A Comprehensive Review on Therapeutic Potentials of Natural Cyclic Peptides

Cyclic peptides have emerged as a promising class of organic compounds that possess polypeptide chains with a cyclic ring structure. There is a circular sequence of bonds in which the ring structure is formed via linkage between one end of the peptide bond and the other end with an amide bond or any other chemically stable bonds like ether, thioether, lactone, and disulfide. Generally, the cyclic peptides are isolated from natural resources like invertebrate animals, micro-organisms of marine habitats, and higher plants. These cyclic peptides possess unique structures with diverse pharmacological activities. Now a day, cyclic peptides possess superior therapeutic value due to several reasons such as greater resistance to enzymatic degradation (in vivo) and higher bio-availability. Some of these cyclic peptides are rich in leucine, proline while some have other amino acids as their major constituents. Numerous novel cyclic peptides isolated from natural sources are successfully developed as bioactive products. Recently, cyclic peptides derived from natural resources have attracted attention for exploring their numerous beneficial effects. Moreover, it is reported that natural cyclic peptides exhibit various therapeutic activities like an anthelmintic, ACE inhibitor, anti-tumor, microtubule inhibitor, anti-fungal, anti-malarial, and platelet aggregation inhibiting activity. In this review, various cyclic peptides are reported with structures and biological activities that are isolated from various natural sources. The natural cyclic peptides possess a wide spectrum of biological activities and can become a drug of the future for replacing the existing drugs which develop resistance

Bispidine Platform as a Tool for Studying Amide Configuration Stability

In this work, the solution conformations of seventeen 3,7-diacyl bispidines were studied by means of NMR spectroscopy including VT NMR experiments. The acyl groups included alkyl, alkenyl, aryl, hetaryl, and ferrocene moieties. The presence of syn/anti-isomers and their ratios were estimated, and some reasons explaining experimental facts were formulated. In particular, all aliphatic and heterocyclic units in the acylic R(CO) fragments led to an increased content of the syn-form in DMSO-d6 solutions. In contrast, only the anti-form was detected in DMSO-d6 and CDCl3 in the case when R = Ph, ferrocenyl, (R)-myrtenyl. In the case of a chiral compound derived from the natural terpene myrtene, a new dynamic process was found in addition to the expected inversion around the amide N-C(O) bond. Here, rotation around the CO-C=C bond in the acylic R fragment was detected, and its energy was estimated. For this compound, ΔG for amide N-C(O) inversion was found to be equal to 15.0 ± 0.2 kcal/mol, and for the rotation around the N(CO)–C2′ bond, it was equal to 15.6 ± 0.3 kcal/mol. NMR analysis of the chiral bispidine-based bis-amide was conducted for the first time. Two X-ray structures are reported. For the first time, the unique syn-form was found in the crystal of an acyclic bispidine-based bis-amide. Quantum chemical calculations revealed the unexpected mechanism for amide bond inversion. It was found that the reaction does not proceed as direct N-C(O) bond inversion in the double-chair (CC) conformation but rather requires the conformational transformation into the chair–boat (CB) form first. The amide bond inversion in the latter requires less energy than in the CC form.

The Biosynthesis and Metabolism of the N-Acylated Aromatic Amino Acids: N-Acylphenylalanine, N-Acyltyrosine, N-Acyltryptophan, and N-Acylhistidine

The fatty acid amides are a family of lipids composed of two chemical moieties, a fatty acid and a biogenic amine linked together in an amide bond. This lipid family is structurally related to the endocannabinoid anandamide (N-arachidonoylethanolamine) and, thus, is frequently referred to as a family of endocannabinoid-related lipids. The fatty acid amide family is divided into different classes based on the conjugate amine; anandamide being a member of the N-acylethanolamine class (NAE). Another class within the fatty acid amide family is the N-acyl amino acids (NA-AAs). The focus of this review is a sub-class of the NA-AAs, the N-acyl aromatic amino acids (NA-ArAAs). The NA-ArAAs are not broadly recognized, even by those interested in the endocannabinoids and endocannabinoid-related lipids. Herein, the NA-ArAAs that have been identified from a biological source will be highlighted and pathways for their biosynthesis, degradation, enzymatic modification, and transport will be presented. Also, information about the cellular functions of the NA-ArAAs will be placed in context with the data regarding the identification and metabolism of these N-acylated amino acids. A review of the current state-of-knowledge about the NA-ArAAs is to stimulate future research about this underappreciated sub-class of the fatty acid amide family.

2.2 CuAAC in Peptidomimetics and Protein Mimics

The tremendous recent developments in click chemistry, including the impressive developments of strain-promoted cycloaddition reagents, all started with the copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction conceived by Meldal et al. and Sharpless et al. This led to a revolution of extremely important applications in the chemical, biological, medical, and materials sciences. It is fair to state that, especially in the synthesis of multifunctional and complex small-to-large biomolecular constructs, CuAAC has been indispensable. This has been particularly evident in the area of peptides, peptidomimetics, and protein mimics. These biomolecules play key roles in the various peptide–peptide, peptide–protein, and protein–protein interactions that are involved in many diseases and disorders, and peptide-based therapeutics can be important in this context. However, it is often important to improve the bioactivity and overall stability, and modulate the spatial structure, of peptide-based therapeutics. The incorporation of the 1,4-disubstituted 1,2,3-triazole moiety as a non-native structural element using CuAAC is explored in this chapter. The resulting incorporated triazole moiety can lead to structural surrogates of the amide bond and disulfide bond. As a consequence, CuAAC can be utilized toward introducing conformational constraints and stabilizing secondary structures of α-helices, β-sheets/turns, or loop-like structures. In addition, CuAAC can be used to combine various peptide sequences with molecular scaffolds to develop protein mimics that can find applications as synthetic vaccines and antibodies.

