Anticancer Activities of Newly Synthesized Chiral Macrocyclic Heptapeptide Candidates

Abo-Ghalia, Mohamed H.; Moustafa, Gaber O.; Amr, Abd El‐Galil E.; Naglah, Ahmed M.; Elsayed, Elsayed Ahmed; Bakheit, Ahmed H.

doi:10.3390/molecules25051253

Cited by 18 publications

(12 citation statements)

References 30 publications

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“…This drawback urged us to overcome such obstacles by the design and synthesis of peptide derivatives with rigid conformations and specific amino acid sequences that impart, simultaneously, anticancer and antimicrobial activities. Our research group has published several studies indicating that peptide candidates are promising as potential anticancer drugs, [5][6][7][8][9][10][11][12][13][14][15] anti-inflammatory and analgesic drugs, 16 and as antibacterial drugs. [17][18][19][20][21][22][23][24][25][26][27][28] The incidence of microbial infections in cancer patients increases due to the low circulating neutrophil levels in these patients in addition to the disruption of the microbial flora.…”

Section: Introductionmentioning

confidence: 99%

Nα-1, 3-Benzenedicarbonyl-Bis-(Amino Acid) and Dipeptide Candidates: Synthesis, Cytotoxic, Antimicrobial and Molecular Docking Investigation

Naglah¹,

Moustafa²,

Elhenawy³

et al. 2021

DDDT

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Purpose The objective of our work was to prepare a potent and safe antimicrobial and anticancer agents, through synthesis of several peptides and examine their biological activities, namely as, cytotoxically potent and antimicrobial and antifungal agents. Introduction Multidrug-resistant microbial strains have arisen against all antibiotics in clinical use. Infections caused by these bacteria threaten global public health and are associated with high mortality rates. Methods The main backbone structure for the novel synthesized linear peptide is Nα-1, 3-benzenedicarbonyl-bis-(Amino acids)-X, ( 3–11 ). A computational docking study against DNA gyrase was performed to formulate a mode of action of the small compounds as antimicrobial agents. Results The peptide-bearing methionine-ester ( 4 ) exhibited potent antimicrobial activity compared to the other synthesized compounds, while, peptide ( 8 ), which had methionine-hydrazide fragment was the most potent as antifungal agent against Aspergillus niger with 100% inhibition percent. Compounds ( 6 and 7 ) showed the highest potency against breast human tumor cell line “MCF-7” with 95.1% and 79.8% of cell inhibition, respectively. The nine compounds possessed weak to moderate antiproliferative effect over colon tumor cell line. The docking results suggest good fitting through different hydrogen bond interactions with the protein residues. In silico ADMET study also evaluated and suggested that these compounds had promising oral bioavailability features. Conclusion The tested compounds need further modification to have significant antimicrobial and antitumor efficacy compared to the reference drugs.

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Section: Introductionmentioning

confidence: 99%

Nα-1, 3-Benzenedicarbonyl-Bis-(Amino Acid) and Dipeptide Candidates: Synthesis, Cytotoxic, Antimicrobial and Molecular Docking Investigation

Naglah¹,

Moustafa²,

Elhenawy³

et al. 2021

DDDT

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“…The promising compounds that exhibited percentage of inhibition ≥70% were further subjected to MTT assay for investigation of their IC 50 (median growth inhibitory concentration necessary to inhibit the cell viability by 50%) [ 34 , 35 , 36 ] and doxorubicin served as a reference. Accordingly, all the newly synthesized GA-based peptides except 1 and 6 were screened for their cytotoxicity against three different human cancer cell lines: MCF-7, HCT-116, and HepG-2 cell lines at different concentrations (10, 5, 2.5, 1.25, and 0.625 µg/mL).…”

Section: Resultsmentioning

confidence: 99%

“…Based on the afro-mentioned investigations, aiming to modify and improve the bioactivity of GA and in continuation of our strenuous efforts in the field of discovery of new potent anticancer and antimicrobial agents [ 26 , 27 , 28 , 29 , 30 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 ], this work represents a facile structural modification strategy to synthesize novel 18β-glycyrrhetinic amide derivatives via its coupling with different amino acids. The new compounds were evaluated as anticancer candidates against three human cancer cells; colon cancer HCT-116, breast cancer (MCF-7), and liver cancer (HepG-2) cell lines.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, In Vitro Anticancer Potentiality, and Antimicrobial Activities of Novel Peptide–Glycyrrhetinic-Acid-Based Derivatives

