Synthesis of new para-aminobenzoic acid derivatives, in vitro biological evaluation and preclinical validation of DAB-2-28 as a therapeutic option for the treatment of bladder cancer

Abstract

Chronic inflammation plays a crucial role in bladder cancer (BCa) development and progression. To offer a unique treatment opportunity for this type of cancer, a hydrazide derivative namely, DAB-1, was recently identified in our laboratory as a potential drug to target cancer-related inflammation. In preclinical models of murine BCa, this particular compound exhibited remarkable anticancer activities. Structurally, DAB-1 is made from para-aminobenzoic acid and bears two different components, a maleimide and a hydrazide moieties, which are critical for its anti-inflammatory activity and its anticancer properties. In order to improve its biological potential, the hydrazide moiety was further modified to provide 3 ​s-generation molecules named, DAB-2-28, DAB-2-31A, and DAB-2-31B, and two third-generation molecules named, DAB-3-27 and DAB-3-33. Data from in vitro studies revealed that, among the different DAB molecules under study, DAB-2-28 has less cytotoxic activity with greater efficiency than DAB-1 to inhibit the production of nitric oxide (NO) induced by the combination of IFNγ with TNFα, as well as the activation of pro-tumoral and pro-inflammatory signaling pathways IL6/STAT3 and TNFα/NFκB. Moreover, while DAB-2-28 exhibited similar anti-inflammatory activity in vivo to DAB-1 in a model of carrageenan-induced acute inflammation, it efficiently inhibited the expression of the enzymes iNOS and COX-2 induced by the combined activation of IFNγ with LPS in peritoneal macrophages. Notably, analysis of the growth kinetics of MB49-I tumors implanted subcutaneously in C57Bl/6 mice showed that DAB-2-28 was more efficient to inhibit tumor development. In conclusion, this study provided preclinical proof-of-principle for DAB-2-28 molecule in the treatment of BCa.