1. Synthesis and crystal structures of Boc-L-Asn-L-Pro-OBzl.CH3OH and dehydration side product, Boc-beta-cyano-L-alanine-L-Pro-OBzl
A N Stroup, L B Cole, M M Dhingra, L M Gierasch Int J Pept Protein Res. 1990 Dec;36(6):531-7. doi: 10.1111/j.1399-3011.1990.tb00992.x.
Boc-L-Asn-L-Pro-OBzl: C21H29O6N3.CH3OH, Mr = 419.48 + CH3 OH, monoclinic, P2(1), a = 10.049(1), b = 10.399(2), c = 11.702(1) A, beta = 92.50(1)degrees, V = 1221.7(3) A3, dx = 1.14 g.cm-3, Z = 2, CuK alpha (lambda = 1.54178 A), F(000) = 484 (with solvent), 23 degrees, unique reflections (I greater than 3 sigma(I)) = 1745, R = 0.043, Rw = 0.062, S = 1.66. Boc-beta-cyano-L-alanine-L-Pro-OBzl: C21H27O5N3, Mr = 401.46, orthorhombic, P2(1)2(1)2(1), a = 15.741(3), b = 21.060(3), c = 6.496(3) A, V = 2153(1) A3, dx = 1.24 g.cm-3, Z = 4, CuK alpha (lambda = 1.54178 A), F(000) = 856, 23 degrees, unique reflections (I greater than 3 sigma(I)) = 1573, R = 0.055, Rw = 0.078, S = 1.86. The tert.-butyloxycarbonyl (Boc) protected dipeptide benzyl ester (OBzl), Boc-L-Asn-L-Pro-OBzl, prepared from a mixed anhydride reaction using isobutylchloroformate, Boc-L-asparagine, and HCl.L-proline-OBzl, crystallized with one methanol per asymmetric unit in an extended conformation with the Asn-Pro peptide bond trans. Intermolecular hydrogen bonding occurs between the methanol and the Asn side chain and between the peptide backbone and the Asn side chain. A minor impurity due to the dehydration of the Asn side chain to a beta-CNala crystallized with a similar extended conformation and a single intermolecular hydrogen bond.
2. Amino acid-linked porphyrin-nitroimidazole antibiotics targeting Porphyromonas gingivalis
Simon A Dingsdag, Benjamin C-M Yap, Neil Hunter, Maxwell J Crossley Org Biomol Chem. 2015 Jan 7;13(1):98-109. doi: 10.1039/c4ob01841a.
The periodontal pathogen Porphyromonas gingivalis requires porphyrin supplementation for growth. Previously, in order to inhibit P. gingivalis growth, we synthesised very effective 'Trojan horse' ester and amide-linked deuterporphyrin-nitroimidazole (DPIX-Nim) adducts that exploited this requirement to transport metronidazole-derived antibiotics with excellent antimicrobial selectivity and recognition by the HA2 porphyrin binding site. Herein, in the context of developing topical agents to target P. gingivalis, l-amino acids are incorporated into adducts as linkers to improve uptake. Ten 13- and 17-propionic amide regioisomers of l-amino acid-linked deuterporphyrin-nitroimidazole adducts were synthesised using a peptide coupling approach. DPIX-Lys regioisomers without attached nitroimidazole were also synthesised as comparison compounds. All the porphyrin adducts bound (Kd50 7 to 20 nM) to a recombinant HA2 receptor with similar binding affinity to haem, except the lysine-proline linked DPIX-Lys(Boc)Pro-Nim adducts (Kd50 300 nM) and the DPIX-Lys(Nim)-Nim adducts (Kd50 200 nM), both of which have large appended groups. DPIX-Lys(Boc)-Nim, DPIX-Lys(OH)-Nim, and DPIX-Pro-Nim adducts were shown to be very effective against P. gingivalis. DPIX-Lys(Boc)Pro-Nim adducts and DPIX-Lys(Nim)-Nim adducts showed weak activity. Importantly, DPIX-Lys(Boc)-Nim adducts were selective for P. gingivalis and, unlike metronidazole, did not kill a range of other anaerobic bacteria isolated from the human gastrointestinal tract.
3. Synthesis, crystal structure, and molecular conformation of peptide N-Boc-L-Pro-dehydro-Phe-L-Gly-OH
H C Patel, T P Singh, V S Chauhan, P Kaur Biopolymers. 1990 Feb 15;29(3):509-15. doi: 10.1002/bip.360290306.
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.
