(1S,5R,7R,30S)-14-De­oxy­isogarcinol

The title compound, C38H50O5 {systematic name: 10-(3-hy­droxy­benzo­yl)-2,2,7,7-tetra­methyl-3,6,8-tris­(3-methyl­but-2-en­yl)-3,4,4a,5,6,7-hexa­hydro-4a,8-methano-2H-cyclo­octa­[b]pyran-9,11(8H)-dione}, is a polyisoprenylated benzophenone, isolated for the first time from the fruits of Garcinia indica during our investigation of bioactive compounds from this plant and their large-scale extraction. The relative configuration of the title compound was chosen based on comparison of its spectroscopic and optical rotation data with that of the isomorphous and isostructural compound isogarcinol, whose absolute configuration is known. The crystal packing features O—H⋯O hydrogen bonds. A Cambridge Structural Database analysis revealed that the crystal structure reported here is isomorphous and isostructural with that of isogarcinol

Stereochemistry of gabapentin and several derivatives: solid state conformations and solution equilibria

Gabapentin (1-(aminomethyl)cycloheaxaneacetic acid; Gpn) is a widely used anti-epileptic drug. The target site of action of Gpn remains controversial. Gpn can exist in two isomeric chair forms. The crystal structures of Gpn 1 and eight derivatives, Gpn hydrochloride 2, Gpn lactam 3, Boc-Gpn-OH 4, Ac-Gpn-OH 5, Piv- Gpn-OH 6, Tosyl-Gpn-OH 7, Boc-Gpn-OSu 8 and Boc-Gpn-NHMe 9, are described. The aminomethyl group occupies an axial position in 1, 3, 6 and 7, while it lies in an equatorial orientation in 2, 4, 5 and 8. The structure of Boc-Gpn-NHMe 9 reveals that the crystals contain both chair forms of the derivative in the ratio 0.7:0.3, favouring the aminomethyl group in an axial position. In all cases, the torsional angles about the Cα–Cβ (θ1) and Cβ–Cγ (θ2) bonds of the g-amino acid residue are characteristic of a gauche, gauche (g, g) conformation. In solution, NMR studies establish rapid conformational exchange, as anticipated, at room temperature. Low temperature NMR studies permit conformational freezing and determination of the freeenergy difference between the two 1,1-disubstituted cyclohexane conformers. The largest free-energy difference is observed in the free amino acid (0.38 kcal mol–1), with the most stable conformer having the aminomethyl group in the equatorial position. The free-energy difference between the two forms is significantly reduced in the protected derivatives, with almost equal populations observed in solution for the fully protected neutral derivatives, Boc-Gpn-NHMe and Gpn lactam

Bioactive isochromenone isolated from Aspergillus fumigatus, endophytic fungus from Bacopa monnieri

Fungal endophytes are a significant reservoir of novel bioactive secondary metabolites. Present communication describes isolation and structure determination of isochromenone, from endophytic microorganism Aspergillus fumigatus hosted in Bacopa monnieri plant. Further, its biological evaluation revealed it as antioxidant and antitubercular. The methanol extract of A. fumigatus inhibits the growth of the virulent strain of Mycobacterium tuberculosis H37RV with minimum inhibitory concentration 500 μg/mL. This is the first report of isolation of isochromenone from A. fumigatus.</em

Nucleation, Growth, and Form in Crystals of Peptide Helices

A model for the nucleation of crystallization in peptide helices is presented. The crystal structures of four polymorphic forms of a hydrophobic helical decapeptide Boc-Leu-Aib-Phe-Phe-Leu-Aib-Ala-Ala-Leu-Aib-OMe (I) exemplify alternative packing modes in cylindrical molecules. Three crystal forms of peptide I are monoclinic $P2_1$, while one is orthorhombic $P22_12_1$. The five different helical molecules characterized have very similar backbone conformations over much of the peptide length. A survey of 117 helical peptide structures with a length \geq 8 residues reveals a preponderance of the triclinic (P1), monoclinic $(P2_1)$, and orthorhombic $(P2_12_12_1)$ crystal forms. Models for the formation of critical nuclei are based on helix association driven by solvophobic forces, resulting in the formation of raftlike structures. Raft association can be further driven by the imperative of minimizing solvent accessible surface area with the formation of blocks, which can be subsequently fitted in Lego set fashion by multiple hydrogen bond interactions in the head-to-tail region. This model provides a rationalization for observed crystal formation based on a postulated structure for an embryonic nucleus, which is determined by aggregation patterns and unconstrained by the dictates of symmetry

Nucleation, growth, and form in crystals of peptide helices

A model for the nucleation of crystallization in peptide helices is presented. The crystal structures of four polymorphic forms of a hydrophobic helical decapeptide Boc-Leu-Aib-Phe-Phe-Leu-Aib-Ala-Ala-Leu-Aib-OMe (I) exemplify alternative packing modes in cylindrical molecules. Three crystal forms of peptide I are monoclinic P21, while one is orthorhombic P22121. The five different helical molecules characterized have very similar backbone conformations over much of the peptide length. A survey of 117 helical peptide structures with a length ≥8 residues reveals a preponderance of the triclinic (P1), monoclinic (P21), and orthorhombic (P212121) crystal forms. Models for the formation of critical nuclei are based on helix association driven by solvophobic forces, resulting in the formation of raftlike structures. Raft association can be further driven by the imperative of minimizing solvent accessible surface area with the formation of blocks, which can be subsequently fitted in Lego set fashion by multiple hydrogen bond interactions in the head-to-tail region. This model provides a rationalization for observed crystal formation based on a postulated structure for an embryonic nucleus, which is determined by aggregation patterns and unconstrained by the dictates of symmetry

