Synthesis, crystal structure, and molecular conformation of N-Ac-dehydro-Phe-L-Val-L-Val-OCH3.

The peptide N-Ac-dehydro-Phe-L-Val-L-Val-OCH3 (C22H31N3O5) was synthesized by the usual workup procedure and finally by coupling the N-Ac-dehydro-Phe-L-Val-OH to valine methyl ester. It was crystallized from its solution in acetonitrile-water mixture at 4 degrees C. The crystals belong to the space group P1 with a = 8.900(3) A, b = 11.135(2) A, c = 12.918(2) A, alpha = 90.36(1) degrees, beta = 110.14(3) 14(3) degrees, V = 1207.7(6) A, 3Z = 2, dm = 1.156(5) Mgm-3, dc = 1.148(5) Mgm-3. The structure was determined by direct methods using SHELXS86. The structure was refined by full-matrix least-squares procedure to an R value of 0.077 for 3916 observed reflections. The molecular dimensions and conformations of the two crystallographically independent molecules are in good agreement. In the dehydro residues, the average C alpha-C beta distance is 1.31(2) A whereas the bond angle C alpha-C beta-C gamma is 132(1) degrees. The average backbone torsion angles are omega 0 = 169(1) degrees, phi 1 = -40(1) degree, psi 1 = -50(1) degree, omega 1 = -177(1) degree, phi 2 = 54(1) degree, psi 2 = 46(1) degree, omega 2 = -174(1) degree, phi 3 = 103(1) degree, psi T3 = -139(1) degree, and theta T3 = -176(1) degree. The acetyl group is in the trans conformation, while the backbone adopts a right-handed and left-handed helical conformation alternatingly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis, crystal structure, and molecular conformation of N-Boc-L-Phe-dehydro-Leu-L-Val-OCH3

The peptide N-Boc-L-Phe-dehydro-Leu-L-Val-OCH3 was synthesized by the usual workup procedure and finally by coupling the N-Boc-L-Phe-dehydro-Leu-OH to valine methyl ester. It was crystallized from its solution in methanol-water mixture at 4 degrees C. The crystals belong to the triclinic space group P1 with a = 5.972(5) A, b = 9.455(6) A, c = 13.101(6) A, alpha = 103.00(4) degrees, beta = 97.14(5) degrees, gamma = 102.86(5) degrees, V = 690.8(8) A, Z = 1, dm = 1.179(5) Mg m-3 and dc = 1.177(5) Mg m-3. The structure was determined by direct methods using SHELXS86. It was refined by block-diagonal least-squares procedure to an R value of 0.060 for 1674 observed reflections. The C alpha 2-C beta 2 distance of 1.323(9) A in dehydro-Leu is an appropriate double bond length. The bond angle C alpha-C beta-C gamma in the dehydro-Leu residue is 129.4(8) degrees. The peptide backbone torsion angles are theta 1 = -168.6(6) degrees, omega 0 = 170.0(6) degrees, phi 1 = -44.5(9) degrees, psi 1 = 134.5(6) degrees, omega 1 = 177.3(6) degrees, phi 2 = 54.5(9) degrees, psi 2 = 31.1(10) degrees, omega 2 = 171.7(6) degrees, phi 3 = 51.9(8) degrees, psi T3 = 139.0(6) degrees, theta T = -175.7(6) degrees. These values show that the backbone adopts a beta-turn II conformation. As a result of beta-turn, an intramolecular hydrogen bond is formed between the oxygen of the ith residue and NH of the (i + 3)th residue at a distance of 3.134(6) A.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis, crystal structure and molecular conformation of N-Ac-dehydro-Phe-L-Val-OH.