Ni-Electrocatalytic C(sp3)–C(sp3) Doubly Decarboxylative Coupling

This work presents a modern spin on one of the oldest known Csp3–Csp3 bond forming reactions in synthetic chemistry: the Kolbe electrolysis. This reaction holds incredible promise for synthesis, yet its use has been near non-existent in mainstream organic synthesis. In contrast to the strongly oxidative electrolytic protocol employed traditionally since the 19th century, the present method utilizes in situ generated redox-active esters (RAEs) which are combined with a mildly reductive Ni-electrocatalytic cycle. It can be used to heterocouple 1o, 2o, and even certain 3o RAEs with a protocol reminiscent of amide bond formation in terms of simplicity. Due to its mild nature the reaction tolerates a range of functional groups, is scalable, and was strategically enlisted for the synthesis of 25 known compounds to reduce overall step-counts by 74%.

Six New Antimicrobial Metabolites from the Deep-Sea Sediment-Derived Fungus Aspergillus fumigatus SD-406

Six new metabolites, including a pair of inseparable mixtures of secofumitremorgins A (1a) and B (1b), which differed in the configuration of the nitrogen atom, 29-hydroxyfumiquinazoline C (6), 10R-15-methylpseurotin A (7), 1,4,23-trihydroxy-hopane-22,30-diol (10), and sphingofungin I (11), together with six known compounds (2–5 and 8–9), were isolated and identified from the deep-sea sediment-derived fungus Aspergillus fumigatus SD-406. Their structures were determined by detailed spectroscopic analysis of NMR and MS data, chiral HPLC analysis of the acidic hydrolysate, X-ray crystallographic analysis, J-based configuration analysis, and quantum chemical calculations of ECD, OR, and NMR (with DP4+ probability analysis). Among the compounds, 1a/1b represent a pair of novel scaffolds derived from indole diketopiperazine by cleavage of the amide bond following aromatization to give a pyridine ring. Compounds 1, 4, 6, 7, 10 and 11 showed inhibitory activities against pathogenic bacteria and plant pathogenic fungus, with MIC values ranging from 4 to 64 μg/mL.

An ultrasound-assisted solvent and catalyst-free synthesis of structurally diverse pyrazole centered 1,5-disubstituted tetrazoles via one-pot four-component reaction

1,5-Disubstituted tetrazoles are vital drug-like scaffold usually encountered as valuable bioisosteres of cis-amide bond. In this article, we reported synthesis of some novel medicinally relevant pyrazole centered 1,5-disubstituted tetrazoles using ultrasound irradiation via a one-pot 4-C reaction from various pyrazole originated aldehyde, amine, isocyanide, and sodium azide. All the synthesized derivatives were characterized by IR, 1H NMR, 13C NMR, spectroscopic techniques, and mass analysis. This ultrasound-assisted green protocol has several advantages like mild reaction condition, high yield, catalyst and solvent-free reaction protocol, 15 minutes reaction time and easy workup.

Biotin Transport-Targeting Polysaccharide-Modified PAMAM G3 Dendrimer as System Delivering α-Mangostin into Cancer Cells and C. elegans Worms

The natural xanthone α-mangostin (αM) exhibits a wide range of pharmacological activities, including antineoplastic and anti-nematode properties, but low water solubility and poor selectivity of the drug prevent its potential clinical use. Therefore, the targeted third-generation poly(amidoamine) dendrimer (PAMAM G3) delivery system was proposed, based on hyperbranched polymer showing good solubility, high biocompatibility and low immunogenicity. A multifunctional nanocarrier was prepared by attaching αM to the surface amine groups of dendrimer via amide bond in the ratio 5 (G32B12gh5M) or 17 (G32B10gh17M) residues per one dendrimer molecule. Twelve or ten remaining amine groups were modified by conjugation with D-glucoheptono-1,4-lactone (gh) to block the amine groups, and two biotin (B) residues as targeting moieties. The biological activity of the obtained conjugates was studied in vitro on glioma U-118 MG and squamous cell carcinoma SCC-15 cancer cells compared to normal fibroblasts (BJ), and in vivo on a model organism Caenorhabditis elegans. Dendrimer vehicle G32B12gh at concentrations up to 20 µM showed no anti-proliferative effect against tested cell lines, with a feeble cytotoxicity of the highest concentration seen only with SCC-15 cells. The attachment of αM to the vehicle significantly increased cytotoxic effect of the drug, even by 4- and 25-fold for G32B12gh5M and G32B10gh17M, respectively. A stronger inhibition of cells viability and influence on other metabolic parameters (proliferation, adhesion, ATP level and Caspase-3/7 activity) was observed for G32B10gh17M than for G32B12gh5M. Both bioconjugates were internalized efficiently into the cells. Similarly, the attachment of αM to the dendrimer vehicle increased its toxicity for C. elegans. Thus, the proposed α-mangostin delivery system allowed the drug to be more effective in the dendrimer-bound as compared to free state against both cultured the cancer cells and model organism, suggesting that this treatment is promising for anticancer as well as anti-nematode chemotherapy.