Total Synthesis and Pharmacological Investigation of Cordyheptapeptide A

Abstract

The present investigation reports the synthesis of a phenylalanine-rich N-methylated cyclopeptide, cordyheptapeptide A (8), previously isolated from the insect pathogenic fungus Cordyceps sp. BCC 1788, accomplished through the coupling of N-methylated tetrapeptide and tripeptide fragments followed by cyclization of the linear heptapeptide unit. Structure elucidation of the newly synthesized cyclopolypeptide was performed by means of FT-IR, 1H-NMR, 13C-NMR, and fast atom bombardment mass spectrometry (FABMS), and screened for its antibacterial, antidermatophytic, and cytotoxic potential. According to the antimicrobial activity results, the newly synthesized N-Methylated cyclopeptide exhibited potent antibacterial activity against Gram-negative bacteria Pseudomonas aeruginosa and Klebsiella pneumoniae and antifungal activity against dermatophytes Trichophyton mentagrophytes and Microsporum audouinii at a concentration of 6 μg/mL, in comparison to the reference drugs, gatifloxacin and griseofulvin. In addition, cyclopolypeptide 8 displayed suitable levels of cytotoxicity against Dalton’s lymphoma ascites (DLA) and Ehrlich’s ascites carcinoma (EAC) cell lines.

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

“…Among these metabolites, cyclopeptides have emerged as a unique group of bioactive analogs with interesting pharmacological and biochemical properties including cytotoxicity [ 2 , 3 , 4 ], insecticidal activity [ 5 ], antimicrobial activity [ 6 , 7 ], antitubercular activity [ 8 ], anti-inflammatory activity [ 9 ], Human Immunodeficiency Virus (HIV)-inhibitory activity [ 10 ], chymotrypsin-inhibitory activity [ 11 ], antimalarial activity [ 12 ], etc. Among cyclooligopeptides, N -methylated peptides have attracted the attention of researchers and scientists in terms of their unique structures and diverse pharmacological activities [ 13 , 14 ]. Evolutionarily speaking, nature has employed the N -methylation of peptides as an ingenious technique to modulate biological function [ 15 ].…”

“…Keeping in view the utilization of N -methylation in modulating the biological properties of peptides and, further, in continuation of the efforts of our research group in the synthesis of bioactive cyclic peptides [ 14 , 22 , 23 , 24 , 25 ], the present study was directed toward the first total synthesis of an N -methylated analog of a natural tetracyclopeptide. The non-methylated natural peptide was previously isolated from the marine bacteria Pseudomonas sp.…”

The Road from Host-Defense Peptides to a New Generation of Antimicrobial Drugs

“…Antimicrobial peptides are usually isolated in very small amounts from the natural sources. Therefore, a chemical synthesis is often implemented to obtain adequate amounts for proper peptide characterization and for the biological assays [ 96 , 97 , 98 , 99 ]. Moreover, the chemical synthesis can provide analogues of natural peptides with improved properties, such as superior potency, selectivity, stability or biodistribution, and is a key technology in drug discovery and development programs [ 1 , 16 , 100 ].…”

“…When an antimicrobial peptide is scarce in nature, chemical synthesis can provide in a relatively short time suitable amounts for its complete characterization and for biological screening [ 98 , 99 ]. In addition, the synthesis of selected analogues is also possible.…”

Total Synthesis of a Natural Cyclooligopeptide From Fruits of Sugar-Apples

“…A natural cyclic pentapeptide, fanlizhicyclopeptide B was isolated from the fruits of Annona squamosa (sugar-apples) and its structure was elucidated by ESI MS/MS, 1D and 2D NMR data and chemical degradation (Wu et al 2014). Keeping in view broad range of pharmacological activities possessed by natural cyclopeptides (Fang et al 2016;Dahiya, 2013;Dahiya and Pathak, 2006a;Pathak and Dahiya, ISSN: 2249-6041 (Print); ISSN: 2249-9245 (Online) 2 2003) and in continuation of synthetic studies of our research group toward natural peptides and their analogs (Dahiya 2007a;2007b;2007c;2008a;2008b;2008c;2008d;Dahiya and Gautam, 2010a;2010b;2010c;2011a;2011b;2011c;2011d;Dahiya and Kaur, 2007a;2008a;Dahiya and Kumar, 2007;Dahiya and Pathak, 2006b;2007a;2007b;Dahiya and Sharma, 2008;Dahiya and Singh, 2017a;2017b;2017c;Dahiya et al 2006;2009a;2009b;2009c;Kumar et al 2017), the present investigation directed toward the synthesis, structure elucidation and the biological evaluation of a sugar-apple derived cyclopentapeptide, fanlizhicyclopeptide B for the antibacterial, antifungal and anthelmintic potential.…”