The peptide N-Ac-dehydro-Phe-L-Val-OH (C16H20N2O4) was synthesized by the usual workup procedure. The peptide crystallizes from its solution in acetonitrile at 4 degrees in hexagonal space group P6(5) with a = b = 11.874(2)A, c = 21.856(9) A, V = 2668(1) A3, Z = 6, dm = 1.151(3) g cm-3, dc = 1.136(4) g cm-3, CuK alpha = 1.5418 A, mu = 0.641 mm-1, F(000) = 972, T = 293 K. The structure was solved by direct methods and refined by least-squares procedure to an R value of 0.074 for 1922 observed reflections. In the dehydro-residue, the C1 alpha-C1 beta distance is 1.35(1) A while the bond angle C1 alpha-C1 beta-C1 gamma is 131.2(9) degrees. The backbone torsion angles are: omega 0 = 172(1) degrees, phi 1 = -60(2) degrees, psi 1 = -31(2) degrees, omega 1 = -179(1) degrees, phi 2 = 59(2) degrees. These values suggest that the peptide tends to adopt an alternating right-handed and left-handed helical conformation. The side chain torsion angles are: chi 1(1) = -6(2) degrees, chi 1(2.1) = -1(2) degrees, chi 1(2.2) = -178(2) degrees, chi 2(1.1) = 63(2) degrees and chi 2(1.2) = -173(1) degrees. These values show that the side chain of dehydro-Phe is planar whereas the valyl side chain adopts a sterically most preferred conformation. The molecules, linked by intermolecular hydrogen bonds and van der Waals forces, are arranged in helices along the c-axis. The helices are held side-by-side by van der Waals contacts.     

Design of peptides with alpha,beta-dehydro-residues: synthesis, and crystal and molecular structure of a 3(10)-helical tetrapeptide Boc-L-Val-deltaPhe-deltaPhe-L-Ile-OCH3.

The peptide Boc-L-Val-deltaPhe-deltaPhe-L-Ile-OCH3 was synthesized using the azlactone method in the solution phase, and its crystal and molecular structures were determined by X-ray diffraction. Single crystals were grown by slow evaporation from solution in methanol at 25 degrees C. The crystals belong to an orthorhombic space group P2(1)2(1)2(1) with a = 12.882(7) A, b = 15.430(5) A, c = 18.330(5) A and Z = 4. The structure was determined by direct methods and refined by a least-squares procedure to an R-value of 0.073. The peptide adopts a right-handed 3(10)-helical conformation with backbone torsion angles: phi1 = 56.0(6)degrees, psi1 = -38.0(6)degrees, phi2 = -53.8(6)degrees, psi2 = 23.6(6)degrees, phi3 = -82.9(6)degrees, psi3 = -10.6(7)degrees, phi4 = 124.9(5)degrees. All the peptide bonds are trans. The conformation is stabilized by intramolecular 4-->1 hydrogen bonds involving Boc carbonyl oxygen and NH of deltaPhe3 and CO of Val1 and NH of Ile4. It is noteworthy that the two other chemically very similar peptides: Boc-Val-deltaPhe-deltaPhe-Ala-OCH3 (i) and Boc-Val-deltaPhe-deltaPhe-Val-OCH3 (ii) with differences only at the fourth position have been found to adopt folded conformations with two overlapping beta-turns of types II and III', respectively, whereas the present peptide adopts two overlapping beta-turns of type III. Thus the introduction of Ile at fourth position in a sequence Val-deltaPhe-deltaPhe-X results in the formation of a 3(10)-helix. The crystal structure is stabilized by intermolecular hydrogen bonds involving NH of Val1 and carbonyl oxygen of a symmetry related (-x, y - 1/2, 1/2 + z) deltaPhe2 and NH of deltaPhe2 with carbonyl oxygen of a symmetry related (x, y1/2, 1/2 + z) Ile4. This gives rise to long columns of helical molecules linked head to tail running along [010] direction.     