Gabapentin: A Stereochemically Constrained gamma Amino Acid Residue in Hybrid Peptide Design

Nature has used the all-alpha-polypeptide backbone of proteins to create a remarkable diversity of folded structures. Sequential patterns of 20 distinct amino adds, which differ only in their side chains, determine the shape and form of proteins. Our understanding of these specific secondary structures is over half a century old and is based primarily on the fundamental elements: the Pauling alpha-helix and beta-sheet. Researchers can also generate structural diversity through the synthesis of polypeptide chains containing homologated (omega) amino acid residues, which contain a variable number of backbone atoms. However, incorporating amino adds with more atoms within the backbone introduces additional torsional freedom into the structure, which can complicate the structural analysis. Fortunately, gabapentin (Gpn), a readily available bulk drug, is an achiral beta,beta-disubstituted gamma amino add residue that contains a cyclohexyl ring at the C-beta carbon atom, which dramatically limits the range of torsion angles that can be obtained about the flanking C-C bonds. Limiting conformational flexibility also has the desirable effect of increasing peptide crystallinity, which permits unambiguous structural characterization by X-ray diffraction methods. This Account describes studies carried out in our laboratory that establish Gpn as a valuable residue in the design of specifically folded hybrid peptide structures. The insertion of additional atoms into polypeptide backbones facilitates the formation of intramolecular hydrogen bonds whose directionality is opposite to that observed in canonical alpha-peptide helices. If hybrid structures mimic proteins and biologically active peptides, the proteolytic stability conferred by unusual backbones can be a major advantage in the area of medicinal chemistry. We have demonstrated a variety of internally hydrogen-bonded structures in the solid state for Gpn-containing peptides, including the characterization of the C-7 and C-9 hydrogen bonds, which can lead to ribbons in homo-oligomeric sequences. In hybrid alpha gamma sequences, district C-12 hydrogen-bonded turn structures support formation of peptide helices and hairpins in longer sequences. Some peptides that include the Gpn residue have hydrogen-bond directionality that matches alpha-peptide helices, while others have the opposite directionality. We expect that expansion of the polypeptide backbone will lead to new classes of foldamer structures, which are thus far unknown to the world of alpha-polypeptides. The diversity of internally hydrogen-bonded structures observed in hybrid sequences containing Gpn shows promise for the rational design of novel peptide structures incorporating hybrid backbones

Asparagine and glutamine differ in their propensities to form specific side chain-backbone hydrogen bonded motifs in proteins

Short range side chain-backbone hydrogen bonded motifs involving Asn and Gln residues have been identified from a data set of 1370 protein crystal structures (resolution = 1.5 angstrom). Hydrogen bonds involving residues i - 5 to i + 5 have been considered. Out of 12,901 Asn residues, 3403 residues (26.4%) participate in such interactions, while out of 10,934 Gln residues, 1780 Gln residues (16.3%) are involved in these motifs. Hydrogen bonded ring sizes (Cn, where n is the number of atoms involved), directionality and internal torsion angles are used to classify motifs. The occurrence of the various motifs in the contexts of protein structure is illustrated. Distinct differences are established between the nature of motifs formed by Asn and Gln residues. For Asn, the most highly populated motifs are the C10 (COdi .NHi + 2), C13 (COdi .NHi + 3) and C17 (NdHi .COi - 4) structures. In contrast, Gln predominantly forms C16 (COei .NHi - 3), C12 (NeHi .COi - 2), C15 (NeHi .COi - 3) and C18 (NeHi .COi - 4) motifs, with only the C18motif being analogous to the Asn C17structure. Specific conformational types are established for the Asn containing motifs, which mimic backbone beta-turns and a-turns. Histidine residues are shown to serve as a mimic for Asn residues in side chain-backbone hydrogen bonded ring motifs. Illustrative examples from protein structures are considered. Proteins 2012; (c) 2011 Wiley Periodicals, Inc

Conformations of \beta-Amino Acid Residues in Peptides: X-Ray Diffraction Studies of Peptides Containing the Achiral Residue 1-Aminocyclohexaneacetic Acid, β3,3Ac6c\beta^{3,3}Ac_6c

The conformational preferences of the 3,3-disubstituted \beta-amino acid residue, 1-aminocyclohexaneacetic acid $(\beta^{3,3}Ac_6c)$ have been investigated by determining the crystal structures of the parent amino acid, the hydrochloride derivative, 10 protected derivatives and di and tripeptides. The symmetrical cyclohexyl substituent at the \beta-position restricts the values of the torsion angles \phi $(N-C^{\beta})$ and \theta $(C^{\beta}-C^ {\alpha})$ to approximately gauche values $(\pm60^o)$. Relatively few intramolecularly hydrogen bonded conformations are observed. In the dipeptide $Boc-\beta^{3,3}Ac_6c-\beta^{3,3}$ $Ac_6c-NHMe$ a $C_6$ hydrogen bond is observed. In Piv-Pro-$\beta^{3,3}Ac_6c-NHMe$ a $C_{11}$ hydrogen bonded hybrid \alpha \beta turn is characterized. In a majority of cases the amino group occupies the axial position in the cyclohexane ring. The conformations observed are compared with crystallographically observed structures for other \beta-residues, including $b^{2,2}Ac_6c$