1. Towards the Synthesis of a Heterocyclic Analogue of Natural Cyclooligopeptide with Improved Bio-properties
Rajiv Dahiya, Sunita Dahiya, Suresh V Chennupati, Vernon Davis, Vijaya Sahadeo, Jayvadan K Patel Curr Org Synth. 2022 Mar 3;19(2):267-278. doi: 10.2174/1570179418666211005141811.
Aims: The present investigation is targeted towards the synthesis of a novel analogue of a natural peptide of marine origin. Background: Marine sponges are enriched with bioactive secondary metabolites, especially circu-lar peptides. Heterocycles are established organic compounds with potential biological value. Tak-ing into consideration the bio-properties of heterocycles and marine sponge-derived natural pep-tides, an effort was made for the synthesis of a heterocyclic analogue of a natural cyclopeptide. Objective: A heterocyclic analogue of a sponge-derived proline-containing cyclic peptide, rolloam-ide A, was synthesized by interaction of Boc-protected L-histidinyl-L-prolyl-L-valine and L-prolyl-L-leucyl-L-prolyl-L-isoleucine methyl ester and compared with synthetic rolloamide A with bioac-tivity against bacteria, fungi, and earthworms. Methods: The synthesis of cycloheptapeptide was accomplished employing the liquid phase method. The larger peptide segment was prepared by interaction of Boc-protected L-prolyl-L-leu-cine with L-prolyl-L-isoleucine methyl ester. Similarly, the tripeptide unit was synthesized from Boc-protected L-histidinyl-L-proline with L-valine ester. The linear heptapeptide segment (7) was cyclized by utilizing pentafluorophenyl (pfp) ester, and the structure was elucidated by elemental and spectral (IR, 1H/13C NMR, MS) analysis. The peptide was also screened for diverse bioactivities such as antibacterial, antifungal, and potential against earthworms and cytotoxicity. Results: The novel cyclooligopeptide was synthesized with 84% yield by making use of car-bodiimides. The synthesized cyclopeptide exhibited significant cytotoxicity against two cell lines. In addition, promising antifungal and antihelmintic properties were observed for newly synthesized heterocyclic peptide derivative (8) against dermatophytes and three earthworm species at 6 μg/mL and 2 mg/mL, respectively. Conclusion: Solution-phase technique employing carbodiimide chemistry was established to be promising for synthesizing the cycloheptapeptide derivative (8), and C5H5N was proved to be a better base for heptapeptide circling when compared to N-methylmorpholine and triethylamine.
2. Conformational characteristics of alternating stereo-co-oligopeptides of D- and L-norleucine: influence of an N-methyl group
E F Schoch, D U Römer, G P Lorenzi Int J Pept Protein Res. 1994 Jul;44(1):10-8. doi: 10.1111/j.1399-3011.1994.tb00398.x.
The conformational behavior of members of the series Boc-(L-Nle)m-(D-Nle-L-Nle)(n-m)/2-OMe (m = 0 or 1; n = total number of residues) with n < or = to 12, and of analogs of comparable chain length having a NMe-group on the (n - 3)th residue has been investigated. The study has shown that D,L-alternating oligonorleucines behave very differently from stereo-co-oligopeptides of D-alloisoleucine and L-isoleucine, D- and L-valine, or D- and L-leucine. In particular, it has been found that oligonorleucines do not form beta-helices as do the other oligopeptides. Instead, they form aggregates (very likely of the alpha-pleated sheet type), which are insoluble in common organic solvents even at moderate chain lengths. In marked contrast with this behavior, N-methylated analogs such as those studied, with n from 9 to 15, cannot generate very stable aggregates owing to the N-methyl group, and they prefer to form beta-helices. These beta-helices have been found by solution 1H NMR techniques to be almost exclusively of the types beta 4.4 (single-stranded with about 4.4 residues per turn) and decreases increases beta 5.6 (double-stranded, antiparallel, with about 5.6 residues per turn).
3. Synthesis, crystal structure, and molecular conformation of N-Boc-L-Phe-dehydro-Leu-L-Val-OCH3
P Narula, H C Patel, T P Singh, V S Chauhan Biopolymers. 1990 May-Jun;29(6-7):935-41. doi: 10.1002/bip.360290606.
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)
