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

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.

Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors

“…The cytotoxic activity of the newly synthesized compounds was assessed against two cancer cell lines; human breast adenocarcinoma (MCF-7) and hepatocellular carcinoma (HepG-2) using MTT assay. 60 These types of cancer cell lines have a high expression of EGFR, VEGFR and BRAF. 10,11,17,18,26 In addition, the cytotoxic effect of the new compounds was also evaluated against the normal lung fibroblast (WI38) to demonstrate their safety profiles.…”

“…Cytotoxic activity screening was performed using MTT assay at Regional Center for Mycology and Biotechnology, Al-Azhar University. 60 More details in the ESI. † 2.2.2.…”

Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias

“…Due to the known role of hLDHA in the “Warburg effect” in malignant cells [ 130 ], the inhibition of this enzyme has been considered as a strategy for diminishing the energy supply in cancer cells, reducing in that sense, the invasive potential of different kinds of cancer, such as breast carcinoma [ 131 , 132 , 133 , 134 , 135 ], pancreatic cancer [ 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 ], brain tumor [ 146 ], hepatocellular carcinoma [ 131 , 134 , 147 ], osteosarcoma [ 148 , 149 , 150 , 151 ], lung carcinoma [ 134 , 152 , 153 , 154 ], ovarian cancer [ 138 ], bladder cancer [ 155 ], colorectal cancer [ 134 , 138 , 155 ], mesothelioma [ 138 ], melanoma [ 134 ], leukemia [ 134 ], lymphoma [ 136 ], gastric cancer [ 156 ], Ewing’s sarcoma [ 145 ], leiomyomatosis, and renal cancer [ 157 ], achieving the in vitro , and in some cases in vivo , reduction of cancer cells.…”

New Benzimidazole-, 1,2,4-Triazole-, and 1,3,5-Triazine-Based Derivatives as Potential EGFRWT and EGFRT790M Inhibitors: Microwave-Assisted Synthesis, Anticancer Evaluation, and Molecular Docking Study

“…Microwave irradiation is an eco-friendly approach without hazardous solvents. It helps in the synthesis of various heterocyclic compounds rapidly and in high yields. , In addition, MAOS has a great contribution in chemical selectivity, catalyst-free conditions, and the absence of side products during the synthesis processes of various aromatic and heterocyclic compounds. , Based on the above-mentioned knowledge and in continuation of our previous efforts in the field of design and generation of new bioactive heterocyclic compounds, − this study deals with the design and microwave-assisted organic synthesis of a new set of benzimidazole, 1,2,4-triazole, and s -triazine derivatives targeting the wild-type EGFR-TK (EGFR WT ) and the mutant EGFR-TK (EGFRT 790M ).…”