Youguang Zheng

Design and synthesis of novel Gefitinib analogues with improved anti-tumor activity

There is an urgent need to design and develop new and more potent EGFR inhibitors with improved anti-tumor activity. Here we describe the design and synthesis of two series of 4-benzothienyl amino quinazolines as new analogues of the EGFR inhibitor Gefitinib. The anti-tumor activity of these novel Gefitinib analogues in 6 human cancer cell lines was examined. Compared with the parental Gefitinib, most of the new compounds show a markedly increased cytotoxicity to cancer cells. Furthermore, several of the series B compounds that side chains at position 7 contain either a methyl or ethyl group are potent pan-RTK inhibitors. Two representative compounds in this class, 15 and 17, have an enhanced capability to inhibit cancer cell growth and induce apoptosis in vitro and inhibit tumor formation in vivo in human cancer cells with high HER-2, as compared with the parental Gefitinib. Thus they may be promising lead compounds to be developed as an alternative for current Gefitinib therapy or for Gefitinb-resistant patients, potentially via simultaneously blocking multiple RTK signaling pathways.

Design, Synthesis, and In vitro Antitumor Activity Evaluation of Novel 4-pyrrylamino Quinazoline Derivatives

Here, we describe the design and synthesis of two series of 4‐pyrrylamino quinazolines as new analogs of the epidermal growth factor receptor inhibitor gefitinib. In vitro antitumor activity of these novel compounds against pancreatic (Miapaca2) and prostate (DU145) cancer cell lines was evaluated. Compared with the parental gefitinib, all 18 derivatives show a greatly increased cytotoxicity to cancer cells. In vitro kinase inhibitory activity on epidermal growth factor receptor was also investigated. Among them, compounds GI‐6, GII‐4, GII‐6, GII‐8, and GII‐9 are more potential receptor tyrosine kinase (RTK) inhibitors. Based on these results, we propose simple structure–activity relationship to provide information for designing and developing more potent antitumor agents.

Design, synthesis, docking and antitumor activity of quinazolino [3, 4-a] thieno [3, 2-d] pyrimidin-8-one derivatives.

Several novel quinazolino [3, 4‐a] thieno [3, 2‐d] pyrimidin‐8‐one derivatives were synthesized. All of the compounds were determined against MiaPaCa2 and DU145 cells in vitro, and the crystal structures of analog 8 and 20 in the active site of the EGFR complexes were presented. The entire compounds had been identified by 1HNMR, 13CNMR, IR, MS and EA.

Design, Synthesis, and In vitro Antitumor Evaluation of Novel Phenylaminopyrimidine Derivatives

Two series of novel phenylaminopyrimidine derivatives were designed and synthesized. All target compounds were determined against the human acute monocytic leukemia cell line U937 and the human chronic myeloid leukemia cell line K562 in vitro. Some of the target compounds demonstrated significant inhibitory activity against both cell lines. Compared with the control drug VX-680, 8a, 8e, 8g, 8h, 8j, and 8k demonstrated more potent antitumor activity. The structures of all target compounds were identified by 1H-NMR, 13C-NMR, IR, MS, and EA.

Design, synthesis of novel quinazolone alkaloids derivatives as potential antitumor agents.

Several novel quinazolone alkaloids derivatives were synthesized. Some of the target compounds were determined against human prostate cancer DU145 and pancreatic cancer Miacapa2 cells in vitro. The entire compounds had been identified by ¹HNMR, ¹³CNMR, IR, MS and EA.

Novel preparation of gefitinib

A new synthesis of the anticancer drug gefitinib is described starting from methyl 3-hydroxy-4-methoxybenzoate. The sequence involves alkylation of the starting material, followed by nitration, reduction, cyclisation, chlorination and amination reactions. This new method has six steps, uses a much cheaper starting material and has higher yields than other methods. It is suitable for industrial production.