Synthesis, crystal structure, and molecular conformation of peptide N-Boc-L-Pro-dehydro-Phe-L-Gly-OH

The peptide N-Boc-L-Pro-dehydro-Phe-L-Gly-OH was synthesized by the usual workup procedure and finally coupling the N-Boc-L-Pro-dehydro-Phe to glycine. The peptide crystallizes in monoclinic space group P2(1) with a = 8.951(4) A, b = 5.677(6) A, c = 21.192(11) A, beta = 96.97(4) degrees, V = 1069(1) A3, Z = 2, dm = 1.295(5) Mgm-3, and dc = 1.297(4) Mgm-3. The structure was determined by direct methods using SHELXS86. The structure was refined by the block-diagonal least-squares procedure to an R value of 0.074 for 1002 observed reflections. The C alpha 2-C beta 2 distance of 1.33(2) A is an appropriate double bond length. The angle C alpha 2-C beta 2-C gamma 2 is 133(1) degrees. The peptide backbone torsion angles are theta 1 = -167(1) degrees, omega 0 = 179(1) degrees, phi 1 = -48(1) degrees, psi 1 = 137(1) degrees, omega 1 = 175(1) degrees, phi 2 = 65(2) degrees, psi 2 = 15(2) degrees, omega 2 = -179(1) degrees, and phi 3 = -166(1) degrees. These values show that the Boc group has a trans-trans conformation while the peptide backbone adopts a beta-turn II conformation, which is stabilized by an intramolecular hydrogen bond of length of 3.05(1) A. The structures of dehydro-Phe containing peptides suggest that the dehydro-Phe promotes the beta-turn II conformation. The five-membered pyrrolidine ring of the Pro residue adopts an ideal C gamma-exo conformation with torsion angles chi 1(1) = -24(1) degrees, chi 2(1) = 34(1) degrees, chi 3(1) = -30(1) degrees, chi 4(1) = 15(1) degrees, and theta 0(1) = 6(1) degrees. The side-chain torsion angles in dehydro-Phe are chi 1(2) = -1(2) degrees, chi 2,1(2) = -176(1) degrees, and chi 2,2(2) = 8(2) degrees. The plane of C alpha 2-C beta 2-C gamma 2 is rotated with respect to the plane of the phenyl ring at 7(1) degrees, which indicates that the atoms of the side chain of dehydro-Phe are essentially coplanar. The molecules form a 2(1) screw axis related hydrogen-bonded rows along the b axis.     

Design of peptides using α,β-dehydro-residues: Synthesis,crystal structure and molecular conformation of Boc-L-Val- ΔPhe-ΔPhe-L-Val-OCH3

The peptide Boc-L-Val-ΔPhe-ΔPhe-L-Val-OCH₃ was synthesized by the azlactone method in solution phase, and its crystal and molecular structures were determined by x-ray diffraction method. Single crystals were grown by slow evaporation from a methanol/water solution at 6°C. The crystals belong to an orthorhombic space group P2₁2₁2₁ with a = 10.478 (6) Å, b = 13.953 (1), c = 24.347 (2) and Z = 4. The structure was determined by direct methods and refined by least squares procedure to an R value of 0.052. The structure consists of a peptide and a water molecule. The peptide adopts two overlapping β-turn conformations of Types II and I′ with torsion angles: ϕ₁ = -54.8 (6), ψ₁ = 130.5 (4), ϕ₂ = 65.8 (5), ψ₂ = 12.8 (6), ϕ₃ = 79.4 (5), ψ₃ = 3.9 (7)°. The conformation is stabilized by intramolecular hydrogen bonds involving Boc CO and NH of ΔPhe³ and CO of Val¹ and NH of Val⁴. The molecules are tightly packed in the unit cell. The crystal structure is stabilized by hydrogen bonds involving NH of ΔPhe² and CO of a symmetry related (x-½, ½ -y, -z) ΔPhe². The solvent-water molecule forms two hydrogen bonds with peptide molecule involving NH of Val¹ as an acceptor and another with CO of a symmetry related (1 -x, y-½, ½ -z) ΔPhe³ as a donor. These studies indicate that a tetrapeptide with two consecutive ΔPhe residues sequenced with valines on both ends adopts two overlapping β-turns of Types II and I′. © 1996 John Wiley & Sons, Inc.     

