Chiral Pyridine-3,5-bis- (L-phenylalaninyl-L-leucinyl) Schiff Base Peptides as Potential Anticancer Agents: Design, Synthesis, and Molecular Docking Studies Targeting Lactate Dehydrogenase-A

Abd El-Galil E Amr; Randa E Abdel Mageid; Mohamed El-Naggar; Ahmed M Naglah; Eman S Nossier; Elsayed A Elsayed

doi:10.3390/molecules25051096

Chiral Pyridine-3,5-bis- (L-phenylalaninyl-L-leucinyl) Schiff Base Peptides as Potential Anticancer Agents: Design, Synthesis, and Molecular Docking Studies Targeting Lactate Dehydrogenase-A

Molecules. 2020 Feb 29;25(5):1096. doi: 10.3390/molecules25051096.

Authors

Abd El-Galil E Amr^{1

2}, Randa E Abdel Mageid³, Mohamed El-Naggar⁴, Ahmed M Naglah^{1

5}, Eman S Nossier⁶, Elsayed A Elsayed^{7

8}

Affiliations

¹ Drug Exploration &amp.
² Applied Organic Chemistry Department, National Research Center, Cairo, Dokki 12622, Egypt.
³ Photochemistry Department, National Research Center, Cairo, Dokki 12622, Egypt, randaabdelmagid@yahoo.com.
⁴ Chemistry Department, Faculty of Sciences, University of Sharjah, Sharjah 27272, UAE.
⁵ Department of Peptide Chemistry, National Research Centre, Cairo 12622, Egypt.
⁶ Pharmaceutical Medicinal Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11311, Egypt.
⁷ Zoology Department, Bioproducts Research Chair, Faculty of Science, King Saud University, Riyadh 11451, Saudi Arabia.
⁸ Chemistry of Natural and Microbial Products Department, National Research Centre, Cairo, Dokki 12622, Egypt.

Abstract

A series of branched tetrapeptide Schiff bases 3-6 were designed and synthesized from corresponding tetrapeptide hydrazide 2 as a starting material.In vitroevaluation of the synthesized compounds 4-6 against breast MCF-7 carcinoma cells identified their excellent anticancer potency, with IC₅₀ ranging from 8.12 ± 0.14 to 17.55 ± 0.27 μM in comparison with the references, cisplatin and milaplatin (IC₅₀= 13.34 ± 0.11and 18.43 ± 0.13 μM, respectively). Furthermore, all derivatives demonstrated promising activity upon evaluation of theirin vitroandin vivosuppression of p53 ubiquitination and inhibition assessment for LDHA kinase. Finally, molecular docking studies were performed to predict the possible binding features of the potent derivatives within the ATP pocket of LDHA in an attempt to get a lead for developing a more potent LDHA inhibitor with anti-proliferative potency.

Keywords: LDHA; Schiff bases; amino acids; anticancer evaluation; molecular docking; p53 ubiquitination; tetrapeptides.

MeSH terms

Animals
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Drug Screening Assays, Antitumor
Female
Humans
L-Lactate Dehydrogenase / antagonists & inhibitors*
L-Lactate Dehydrogenase / metabolism
MCF-7 Cells
Mice
Mice, Nude
Molecular Docking Simulation*
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / metabolism
Neoplasms, Experimental / drug therapy*
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Peptides* / chemical synthesis
Peptides* / chemistry
Peptides* / pharmacology
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology
Schiff Bases

Substances

Antineoplastic Agents
Neoplasm Proteins
Peptides
Pyridines
Schiff Bases
L-Lactate Dehydrogenase
LDHA protein, human

Grants and funding

Researchers Supporting Project (Project No. RSP-2019/66)/King Saud University