Design, Synthesis and Docking Studies of Novel Macrocyclic Pentapeptides as Anticancer Multi-Targeted Kinase Inhibitors

• Published in: Molecules (Basel, Switzerland) Switzerland), 2018-09, Vol.23 (10), p.2416
• Main Authors: Amr, Abd El-Galil E, Abo-Ghalia, Mohamed H, Moustafa, Gaber O, Al-Omar, Mohamed A, Nossier, Eman S, Elsayed, Elsayed A
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclin-Dependent Kinase 2 - genetics; Drug Screening Assays, Antitumor; Gene Expression Regulation, Neoplastic - drug effects; Hep G2 Cells; Humans; in vitro anticancer activity; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; macrocyclic pentapeptides; MCF-7 Cells; Molecular Docking Simulation; molecular modeling studies; Molecular Structure; multitarget; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Peptides - chemistry; Peptides - pharmacology; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptor, Platelet-Derived Growth Factor beta - antagonists & inhibitors; Receptor, Platelet-Derived Growth Factor beta - genetics; Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - genetics
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23102416

A series of macrocyclic pyrido-pentapeptide candidates ⁻ were synthesized by using , -bis-[1-carboxy-2-(benzyl)]-2,6-(diaminocarbonyl)pyridine , as starting material. Structures of the newly synthesized compounds were established by IR, ¹H and C-NMR, and MS spectral data and elemental analysis. The in-vitro cytotoxicity activity was investigated for all compounds against MCF-7 and HepG-2 cell lines and the majority of the compounds showed potent anticancer activity against the tested cell lines in comparison with the reference drugs. Out of the macrocyclic pyrido-pentapeptide based compounds, showed encouraging inhibitory activity on MCF-7 and HepG-2 cell lines with IC values 9.41 ± 1.25 and 7.53 ± 1.33 μM, respectively. Interestingly, also demonstrated multitarget profile and excellent inhibitory activity towards VEGFR-2, CDK-2 and PDGFRβ kinases. Furthermore, molecular modeling studies of the compound revealed its possible binding modes into the active sites of those kinases.