Phenoxy- and Phenylamino-Heterocyclic Quinones: Synthesis and Preliminary Anti-Pancreatic Cancer Activity

The successful application of fragment-based drug discovery strategy for the efficient synthesis of phenoxy- or phenylamino-2-phenyl-benzofuran, -benzoxazole and -benzothiazole quinones is described. Interestingly, in the final step of the synthesis of the target compounds, unusual results were observed on the regiochemistry of the reaction of bromoquinones with phenol and aniline. A theoretical study was carried out for better understanding the factors that control the regiochemistry of these reactions. The substituted heterocyclic quinones were evaluated in vitro to determine their cytotoxicity by the MTT method in three pancreatic cancer cell lines (MIA-PaCa-2, BxPC-3, and AsPC-1). Phenoxy benzothiazole quinone 26a showed potent cytotoxic activity against BxPC-3 cell lines, while phenylamino benzoxazole quinone 20 was the most potent on MIA-PaCa-2 cells. Finally, electrochemical properties of these quinones were determined to correlate with a potential mechanism of action. All these results, indicate that the phenoxy quinone fragment led to compounds with increased activity against pancreatic cancer cells.

Automated summary

This study describes the successful application of fragment-based drug discovery strategy to efficiently synthesize phenylamino or phenoxy-substituted benzofuran, benzoxazole, and benzothiazole quinones. Unusual results were observed in the regiochemistry of the reactions between bromoquinones and phenol/aniline during the final step of the synthesis. The findings indicate that the phenoxy quinone fragment led to compounds with increased cytotoxic activity against pancreatic cancer cells. Electrochemical properties of these quinones were also determined to understand their potential mechanism of action.