Modified chemotactic peptides: synthesis,crystal conformation,and activity of For-Hse(Me)-Leu-Phe-OMe

The presence of the sulfur atom of the methionine side chain exerts significant effects at different levels on biochemical behavior of chemotactic N-formylpeptides. In order to acquire more information on this point, the synthesis, the conformation in the crystal, and the activity of For-Hse(Me)-Leu-Phe-OMe (2) —an oxygen analogue of For-Met-Leu-Phe-OMe (f MLP-OMe) containing the O-methyl-L -homoserine in place of the native methionine at position 1—is reported. The new analogue 2 adopts a conformation that is extended at the first two residues and folded at the C-terminal phenylalanine. This conformation is different from that of the parent f MLP-OMe and strikingly similar to that adopted by f MLP-OBu^t. The side-chain spatial orientation of 2 corresponds to that adopted by f MLP-OH when cocrystallized with an immunoglobulin possessing binding properties similar to those of neutrophil receptors. When tested on human neutrophils the formylpeptide 2 is more active than the parent in the stimulation of directed mobility and maintains both the granule enzyme release activity an the superoxide anion production. © 1994 John Wiley & Sons, Inc.     

5-Nitrouridine-monohydrate: crystal structure and conformation.

The crystal structure of 5-nitrouridine was determined by X-ray analysis. The pyrimidine ring is slightly non-planar, showing a shallow boat conformation. The nitro group has no influence on the C4 - O4 bond length as compared to uridine. The ribose shows the C3'-endo conformation and the base is in the anti orientation to the sugar with a torsion angle of 25.6 degrees. This conformation is stabilized by a hydrogen bond from the base to the ribosyl moiety (H6 ... 05'). Stacking interactions between neighboring bases are almost negligible in the crystal. A water molecule is involved in a bifurcated donating hydrogen bond to 04 and to 052 of the nitro group of the one base and an accepting bond from the H3 of the other base. Two more hydrogen bonds are formed between the water molecule and the ribose. The structural aspects of 5-nitrouridine are discussed with respect to the special stacking features found for 5-nitro-1-(beta-D-ribosyluronic acid)-uracil monohydrate in the crystal (1).     

Structure and conformation of peptides containing the sulphonamide junction. III. Synthesis, crystal and molecular structure of a taurine containing peptidic oxa-cyclol

The insertion of the (S)-lactyl residue into the cyclodipeptide cyclo (-Tau-Pro-) 3 leads in good yields to the first example of a stable tetrahedral adduct (oxa-cyclol) 5 containing the sulphonamide junction. Compound 5 does not show a significant tendency towards tautomeric equilibria and possesses an unexpected syn-orientation involving the hydroxyl group and the Pro-H alpha. The crystal structure and molecular conformation of 5 has been determined. Crystals are orthorhombic, s.g. P2(1)2(1)2(1), with a = 6.607, b = 12.297, c = 16.622 A. The cisoidal conformation around the S-N bond is very similar to that found in the previously studied linear and cyclic peptides containing a sulphonamide junction. The taurine nitrogen is practically planar whereas the proline nitrogen, bound to the SO2 group, is highly pyramidal. In the tricyclic system of 5 the seven-membered ring adopts a twist-chair conformation while the pyrrolidine and oxazolidinone rings show an envelope conformation. The crystal packing is characterized by three hydrogen bonds all formed by means of a water molecule.     

Design and synthesis of cationic Aib-containing antimicrobial peptides: conformational and biological studies.

