Design, synthesis and anticancer evaluation of 1H-pyrazolo[3,4-d] pyrimidine derivatives as potent EGFRWT and EGFRT790m inhibitors and apoptosis inducers

被引:108
|
作者
Gaber, Ahmed A. [1 ]
Bayoumi, Ashraf H. [1 ]
El-morsy, Ahmed M. [1 ]
Sherbiny, Farag F. [1 ]
Mehany, Ahmed B. M. [2 ]
Eissa, Ibrahim H. [3 ]
机构
[1] Al Azhar Univ, Dept Organ Pharmaceut Chem, Fac Pharm Boys, Cairo 11884, Egypt
[2] Al Azhar Univ, Fac Sci, Dept Zool, Cairo 11884, Egypt
[3] Al Azhar Univ, Fac Pharm Boys, Dept Med Chem, Cairo 11884, Egypt
关键词
Anticancer; EGFR-TKIs; Docking; NSCLC; 1H-Pyrazolo [3,4-d]pyrimidine; EGFR(WT); EGFR(T790M); ANTI-HYPERGLYCEMIC EVALUATION; PROTEIN-KINASE INHIBITORS; BIOLOGICAL EVALUATION; QUINOXALINE DERIVATIVES; LUNG-CANCER; ACQUIRED-RESISTANCE; MOLECULAR DOCKING; DNA INTERCALATORS; BINDING MODE; PPAR-GAMMA;
D O I
10.1016/j.bioorg.2018.06.017
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In our attempt to develop effective EGFR-TKIs, two series of 1H-pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated in vitro for their inhibitory activities against EGFR(WT). Compounds 15(b), 15(j), and 18(d) potently inhibited EGFR(WT) at sub-micro molar IC50 values comparable to that of erlotinib. Moreover, thirteen compounds that showed promising IC50 values against EGFR(WT) were tested in vitro for their inhibitory activities against mutant EGFR(T790m). Compounds 17(d) and 17(f), exhibited potent inhibitory activities towards EGFR(T790M) comparable to osimertinib. Compounds that showed promising IC50 values against EGFR(WT) were further tested for their anti-proliferative activities against three cancer cell lines bearing EGFR(WT)(MCF-7, HepG2, A549), and two cancer cell lines bearing EGFR(T79OM )(H1975 and HCC827). Compounds 15(g), 15(j),15(n), 18(d) and 18(e) were the most potent anticancer agents against the EGFR(WT) containing cells, while compounds 15(e), 17(d) and 17(f) showed promising anti-proliferative activities against EGFR(T79OM )containing cells. Furthermore, the most active compound 18(d) was selected for further studies regarding to its effects on cell cycle progression and induction of apoptosis in the HepG2 cell line. The results indicated that this compound is good apoptotic agent and arrests G(0)/G(l) and G(2)/M phases of cell cycle. Finally, molecular docking studies were performed to investigate binding pattern of the synthesized compounds with the prospective targets, EGFR(WT)(PDB: 4HJO) and EGFR(T79OM)(PDB: 3W2O).
引用
收藏
页码:375 / 395
页数:21
相关论文
共 50 条
  • [21] Design, synthesis, molecular modeling and biological evaluation of novel 1H-pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents
    Eissa, Ibrahim H.
    El-Naggar, Abeer M.
    El-Hashash, Maher A.
    BIOORGANIC CHEMISTRY, 2016, 67 : 43 - 56
  • [23] Design, Synthesis, and Antiproliferative Activity of New 5-Chloro-indole-2-carboxylate and Pyrrolo[3,4-b]indol-3-one Derivatives as Potent Inhibitors of EGFRT790M/BRAFV600E Pathways
    Al-Wahaibi, Lamya H.
    Mohammed, Anber F.
    Abdelrahman, Mostafa H.
    Trembleau, Laurent
    Youssif, Bahaa G. M.
    MOLECULES, 2023, 28 (03):
  • [24] Combined Computational Techniques for Discovery of Novel Pyrazolo[3,4-d]pyrimidine Derivatives as PAK1 Inhibitors
    Asati, Vivek
    Gupta, Shankar
    Baweja, Gurkaran Singh
    Irani, Mehdi
    Monga, Vikramdeep
    Almehizia, Abdulrahman A.
    CHEMISTRYSELECT, 2025, 10 (06):
  • [25] A NEW EFFICIENT SYNTHESIS OF 4-ALKOXY-1,6-DIARYL-1H-PYRAZOLO[3,4-d]PYRIMIDINE DERIVATIVES
    Liu, Ju
    Zhang, Xin-wei
    Wang, Yang
    Chen, Ye
    Zhang, Mei-rong
    Cai, Zhi-qiang
    Zhou, Yun-peng
    Xu, Li-feng
    SYNTHETIC COMMUNICATIONS, 2015, 45 (08) : 1009 - 1017
  • [26] Synthesis, biological evaluation and docking studies of 4-amino substituted 1H-pyrazolo[3,4-d]pyrimidines
    Schenone, Silvia
    Brullo, Chiara
    Bruno, Olga
    Bondavalli, Francesco
    Mosti, Luisa
    Maga, Giovanni
    Crespan, Ernmanuele
    Carraro, Fabio
    Manetti, Fabrizio
    Tintori, Cristina
    Botta, Maurizio
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2008, 43 (12) : 2665 - 2676
  • [27] Bisarylureas Based on 1H-Pyrazolo[3,4-d]pyrimidine Scaffold as Novel Pan-RAF Inhibitors with Potent Anti-Proliferative Activities: Structure-Based Design, Synthesis, Biological Evaluation and Molecular Modelling Studies
    Fu, Yu
    Wang, Yuanyuan
    Wan, Shanhe
    Li, Zhonghuang
    Wang, Guangfa
    Zhang, Jiajie
    Wu, Xiaoyun
    MOLECULES, 2017, 22 (04):
  • [28] Synthesis, anti-microbial evaluation, and molecular modeling of new pyrazolo[3,4-d]pyrimidine derivatives
    Eweas, Ahmad F.
    Swelam, S. A.
    Fathalla, O. A.
    Fawzy, N. M.
    Abdel-Moez, Sh I.
    MEDICINAL CHEMISTRY RESEARCH, 2012, 21 (11) : 3848 - 3857
  • [29] Pyrazolo[3,4-d]pyrimidine Derivatives as COX-2 Selective Inhibitors: Synthesis and Molecular Modelling Studies
    Raffa, Demetrio
    Maggio, Benedetta
    Plescia, Fablana
    Cascioferro, Stella
    Railmondi, Maria Valeria
    Plescia, Salvatore
    Cusimano, Maria Grazia
    ARCHIV DER PHARMAZIE, 2009, 342 (06) : 321 - 326
  • [30] Design, synthesis, docking, ADMET studies, and anticancer evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and apoptosis inducers
    Alanazi, Mohammed M.
    Eissa, Ibrahim H.
    Alsaif, Nawaf A.
    Obaidullah, Ahmad J.
    Alanazi, Wael A.
    Alasmari, Abdullah F.
    Albassam, Hussam
    Elkady, Hazem
    Elwan, Alaa
    JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2021, 36 (01) : 1760 - 1782