Synthesis, preliminary structure-activity relationships, and in vitro biological evaluation of 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives as potential anti-inflammatory agents.

In our previous study, a series of 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives exhibited potent antiproliferative activities and an unique hepatocellular carcinoma (HCC)-specific anticancer activity was also observed. In further anti-inflammatory research, thienopyridine derivative 1a showed potent inhibition of nitric oxide (NO) production. So a series of thienopyridine analogues of 1a were synthesized and evaluated for anti-inflammatory activities. The structure-activity relationships (SARs) revealed that the most potent analogues 1f and 1o were identified as potent inhibitors of NO production with IC50 values of 3.30 and 3.24 µM, respectively. These results suggest that these 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives might potentially constitute a novel class of anti-inflammatory agents, which require further studies.

Novel pyrazolo[3,4-d]pyrimidine derivatives as potential antitumor agents: exploratory synthesis, preliminary structure-activity relationships, and in vitro biological evaluation.

In a cell-based screen of novel anticancer agents, the hit compound 1a which bears a pyrazolo[3,4-d]pyrimidine scaffold exhibited high inhibitory activity against a panel of four different types of tumor cell lines. In particular, the IC50 for A549 cells was 2.24 µM, compared with an IC50 of 9.20 µM for doxorubicin, the positive control. Four synthetic routes of the key intermediate 3 of 1a were explored and 1a was prepared via route D on the gram scale for further research. Two analogs of 1a were synthesized and their preliminary structure-activity relationships were studied. Flow cytometric analysis revealed that compound 1a could significantly induce apoptosis in A549 cells in vitro at low micromolar concentrations. These results suggest that the target compound 1a and its analogs with the pyrazolo[3,4-d]pyrimidine scaffold might potentially constitute a novel class of anticancer agents, which requires further studies.

A general synthetic procedure for 2-chloromethyl-4(3H)-quinazolinone derivatives and their utilization in the preparation of novel anticancer agents with 4-anilinoquinazoline scaffolds.

In our ongoing research on novel anticancer agents with 4-anilinoquinazoline scaffolds, a series of novel 2-chloromethyl-4(3H)-quinazolinones were needed as key intermediates. An improved one-step synthesis of 2-chloromethyl-4(3H)-quinazolinones utilizing o-anthranilic acids as starting materials was described. Based on it, 2-hydroxy-methyl-4(3H)-quinazolinones were conveniently prepared in one pot. Moreover, two novel 4-anilinoquinazoline derivatives substituted with chloromethyl groups at the 2-position were synthesized and showed promising anticancer activity in vitro.

Novel thienopyridine derivatives as specific anti-hepatocellular carcinoma (HCC) agents: synthesis, preliminary structure-activity relationships, and in vitro biological evaluation.

Novel thienopyridine derivatives 1b-1r were synthesized, based on a hit compound 1a that was found in a previous cell-based screening of anticancer drugs. Compounds 1a-1r have the following features: (1) their anticancer activity in vitro was first reported by our group. (2) The most potent analog 1g possesses hepatocellular carcinoma (HCC)-specific anticancer activity. It can specifically inhibit the proliferation of the human hepatoma HepG2 cells with an IC(50) value of 0.016µM (compared with doxorubicin as a positive control, whose IC(50) was 0.37µM). It is inactive toward a panel of five different types of human cancer cell lines. (3) Compound 1g remarkably induces G(0)/G(1) arrest and apoptosis in HepG2 cells in vitro at low micromolar concentrations. These results, especially the HCC-specific anticancer activity of 1g, suggest their potential in targeted chemotherapy for HCC.