Elshaier Yaseen A M M, Shaaban Mohamed A, Abd El Hamid Mohammed K, Abdelrahman Mostafa H, Abou-Salim Mahrous A, Elgazwi Sara M, Halaweish Fathi
Al-Azhar University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry Department, Assiut 71524, Egypt.
Cairo University, Faculty of Pharmacy, Pharmaceutical Organic Chemistry Department, Cairo 11562, Egypt.
Bioorg Med Chem. 2017 Jun 15;25(12):2956-2970. doi: 10.1016/j.bmc.2017.03.002. Epub 2017 Mar 7.
A new series of pyrazolo[3,4-d]pyrimidines tethered with nitric oxide (NO) producing functionality was designed and synthesized. Sulforhodamine B (SRB) protein assay revealed that NO releasing moiety in the synthesized compounds significantly decreased the cell growth more than the des-NO analogues. Compounds 7C and 7G possessing N-para-substituted phenyl group, released the highest NO concentration of 4.6% and 4.7% respectively. Anti-proliferative activity of synthesized compounds on HepG2 cell line identified compounds 7h, 7p, 14a and 14b as the most cytotoxic compounds in the series of IC=3, 5, 3 and 5μM, respectively, compared to erlotinib as a reference drug (IC=25μM). Flow cytometry studies revealed that 7h arrested the cells in G0/G1 phase of cell cycle while 7p arrested the cells in S phase. Moreover, docking study of the synthesized compounds on EGFR (PDB code: 1M17) and cytotoxicity study indicated that N-1 phenyl para substitution, pyrazole C-3 alkyl substitution and tethering the nitrate moiety through butyl group had a significant impact on the activity.
设计并合成了一系列新的与产生一氧化氮（NO）功能基团相连的吡唑并[3,4-d]嘧啶。磺基罗丹明B（SRB）蛋白质分析表明，合成化合物中的NO释放部分比去NO类似物更显著地降低细胞生长。具有对-N-取代苯基的化合物7C和7G分别释放出最高的NO浓度，为4.6%和4.7%。合成化合物对HepG2细胞系的抗增殖活性确定化合物7h、7p、14a和14b是该系列中细胞毒性最强的化合物，其IC分别为3、5、3和5μM，相比作为参考药物的厄洛替尼（IC=25μM）。流式细胞术研究表明，7h使细胞停滞在细胞周期的G0/G1期，而7p使细胞停滞在S期。此外，合成化合物在表皮生长因子受体（EGFR，PDB代码：1M17）上的对接研究和细胞毒性研究表明，N-1苯基对位取代、吡唑C-3烷基取代以及通过丁基连接硝酸根部分对活性有显著影响。
