Toward the Synthesis and Improved Biopotential of an N -methylated Analog of a Proline-Rich Cyclic Tetrapeptide from Marine Bacteria

• Published in: Marine drugs Vol. 16; no. 9; p. 305
• Main Authors: Dahiya, Rajiv, Kumar, Suresh, Khokra, Sukhbir Lal, Gupta, Sheeba Varghese, Sutariya, Vijaykumar B, Bhatia, Deepak, Sharma, Ajay, Singh, Shamjeet, Maharaj, Sandeep
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI 30.08.2018; MDPI AG
• Subjects: Animals; Anthelmintics - chemical synthesis; Anthelmintics - pharmacology; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Aquatic Organisms - chemistry; Arthrodermataceae - drug effects; Bacteria - chemistry; Carbon-13 Magnetic Resonance Spectroscopy; Cyclization; Dipeptides - chemistry; Helminths - drug effects; macrocyclization; marine sponge; Methylation; Microbial Sensitivity Tests; Molecular Structure; N-methylation; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - pharmacology; pharmacological activity; Proline - chemistry; Pseudoalteromonas sp; Pseudomonas sp; solution-phase peptide synthesis; Spectroscopy, Fourier Transform Infrared; tetracyclopeptide; N-methylation; macrocyclization; pharmacological activity; tetracyclopeptide; marine sponge; Pseudomonas sp; Pseudoalteromonas sp; solution-phase peptide synthesis
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md16090305

An -methylated analog of a marine bacteria-derived natural proline-rich tetracyclopeptide was synthesized by coupling the deprotected dipeptide fragments Boc-l-prolyl-l- -methylleucine-OH and l-prolyl-l- -methylphenylalanine-OMe. A coupling reaction was accomplished utilizing , '-Dicyclohexylcarbodidimde (DCC) and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC·HCl) as coupling agents and Triethylamine (TEA) or -methylmorpholine (NMM) as the base in the presence of the racemization suppressing agent. This was followed by the cyclization of the linear tetrapeptide fragment under alkaline conditions. The structure of the synthesized cyclooligopeptide was confirmed using quantitative elemental analysis, FTIR (Fourier-transform infrared spectroscopy), ¹H NMR (Nuclear magnetic resonance spectroscopy), C NMR, and mass spectrometry. From the bioactivity results, it was clear that the newly synthesized proline-rich tetracyclopeptide exhibited better anthelmintic potential against , , and at a concentration of 2 mg/mL as well as improved antifungal activity against pathogenic dermatophytes and at a concentration of 6 μg/mL, as compared to non-methylated tetracyclopeptide. Moreover, -methylated tetracyclopeptide displayed significant activity against pathogenic .