Synthesis Andantitumor Activity Of Salicylaldehyde Acylhydrazone Having 1,4-Benzodioxanfragment As A Novel Class Of Potent Epidermal Growth Factor Receptor (EGFR) Inhibitors

The increase of the daily pressure and environmental deterioration are trigger to the surging in carcinoma morbidity. Cancer is becoming the top killer for human. From 1991 to 2000, the global morbidity of cancer and death toll is inclined to 22%. By 2020, the number of new onset will reach to 15 million. The cancer, exceeding Cardio-cerebrovascular diseases, will become the most important lethal disease by then. Becoming the most serious problem in public health, cancer also impacts the family happiness and life quality. There are all kinds of cancer. For the male, it often occur in the lung, stomach, prostate and colon; for the women, however, it usually be seen in breast, uterus, colon and lung. In China, the cancers in high incidence are the lung, liver, stomach, esophageal and colon carcinoma. With the development of the science and technology, some treatments to cancer were invented. Although the conventional surgery and chemotherapy were improved mostly, many insufficiencies, such as incomplete removal and the serious side-effects, are still existed. So, it maintains practical significance for researching the target-specificity drug to cancer.There are many target for cancer occurrence. The Epidermal Growth Factor Receptor (EGFR) that modulates the proliferation of tumor cells, one kind of tyrosine kinase receptor, has the direct relationship with cancer’s triggering. Through inhibiting the EGFR, most anti-cancer drugs, such as Erlotinib and Lapatinib, could achieve the purpose of treating cancer.Acylhydrazones are a class of Schiff base compounds with a common structure of-C(O)-NH-N=C-, which are usually prepared via the condensation of aldehydes or ketones with acylhydrazines. Moreover, acylhydrazones have aroused considerable attention due to their particular physical, chemical, and biological activities based on their unique structures and they are known to present a wide spectrum of biological properties, such as antimicrobial, and anticancer activities. The salicylaldehyde, a spice, is widely used in drug synthesis. Many reports acclaimed salicylaldehyde obtains the action to anticancer. What’s more, the 1,4-benzodioxanis an important structure for medicine and found widely in nature. It was reported that a variety of compounds of the 1,4-benzodioxan showed potent biological activities, such as anticancer and antidepressant.Now, many compounds with hydrazone scaffold could be showed anti-proliferative action to the cancer cell line in vitro. However, the targets of them were under unknown. Many small molecular EGFR inhibitors, such as Geftinib, Erlotinib and Lapatinib, are belong to the 4-anilinoquinazoline series. The research have been found that the the hydrogen bond array of salicylamidecould mimic the prymidine ring of quinazolines. And these compounds similarly showed the inhibition for EGFR. For the more, according to mimic the 4-anilinoquinazoline series, the 4-amino-6-arylamino-pyrimidine-5-carbaldehyde oxime and 4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazon with dual EGFR inhibitory functions have been reported to inhibit tumor cell proliferation of breast carcinoma in vitro. Based on the above research, we inferred that our compounds D1-D8, E1-E8, F1-F8 might be showed the inhibitory activity to EGFR by the same means.Based on the above statement, Three series of salicylaldehyde acylhydrazone derivatives D1-D8, E1-E8 and F1-F8 had been synthesized and evaluated for their EGFR inhibitory and anti-proliferation activities. Compound D4 displayed the most potent activity against A549 and MCF-7 cancer cell lines (IC50=0.04μM,GI50-A549= 0.11μM, GI50-MCF-7= 012μM), which was compared with the positive control. Docking simulation by positioning compound D4 into the EGFR structure active site was performed to explore the possible binding model. And 24 compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Therefore, compound D4 with potent inhibitory activity in tumor growth inhibition might be a potential antitumor agent against cancer cell.