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Mar. Drugs 2018, 16(9), 305; https://doi.org/10.3390/md16090305

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

1
Laboratory of Peptide Research and Development, School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, Saint Augustine, Trinidad and Tobago
2
Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra 136119, Haryana, India
3
Department of Pharmaceutical Sciences, USF College of Pharmacy, University of South Florida, Tampa, FL 33612-4749, USA
4
Department of Pharmacogenomics, ICPH Fairfax Bernard J. Dunn School of Pharmacy, Shenandoah University, Fairfax, VA 22031, USA
5
Department of Pharmacognosy, Amity Institute of Pharmacy, Amity University, Gwalior 474020, Madhya Pradesh, India
These two authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 21 June 2018 / Revised: 24 August 2018 / Accepted: 27 August 2018 / Published: 30 August 2018
(This article belongs to the Special Issue Marine Bacteria as Sources of Bioactive Compounds)
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Abstract

An N-methylated analog of a marine bacteria-derived natural proline-rich tetracyclopeptide was synthesized by coupling the deprotected dipeptide fragments Boc-l-prolyl-l-N-methylleucine-OH and l-prolyl-l-N-methylphenylalanine-OMe. A coupling reaction was accomplished utilizing N,N′-Dicyclohexylcarbodidimde (DCC) and 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC·HCl) as coupling agents and Triethylamine (TEA) or N-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), 13C NMR, and mass spectrometry. From the bioactivity results, it was clear that the newly synthesized proline-rich tetracyclopeptide exhibited better anthelmintic potential against Megascoplex konkanensis, Pontoscotex corethruses, and Eudrilus eugeniae at a concentration of 2 mg/mL as well as improved antifungal activity against pathogenic dermatophytes Trichophyton mentagrophytes and Microsporum audouinii at a concentration of 6 μg/mL, as compared to non-methylated tetracyclopeptide. Moreover, N-methylated tetracyclopeptide displayed significant activity against pathogenic Candida albicans. View Full-Text
Keywords: N-methylation; tetracyclopeptide; Pseudomonas sp.; macrocyclization; marine sponge; Pseudoalteromonas sp.; solution-phase peptide synthesis; pharmacological activity N-methylation; tetracyclopeptide; Pseudomonas sp.; macrocyclization; marine sponge; Pseudoalteromonas sp.; solution-phase peptide synthesis; pharmacological activity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Dahiya, R.; Kumar, S.; Khokra, S.L.; Gupta, S.V.; Sutariya, V.B.; Bhatia, D.; Sharma, A.; Singh, S.; Maharaj, S. Toward the Synthesis and Improved Biopotential of an N-methylated Analog of a Proline-Rich Cyclic Tetrapeptide from Marine Bacteria. Mar. Drugs 2018, 16, 305.

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