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

Journal Article
Elsayed, Abd Amr, Mohamed Abo-Ghalia, Gaber Moustafa, Mohamed Al-Omar, Eman Nossier, Elsayed . 2018
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Publication Abstract: 

A series of macrocyclic pyrido-pentapeptide candidates 2–6 were synthesized by using
N,N-bis-[1-carboxy-2-(benzyl)]-2,6-(diaminocarbonyl)pyridine 1a,b as starting material. Structures
of the newly synthesized compounds were established by IR, 1H and 13C-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, 5c showed encouraging inhibitory activity on MCF-7 and
HepG-2 cell lines with IC50 values 9.41 1.25 and 7.53 1.33 M, respectively. Interestingly, 5c also
demonstrated multitarget profile and excellent inhibitory activity towards VEGFR-2, CDK-2 and
PDGFR kinases. Furthermore, molecular modeling studies of the compound 5c revealed its possible
binding modes into the active sites of those kinases.