RESUMO
A new series of 1,3,4-thiadiazolo-adamantane derivatives were synthesized through molecular hybridization approach, then used as starting material to synthesize chloro and cyano acetamide-thiadiazole derivatives 2, 3. The newly designed compounds 1-3 were treated with different reagents to design 5-adamantyl thiadiazole derivatives 4-17 and evaluate their in vitro anti-proliferative activity against three cancer cell lines (MCF-7, HepG-2 and A549). Doxorubicin was used as a positive control. The most promising compounds 5, 6, 10a, 10b, 14b, 14c, and 17 showed up-regulation for BAX and down-regulation of Bcl-2, these findings proved their role as hopeful apoptotic inducers. In addition, the inhibitory activity against both wild EGFRWT and mutant EGFRL858R-TK for these derivatives revealed that compounds 5, 14c, and 17 have IC50 value ranging from 85 nM to 71.5 nM against wild EGFRWT and 37.85-41.19 nM against the mutant type, Lapatinib was used as a reference standard with IC50 values of 31.8 nM and 39.53 nM, respectively. The most potent derivatives were subjected to further evaluation against double mutant EGFR L858R/T790M and showed good IC50 values between (0.27-0.78 nM) compared to Lapatinib (0.18 nM) and Erlotinib (0.21 nM). Among them, thiazolo-thiadiazole adamantane derivative 17 exhibited the strongest inhibitory activity to the EGFR. Molecular docking studies were performed inside the active site of EGFR (1M17), and binding energy scores ranged between (-19.19 to -22.07 Kcal/mol) compared to Erlotinib (-19.10 Kcal/mol). Furthermore, oral bioavailability beside some pharmacokinetics properties of these derivatives were also investigated in this research work.
Assuntos
Adamantano/farmacologia , Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Inibidores de Proteínas Quinases/farmacologia , Tiadiazóis/farmacologia , Moduladores de Tubulina/farmacologia , Adamantano/síntese química , Adamantano/química , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Polimerização/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiadiazóis/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
Reaction of 5-morphilinosulfonylisatin (1) with acetophenones (2a-e) afforded 3-hydroxy-3-substituted-2-oxoindoles 3a-e, when treated with acetic acid the expected 3-phenacylidene-2-oxoindoles 4a-d and 4-hydroxy-5'-(morpholinosulfonyl) spiro [chromene-2, 3'-indolin]-2'-one 6 were obtained. Isatin derivative (1) was stirred with cyano derivatives to produce the arylidines (7a-c), while under reflux condition, it gave pyrrolo[2,3-b]indoles (8, 9). Moreover, istain (1) reacted with pyrazolo-5-one or 3-substituted phenol in presence of malononitrile to afford spiroxindole derivatives (10a,b) and (11a,b). Also, compounds (10a,b) and (11a,b) were obtained through cyclization of (7a) with pyrazolo-5-one or 3-substituted phenol. The obtained compounds were identified by IR, 1H NMR, 13C NMR and elemental analysis. Anticancer activity against three cancer cell lines (HepG-2, HCT-116 and MCF-7) were evaluated using sulforhodamine B assay method. Compounds 4b, 4c, 7a, 7c and 9 showed broad spectrum anticancer activity on the three tested cell lines with IC50 values less than 10⯵M. Cell cycle analysis was performed for the most promising derivatives, compounds 4b and 7c arrested HepG-2 cells at G2-M phase, while compounds 7a and 9 accumulated cells at G0-G1 phase, all of them induced apoptosis at priG1 phase in the range of (11.32-19.17%). Additionally compounds 4b, 7a and 9 showed more potent activity against EGFR than Lapatinib, their IC50 values are from 0.019 to 0.026⯵M while IC50 of Lapatinib is 0.028⯵M. Molecular docking studies were conducted to investigate the binding mode, amino acid interactions and free binding energy of these potent derivatives.