Development of antimicrobial peptides has attracted considerable attention in recent years due to the excessive use of antibiotics, which has led to multiresistant bacteria. Cationic amphiphilic Aib-containing peptide models Ac-(Aib-Arg-Aib-Leu)(n)-NH2, n = 1-4, and sequential cationic polypeptides (Arg-X-Gly)(n), X = Ala, Val, Leu, were prepared and studied for their antimicrobial and hemolytic activity, as well as for their proteolytic stability. Ac-(Aib-Arg-Aib-Leu)(n)-NH2, n = 2, 3 and the polypeptide (Arg-Leu-Gly)(n) exhibited significant antimicrobial activity, and they were nontoxic at their MIC values and resistant, in particular the Aib-peptide models, to enzymatic degradation. The conformational characteristics of the peptide models were studied by circular dichroism (CD). Structure-activity relationship studies revealed the importance of the amphipathic alpha-helical conformation of the reported peptides in inducing antimicrobial effects. It is concluded that peptide models comprising cationic amino acids (Arg), helicogenic and noncoding residues (Aib) and/or hydrophobic and helix-promoting components (Leu) may lead to the development of antimicrobial therapeutics.     

6-Azauridine, a nucleoside with unusual ribose conformation. The molecular and crystal structure

The cytostatic analogue ribo-6-azauridine crystallizes in the orthorhombic space group P2₁2₁2₁ with eight molecules per unit cell of dimensions $\text{a = 20.230, b = 7.709, c = 12.863}\text{A}\text{?}$. A trial structure was obtained by direct methods. Least-squares refinement of co-ordinates and anisotropic thermal parameters based on 1998 reflections measured on a four-circle diffractometer led to a discrepancy index R = 4.0%. Like uridine, 6-azauridine has the anti conformation about the glycosidic bond and a C(3′)-endo sugar pucker. Unlike uridine, it exhibits a close approach of N(6) to C(2′) at only 2.814 and 2.844 Å in the two independent molecules, and a C(5′)(5′) bond that is gauche to C(4′)O(1′) but trans to C(4′)C(3′); this conformation about a C(4′)C(5′) bond has never been observed before for C(3′)-endo puckered riboses in the crystalline state. The crystal structure displays a pseudo-A face centering and very similar conformational parameters for the two independent molecules. Every OH and NH group in the structure serves as a proton donor in a hydrogen bond, including an unusual N(3)—H(3) … O(1′) link. Molecular orbital calculations by the extended Hückel method indicate that from uridine to 6-azauridine the net charge changes sign at ring positions 5 and 6 and disappears at 1.     

Design,synthesis, crystal structure,biological evaluation and molecular docking studies of carbazole-arylpiperazine derivatives

Subtype-selective α₁-adrenoceptor (AR) antagonists display optimum therapeutic efficacies for the treatment of benign prostatic hyperplasia (BPH). In this study, we designed and synthesized novel carbazole-arylpiperazines derivatives (1 and 2) on the basis of the proposed pharmacophore model for α₁-AR antagonists. Structural properties were investigated using single-crystal X-ray diffraction analysis. Comparison of crystal structures with ligand-based pharmacophore models revealed that the two agents may possess antagonistic effects on α_1D subtype. Tissue functional assay in vitro showed that compound 2 exerted strong antagonistic activity on α_1B-AR (pA₂ 7.13) with a poor selectivity for α_1A and α_1D subtypes. Compound 1 exhibited enhanced antagonistic effect on α_1D subtype (pA₂ 7.06) and excellent selectivity for α_1D over α_1B (α_1D/α_1B ratio = 79.4). To illustrate the relationship between antagonistic activity and chemical structure, molecular docking studies were performed using the homology models of α₁ receptors. Binding mechanism indicated that small hydrophobic substituents attached to the arylpiperazine moiety were essential for rational design of α_1D-selective antagonists.     

Design of peptides with branched beta-carbon dehydro-residues: syntheses, crystal structures and molecular conformations of two peptides, (I) N-Carbobenzoxy-DeltaVal-Ala-Leu-OCH3 and (II) N-Carbobenzoxy-DeltaIle-Ala-Leu-OCH3.

