From COX-2 inhibitor nimesulide to potent anti-cancer agent: Synthesis, in vitro, in vivo and pharmacokinetic evaluation

Cyclooxygenase-2 (COX-2) inhibitor nimesulide inhibits the proliferation of various types of cancer cells mainly via COX-2 independent mechanisms, which makes it a good lead compound for anti-cancer drug development. In the presented study, a series of new nimesulide analogs were synthesized based on the structure–function analysis generated previously. Some of them displayed very potent anti-cancer activity with IC50s around 100 nM–200 nM to inhibit SKBR-3 breast cancer cell growth. CSUOH0901 (NSC751382) from the compound library also inhibits the growth of the 60 cancer cell lines used at National Cancer Institute Developmental therapeutics Program (NCIDTP) with IC50s around 100 nM–500 nM. Intraperitoneal injection with a dosage of 5  mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound.

Graphical abstractCSUOH0901, a non-COX-2 inhibitory derivative of COX-2 inhibitor nimesulide, significantly suppresses the growth of multiple cancer cell lines with IC50s around 100–500 nM.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► COX-2 inhibitor nimesulide inhibited cancer cell growth independent of COX-2. ► A set of non-COX-2 active nimesulide anti-cancer derivatives were synthesized. ► The potential hepatotoxicity of nimesulide derivatives was also abolished. ► New analogs showed very promising in vitro and vivo anti-cancer activity.