans-octahydroindole.

The configuration of C3-methyl group in each isomer of 2-oxo-3-methyl-trans-octahydroindole (VIIa and VIIb) was determined by the evidence of their NMR spectra and the conformational analyses using Dreiding model. Accordingly, the C3-ethoxycarbonyl group in 2-oxo-3-ethoxycarbonyl-trans-octahydroindole (I), which was obtained by the reaction of meso-cis-cyclohexenimine and diethyl malonate, was proved to have cis-configuration in relation to C3a-H. The methylation of I and its N-benzylsulfonyl derivative (X) gave Vb, and XI of which C3-methyl group had trans-configuration to C3a-H, respectively. On the other hand, the methylation of 2-oxo-1, 3-diethoxycarbonyl-trans-octahydroindole (XII) gave also C3-methyl derivative (XIII), but the configuration of C3-methyl group of XIII was cis to C3a-H.