Synthesis And Bioactivity Evaluation Of New1,3,4-thiadiazoles Derivatives And Pyrazole Derivatives

In1992, focal adhesion kinase (FAK) was identified as a substrate for viral Src and as a highly tyrosine-phosphorylated protein that localized to cell adhesion sites known as focal contacts. It is known that FAK is activated from integrin and growth factor receptors by auto-phosphorylation, followed by subsequent activation of other functional phosphorylation sites to advance the signals to downstream pathways. FAK is overexpressed in many tumors. Furthermore, FAK overexpression is highly correlated with an invasive phenotype in these tumors. Based on these facts, FAK is thought to play a critical role in malignant behavior including proliferation, survival, and invasion. FAK therefore represents an important target for the development of anti-neoplastic and anti-metastatic drugs.A few differently substituted1,3,4-thiadiazoles have been found to exhibit anti-cancer activities which establishes this moiety as a member of the privileged structures class in pharmaceutical fields. Herein, we designed a series of1,3,4-thiadiazol-2-amide derivatives have been designed and synthesized, and their biological activities were also evaluated as potential antiproliferation and FAK inhibitors. Most of the synthesized compounds were proved to be potent anti-neoplastic drugs and FAK inhibitory. Among them, compound C8displayed the most potent inhibitory activity (IC50=0.45μM for MCF-7; IC50=0.31μM for B16-F10and IC50=5.32μM for FAK), comparable to the positive control Staurosporine (IC50=3.07μM for MCF-7; IC50=2.82μM for B16-F10and IC50=11.32μM for FAK respectively). This compound may be useful as a lead compound for superior FAK inhibitors. And the small-molecule docking simulations were performed to give the probable binding modes of these compounds into the FAK active binding site of FAK, which would give the support to these results.The tumor growth and metastatic depend on vascular network. In order to inhibit the occurrence and development of tumor, EGFR/HER-2have been proved to be key roles in tumor angiogenesis through the study of tumor vascular system. Researches on EGFR/HER-2as anticancer targets have become a hotspot.Pyrazole is a five membered heterocyclic ring which is a versatile lead compound for designing potent bioactive agents. This interesting group of compound has diverse biological activities such as anticancer, antimicrobial, anti-inflammatory, analgesic, anticonvulsant, antihelmintic, antioxidant, and herbicidal. Cinnamic acid derivatives are naturally occurring substances found in fruits, vegetables, flowers and are consumed as dietary phenolic compounds. These play a vital role in the formation of commercially important intermediate molecules which are necessary for the production of different pharmaceutical ingradients. Cinnamic acid derivatives have a great value for development because of their good anti-tumor activity.Herein, a series of (Z)-(1,3-Diphenyl-lH-pyrazol-4-yl)methyl3-phenylacrylate derivatives (le-30e) have been designed and synthesized, and their biological activities were evaluated for EGFR and HER-2inhibition and tumor cell antiproliferation. Most of the synthesized compounds were proved to be potent anti-neoplastic drugs and EGFR/HER-2inhibitory. Among all the compounds,30e showed the most potent activity (IC50=0.10μM for MCF-7; IC50=0.15μM for B16-F10; IC50=0.06μM for EGFR and IC50=0.19μM for HER2), comparable to the positive control Erlotinib (IC50=0.08μM for MCF-7; IC50=0.12μM for B16-F10; IC50=0.03μM for EGFR and IC50=0.14μM for HER-2). This compound may be useful as a lead compound for superior EGFR/HER-2inhibitors. And the small-molecule docking simulations were performed to give the probable binding modes of these compounds into the EGFR active binding site of EGFR, which would give the support to these results.