Highly specific structures can be designed by inserting dehydro-residues into peptide sequences. The conformational preferences of branched beta-carbon residues are known to be different from other residues. As an implication it was expected that the branched beta-carbon dehydro-residues would also induce different conformations when substituted in peptides. So far, the design of peptides with branched beta-carbon dehydro-residues at (i + 1) position has not been reported. It may be recalled that the nonbranched beta-carbon residues induced beta-turn II conformation when placed at (i + 2) position while branched beta-carbon residues induced beta-turn III conformation. However, the conformation of a peptide with a nonbranched beta-carbon residue when placed at (i + 1) position was not found to be unique as it depended on the stereochemical nature of its neighbouring residues. Therefore, in order to induce predictably unique structures with dehydro-residues at (i + 1) position, we have introduced branched beta-carbon dehydro-residues instead of nonbranched beta-carbon residues and synthesized two peptides: (I) N-Carbobenzoxy-DeltaVal-Ala-Leu-OCH3 and (II) N-Carbobenzoxy-DeltaIle-Ala-Leu-OCH3 with DeltaVal and DeltaIle, respectively. The crystal structures of peptides (I) and (II) have been determined and refined to R-factors of 0.065 and 0.063, respectively. The structures of both peptides were essentially similar. Both peptides adopted type II beta-turn conformations with torsion angles; (I): phi1 = -38.7 (4) degrees, psi1 = 126.0 (3) degrees; phi2 = 91.6 (3) degrees, psi2 = -9.5 (4) degrees and (II): phi1 = -37.0 (6) degrees, psi1 = 123.6 (4) degrees, phi2 = 93.4 (4), psi2 = -11.0(4) degrees respectively. Both peptide structures were stabilized by intramolecular 4-->1 hydrogen bonds. The molecular packing in both crystal structures were stabilized in each by two identical hydrogen bonds N1...O1' (-x, y + 1/2, -z) and N2...O2' (-x + 1, y + 1/2, -z) and van der Waals interactions.     

Synthesis, crystal structure and molecular conformation of the tBuCO-D,L-Ala-delta Z-Phe-NHiPr alpha,beta-unsaturated dipeptide

The crystal structure of the tBuCO-D,L-Ala-delta Z-Phe-NHiPr dipeptide has been solved by X-ray diffraction. The peptide crystallizes in monoclinic space group P2(1)/c with a = 13.445 (3) A, b = 35.088 (4) A, c = 14.755 (3) A, beta = 116.73 (1) degree, Z = 12 and dc = 1.151 g.cm-3. The three independent molecules per asymmetric unit accommodate a beta II-folded conformation, but only one of them contains the typical i + 3----i interaction characterizing a beta-turn. In the other two molecules, the N...O distance exceeds 3.2 A, a value generally considered the upper limit for hydrogen bonds in peptides. In solution, the beta II-turn conformation is largely predominant.     

Glycerol conformation and molecular packing of membrane lipids: The crystal structure of 2,3-dilauroyl-d-glycerol

The single-crystal structure of 2,3-dilauroyl-d-glycerol has been determined by Patterson rotation and translation methods and refined to R = 0.069. 2,3-dilauroyl-d-glycerol crystallizes in the monoclinic space group P2₁, with unit cell dimensions: $\text{a = 5.46}\text{A}\text{?}\text{, b = 7.59}\text{A}\text{?}\text{, c = 34.2}\text{A}\text{?}\text{and}\text{β = 93.1 °}$, and with two molecules per unit cell. The molecules have their hydrocarbon chains aligned parallel, and are arranged in a bilayer structure. The chain stacking is achieved by a bend in the fatty acid. The hydrocarbon chains pack according to the orthorhombic perpendicular chain packing mode, and are tilted 26.5 ° from the layer normal.The structural features of 2,3-dilauroyl-d-glycerol have been analysed with reference to the corresponding hydrophobic moieties in the crystal structures of different membrane lipids. The glycerol group in 2,3-dilauroyl-d-glycerol is oriented parallel to the layer plane, but changes to an approximately layer-perpendicular orientation when a polar group is attached. The molecular conformation of the glycerol-dicarboxylic ester group, however, is identical in both the absence and presence of a head group, indicating extensive conformational restrictions for this group due to both intrinsic properties and chain stacking. The gathered data provide detailed information on the structural properties of the hydrophobic moiety of membrane lipids.