Design,Synthesis And Anti-tumor Evaluation Of Quinazoline Libraries

The family of EGFR has been intensively studied by researchers in the past decades due to its strong influence on the formulation and deterioration of carcinoma. Meanwhile, the EGFR path way plays a vital role in the apoptosis, proliferation, differentiation, migration and cell cycle of cancer cells. On the basis of a deep understanding of the EGFR path way, it should be possible to artificially interfere with certain targets to block its signal transmission. Thus, it is a good strategy that design anti-cancer drug by inhibiting the activities of TK which is a key protein in the EGFR path way.The concept of Combinatorial Chemistry is firstly brought out in the early 1990s. In its few decades of development, Combinatorial Chemistry dramatically bloomed into a whole new field of study, whose main approach is by verifying different building blocks in the synthesis of a specific family of compounds. In addition, with the assist of high though-put screening method, it accelerates the procedure of discovering lead compounds.On the basis of early stages of study, our group has discovered a new co -mpound with much better antitumor activity than IRESSA (a commercialized a -nti-cancer drug). It has been reported that a family of thio-benzimidazole compounds to be an efficacious non-peptide luteinizing hormone-releasing hormone (LHRH) antagonists. For the purpose of identifyying better efficacy derivatives of this family and further exploration of the functionality of the structural relat -ed compounds, we initially synthesized a series of 4-aryl-7-fluoro-6-nitroquinaz -oline derivatives using solid phase parallel synthesis strategy, resulting 37 2-sulfanylsubstituted-3-substitutedl-8-arylamino-3H-imidazo[4,5-g]quinazoline compounds and 120 2-sulfonyl substituted-3-substitutedl-8-arylamino-3H-imidazo[4,5-g]quinazoline compounds for screening.Solid phase approach has the advantage of synthesizing a variety of compounds with a wide range of molecular diversity. However, this method is not able to produce a certain amount of the target compounds (> a few hundred mg). Since it has been proved that it is not very easy to synthesize arylamines with electron withdrawing groups which have pretty good pharmacological activity as the first building block, we synthesized 22 2,3-Disubstituted 8-Arylamino-3H-imidazo[4,5-g]quinazolines in solution. All compounds were tested their cytotoxicities against four human tumor cell lines, K562, Hela, KB and HePG2 cell lines. And compound 2-17 showed good inhibition activity against KB cell line. Further mechanism study is under way.