Hossam Monia, Lasheen Deena S, Ismail Nasser S M, Esmat Ahmed, Mansour Ahmed M, Singab Abdel Nasser B, Abouzid Khaled A M
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt; Center for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt; Center for Drug Discovery and Development Research, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.
Eur J Med Chem. 2018 Jan 20;144:330-348. doi: 10.1016/j.ejmech.2017.12.022. Epub 2017 Dec 9.
Being responsible for the development of many cancer types, EGFR (Epidermal Growth Factor Receptor) and HER2 (Human Epidermal growth factor Receptor 2) were the focus of this study where a series of novel 4-anilino-furo[2,3-d]pyrimidine derivatives was designed, synthesized and biologically evaluated. Modification of the solvent accessible 5-position side chain greatly affected the in-vitro EGFR/HER2 inhibitory activity. Three derivatives bearing 5-carboxylic acid side chain, namely the 3-chloroanilino derivative (8c), the 3-bromoaniline (8d) and the lapatinib analogue (10) demonstrated the most significant submicromolar EGFR inhibition. Surprisingly, the in-vitro assay of the ester 7h and its acid analogue 10 showed a significant variation of results between the antiproliferative activity against A549 cell line (IC 0.5 and 21.4 μM) respectively and EGFR inhibitory activity (18% and 100%) respectively, suggesting that 7h might be a prodrug for 10. This assumption was also affirmed by the in-vivo results, where the in-vivo antitumor assessment against EAC (Ehrlich Ascites Carcinoma) solid tumor model revealed that 7h and 8d (10 mg/kg dose) exhibited antitumor activity comparable to that of gefitinib at the same dose, exhibiting TGI% of 67%, 71% and 70%, respectively. This effect could be explained, at least partly, via activation of apoptosis, where 7h and 8d caused more than 2-fold increase of caspase 3 and cytochrome c expression than the control group which is comparable to that of gefitinib-treated group. Finally, 7h was the most effective apoptotic inducer, resulting in a significant elevation in annexin V-FITC-positive apoptotic cells (both early and late apoptosis) by 25 and 79-folds, respectively, compared to control, which is higher than that of gefitinib (22 and 61-folds, respectively).
表皮生长因子受体（EGFR）和人表皮生长因子受体2（HER2）在多种癌症类型的发展中起作用，是本研究的重点。在此，设计、合成了一系列新型4-苯胺基-呋喃并[2,3-d]嘧啶衍生物，并进行了生物学评估。对溶剂可及的5位侧链进行修饰极大地影响了体外EGFR/HER2抑制活性。三种带有5-羧酸侧链的衍生物，即3-氯苯胺衍生物（8c）、3-溴苯胺（8d）和拉帕替尼类似物（10）表现出最显著的亚微摩尔EGFR抑制作用。令人惊讶的是，酯7h及其酸类似物10的体外试验显示，针对A549细胞系的抗增殖活性（IC分别为0.5和21.4 μM）与EGFR抑制活性（分别为18%和100%）之间结果存在显著差异，表明7h可能是10的前体药物。体内结果也证实了这一假设，在针对艾氏腹水癌（EAC）实体瘤模型的体内抗肿瘤评估中，7h和8d（剂量为10 mg/kg）在相同剂量下表现出与吉非替尼相当的抗肿瘤活性，TGI%分别为67%、71%和7%。这种效应至少部分可以通过凋亡激活来解释，其中7h和8d导致半胱天冬酶3和细胞色素c表达比对照组增加超过2倍，这与吉非替尼治疗组相当。最后，7h是最有效的凋亡诱导剂，与对照组相比，膜联蛋白V-FITC阳性凋亡细胞（早期和晚期凋亡）分别显著增加25倍和79倍，高于吉非替尼（分别为22倍和61倍）。
