Anti-esophageal Cancer Activity Of The Novel Diary [1,3] Diazepines And Their Derivatives

Esophageal cancer is one of the six most common cancers worldwide. With itshighest incidence rate and fatality rate in China, identification of small molecules asnovel drugs in esophageal cancer treatment has been an important effort in cancerresearch. Avoiding apoptosis and cell cycle disorders are two critical aspects affectingsix biological hallmarks of esophageal cancer cells. Activation of anti-apoptoticsignaling pathways significantly contributes to tumorigenesis and drug resistancewhich leads to poor clinical outcome. On the other hand, cell cycle disorders causedby environmental stresses or spontaneous mutations may also promote tumorigenesis.As such, apoptotic or cell cycle signaling molecules are still the major targets in thedevelopment of anti-cancer drugs.Design, synthesis and optimization of lead compounds is an important step ininnovative drug research. Lead compounds often fail to be candidates for clinicalapplication due to their various shortcomings such as weak activity, low specificity,unreasonable pharmacokinetic properties, and unacceptable toxicity and so on.However, as the starting molecule for structure and activity study, lead compoundsplay an integral guiding role. Searching for lead compounds is a crucial step indeveloping novel drugs.By analyzing compound library, we obtained the novel compoundsDiaryl[1,3]diazepines. First, we identified the hit compounds by screening the growthinhibitory activity of these compounds to esophageal cancer cells. Second, theoptimized hit compounds were further evaluated on their toxicity to esophageal cancercells, resulting in identification of two more potent compounds named as500191and500192. Third, analysis of apoptosis and cell cycles by flow cytometry in500191or500192treated cells indicated that these two compounds were able to induce apoptosis while causing minor cell cycle arrest if any. Finally, the experimentalresults of the ELISA detecting caspase activity and western blot detecting caspaseactivation indicated that500191and500192induced apoptosis in esophageal cancercells probably by cell death receptor pathway and mitochordria pathway. Theseresults provided important experimental basis for further research and development ofnovel chemotherapy drugs for esophageal carcinoma.