Τίτλος:
Design, synthesis and biological evaluation of novel substituted purine isosters as EGFR kinase inhibitors, with promising pharmacokinetic profile and in vivo efficacy
Περίληψη:
Novel substituted purine isosters, were designed and synthesized as potential inhibitors of the Epidermal Growth Factor Receptor (EGFR). The compounds were rationally designed through bioisosteric replacement of the central quinazoline core of lapatinib, an approved drug that inhibits both EGFR and HER2, another important member of this family of receptors. The new target molecules were evaluated as inhibitors of receptor phosphorylation at the cellular level, for their direct inhibitory action on the intracellular receptor kinase domain and for their cytotoxicity against the non-small cell lung cancer cell line A549 and breast cancer HCC1954, cell lines which are associated with overexpression of EGFR and HER2, respectively. The most potent derivatives were further studied for their cellular uptake levels and in vivo pharmacokinetic properties. One compound (23)displayed a noteworthy pharmacokinetic profile, and higher intracellular accumulation in comparison to lapatinib in the A549 cells, possibly due to its higher lipophilicity. This lead compound (23)was assessed for its efficacy in an EGFR positive xenograft model, where it successfully inhibited tumor growth, with a similar efficacy with that of lapatinib and with minimal phenotypic toxicity. © 2019 Elsevier Masson SAS
Συγγραφείς:
Gavriil, E.-S.
Doukatas, A.
Karampelas, T.
Myrianthopoulos, V.
Dimitrakis, S.
Mikros, E.
Marakos, P.
Tamvakopoulos, C.
Pouli, N.
Λέξεις-κλειδιά:
1 [3 chloro 4 (3 fluorobenzyloxy)phenyl] 2 (furan 2 yl) 1h imidazo[4,5 c]pyridin 4 amine; 1 [3 chloro 4 (3 fluorobenzyloxy)phenyl] 2 [5 [2 (methylsufonyl)ethylaminomethyl]furan 2 yl] 3h imidazo[4,5 b]pyridin 7 amine; 2 n [3 chloro 4 (3 fluorobenzyloxy)phenyl] 3 nitropyridine 2,4 diamine; 2 n [3 chloro 4 (3 fluorobenzyloxy)phenyl] 5 fluoro 3 nitropyridine 2,4 diamine; 2 n [3 chloro 4 (3 fluorobenzyloxy)phenyl] 5 fluoropyridine 2,3,4 triamine; 2 n [3 chloro 4 (3 fluorobenzyloxy)phenyl]pyridine 2,3,4 triamine; 3 [3 chloro 4 (3 fluorobenzyloxy)phenyl] 2 (furan 2 yl) 3h imidazo[4,5 b]pyridin 7 amine; 3 [3 chloro 4 (3 fluorobenzyloxy)phenyl] 7 fluoro 2 (furan 2 yl) 1h imidazo[4,5 c]pyridin 4 amine; 3 [3 chloro 4 (3 fluorobenzyloxy)phenyl] 7 fluoro 2[5 [2 (methylsulfonyl)ethylaminomethyl]furan 2 yl] 1h imidazo[4,5 c]pyridin 4 amine; 4 chloro 2 (furan 2 yl) 1h imidazo[4,5 c]pyridine; 4 n [3 chloro 4 (3 fluorobenzyloxy)phenyl] 3 nitropyridine 2,4 diamine; 4 n [3 chloro 4 (3 fluorobenzyloxy)phenyl]pyridine 2,3,4 triamine; 4 n [3 chloro 4 (3 fluorobenzyloxy)phenyl]pyrimidine 4,5,6 triamine; 4 n,6 n bis[3 chloro 4 (3 fluorobenzyloxy)phenyl]pyrimidine 4,5,6 triamine; 5 [[2 (methylsulfonyl)ethylamino]methyl]furan 2 carboxaldehyde; 6 n [3 chloro 4 (3 fluorobenzyloxy)phenyl] 8 (furan 2 yl) 9h purin 6 amine; 6 n [3 chloro 4 (3 fluorobenzyloxy)phenyl] 8 [5 [2 (methylsulfonyl)ethylaminomethyl]furan 2 yl] 9h purin 6 amine; 9 [3 chloro 4 (3 fluorobenzyloxy) phenyl] 8 (furan 2 yl) 9h purin 6 amine; 9 [3 chloro 4 (3 fluorobenzyloxy)phenyl] 8 [5 [2 (methylsulfonyl)ethylaminomethyl]furan 2 yl] 9h purin 6 amine; antineoplastic agent; epidermal growth factor receptor 2; epidermal growth factor receptor kinase inhibitor; lapatinib; n [3 chloro 4 (3 fluorobenzyloxy)phenyl] 2 (furan 2 yl) 1h imidazo[4,5 c]pyridin 4 amine; n [3 chloro 4 (3 fluorobenzyloxy)phenyl] 2 [5 [2 (methylsufonyl)ethylaminomethyl]furan 2 yl] 3h imidazo[4,5 b]pyridin 7 amine; n [3 chloro 4 (3 fluorobenzyloxy)phenyl] 7 fluoro 2 (furan 2 yl) 1h imidazo[4,5 c]pyridin 4 amine; n [3 chloro 4 (3 fluorobenzyloxy)phenyl] 7 fluoro 2[5 [2 (methylsulfonyl)ethylaminomethyl]furan 2 yl] 1h imidazo[4,5 c]pyridin 4 amine; n [3 chloro 4 (3-fluorobenzyloxy)phenyl] 2 (furan 2 yl) 3h imidazo[4,5 b]pyridin 7 amine; purine derivative; quinazoline; unclassified drug; antineoplastic agent; epidermal growth factor receptor 2; ERBB2 protein, human; lapatinib; protein kinase inhibitor; purine derivative, A-549 cell line; animal experiment; animal model; antineoplastic activity; area under the curve; Article; breast cancer; cancer cell culture; cancer inhibition; carbon nuclear magnetic resonance; chemical structure; crystal structure; cyclization; drug bioavailability; drug design; drug efficacy; drug screening; drug synthesis; HCC1954 cell line; heteronuclear multiple bond correlation; heteronuclear multiple quantum coherence; human; human cell; human cell culture; hydrogen bond; in vitro study; in vivo study; lipophilicity; liquid chromatography-mass spectrometry; maximum concentration; molecular docking; mouse; non small cell lung cancer; nonhuman; nuclear Overhauser effect; pharmacokinetic parameters; proton nuclear magnetic resonance; tumor growth; tumor volume; tumor xenograft; analogs and derivatives; animal; antagonists and inhibitors; C57BL mouse; chemistry; enzyme active site; female; male; nonobese diabetic mouse; SCID mouse; synthesis; tumor cell line, Animals; Antineoplastic Agents; Catalytic Domain; Cell Line, Tumor; Female; Humans; Lapatinib; Male; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, SCID; Molecular Docking Simulation; Protein Kinase Inhibitors; Purines; Receptor, ErbB-2