et al. 2021

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Glycyrrhetinic acid (GA) is one of many interesting pentacyclic triterpenoids showing significant anticancer activity by triggering apoptosis in tumor cell lines. This study deals with the design and synthesis of new glycyrrhetinic acid (GA)–amino acid peptides and peptide ester derivatives. The structures of the new derivatives were established through various spectral and microanalytical data. The novel compounds were screened for their in vitro cytotoxic activity. The evaluation results showed that the new peptides produced promising cytotoxic activity against the human breast MCF-7 cancer cell line while comparing to doxorubicin. On the other hand, only compounds 3, 5, and 7 produced potent activity against human colon HCT-116 cancer cell line. The human liver cancer (HepG-2) cell line represented a higher sensitivity to peptide 7 (IC50; 3.30 μg/mL), while it appeared insensitive to the rest of the tested peptides. Furthermore, compounds 1, 3, and 5 exhibited a promising safety profile against human normal skin fibroblasts cell line BJ-1. In order to investigate the mode of action, compound 5 was selected as a representative example to study its in vitro effect against the apoptotic parameters and Bax/BCL-2/p53/caspase-7/caspase-3/tubulin, and DNA fragmentation to investigate beta (TUBb). Additionally, all the new analogues were subjected to antimicrobial assay against a panel of Gram-positive and Gram-negative bacteria and the yeast candida Albicans. All the tested GA analogues 1–8 exhibited more antibacterial effect against Micrococcus Luteus than gentamicin, but they exhibited moderate antimicrobial activity against the tested bacterial and yeast strains. Molecular docking studies were also simulated for compound 5 to give better rationalization and put insight to the features of its structure.

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“…In all biological kingdoms, CYP51 orthologs are located and united into one (CYP51) family (despite very low identity sequence of amino acid across phylogeny) [ 23 ]. Depending on these observations and in continuation of our previous studies for anti-microbial and anticancer agents [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ], this study was aimed at synthesizing a series of novel dipeptide compounds that were hypothesized to affect systemic anti-microbial measurements.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Docking, Computational Studies, and Antimicrobial Evaluations of New Dipeptide Derivatives Based on Nicotinoylglycylglycine Hydrazide

et al. 2020

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Within a series of dipeptide derivatives (5–11), compound 4 was refluxed with d-glucose, d-xylose, acetylacetone, diethylmalonate, carbon disulfide, ethyl cyanoacetate, and ethyl acetoacetate which yielded 5–11, respectively. The candidates 5–11 were characterized and their biological activities were evaluated where they showed different anti-microbial inhibitory activities based on the type of pathogenic microorganisms. Moreover, to understand modes of binding, molecular docking was used of Nicotinoylglycine derivatives with the active site of the penicillin-binding protein 3 (PBP3) and sterol 14-alpha demethylase’s (CYP51), and the results, which were achieved via covalent and non-covalent docking, were harmonized with the biological activity results. Therefore, it was extrapolated that compounds 4, 7, 8, 9, and 10 had good potential to inhibit sterol 14-alpha demethylase and penicillin-binding protein 3; consequently, these compounds are possibly suitable for the development of a novel antibacterial and antifungal therapeutic drug. In addition, in silico properties of absorption, distribution, metabolism, and excretion (ADME) indicated drug likeness with low to very low oral absorption in most compounds, and undefined blood–brain barrier permeability in all compounds. Furthermore, toxicity (TOPKAT) prediction showed probability values for all carcinogenicity models were medium to pretty low for all compounds.

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Anticancer Activities of Newly Synthesized Chiral Macrocyclic Heptapeptide Candidates

Cited by 18 publications

References 30 publications

Nα-1, 3-Benzenedicarbonyl-Bis-(Amino Acid) and Dipeptide Candidates: Synthesis, Cytotoxic, Antimicrobial and Molecular Docking Investigation

Nα-1, 3-Benzenedicarbonyl-Bis-(Amino Acid) and Dipeptide Candidates: Synthesis, Cytotoxic, Antimicrobial and Molecular Docking Investigation

Synthesis, Characterization, In Vitro Anticancer Potentiality, and Antimicrobial Activities of Novel Peptide–Glycyrrhetinic-Acid-Based Derivatives

Synthesis, Docking, Computational Studies, and Antimicrobial Evaluations of New Dipeptide Derivatives Based on Nicotinoylglycylglycine Hydrazide

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