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

Abstract

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 100nM to 200nM 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 100nM to 500nM. Intraperitoneal injection with a dosage of 5mg/kg/d of CSUOH0901 to nude mice suppresses HT29 colorectal xenograft growth. Pharmacokinetic studies demonstrate the good bioavailability of the compound.

Synthesis and Anticancer Mechanism Investigation of Dual Hsp27 and Tubulin Inhibitors

“…Our previous efforts to develop the potent anticancer agents led to the discovery of compound 48 (NSC751382, 25 Figure 1), benzo[1,3]dioxole-5-carboxylic acid [3-(2,5-dimethylbenzyloxy)-4-(methanesulfonylmethylamino)phenyl]amide, which displayed potent antiproliferative activity against various cancer cell lines with IC 50 values in the range of 0.1–0.5 μ M. The molecular targets of this compound were subsequently identified to be Hsp27 and tubulin. 24 In the present study, a total of 42 new derivatives based on compound 48 were synthesized using combinatory strategy.…”

“…These six substituted aryl groups were previously demonstrated to be the best fit while keeping B position as 2,5-dimethylbenzyl and C position as methylsulfonamide and D position as methyl group. 25 We anticipated that the new combination of A and B moieties would generate more active compounds. Additionally, the alternative to methylsulfonamide at C position was investigated by substitution with the trifluoromethylsulfonamide group.…”

Hyaluronic acid–nimesulide conjugates as anticancer drugs against CD44-overexpressing HT-29 colorectal cancer in vitro and in vivo

“…33 Nimesulide, a selective cyclooxygenase 2 inhibitor, is a drug with anti-inflammatory, analgesic, antipyretic properties 34,35 and chemopreventive activity against urinary bladder, colon, liver and breast carcinogenesis. [36][37][38] It is reported that nimesulide induces cell apoptosis and inhibits tumor growth in various types of cancer in both in vitro and in vivo studies; [39][40][41][42][43] however, poor water solubility of nimesulide limits its biomedical applications. 44,45 General dosage forms of nimesulide are tablets or capsules for anti-inflammatory treatments.…”

In vitro and in vivo evaluation of tubulin inhibitors with non-small cell lung cancer pre-clinical models

“…Some of these agents interfere with tubulin and Hsp27 to suppress proliferation of cancer cells. These dual inhibitors represent a class of new agents that can block two anti-cancer targets [24][25][26]. They showed different selectivity on inhibiting tubulin polymerization and Hsp27 chaperone function, however decreased cancer cell proliferation with IC 50 s around sub nano-molar level.…”

“…Previously we developed a series of novel anti-cancer agents [24][25][26]. Some of these agents interfere with tubulin and Hsp27 to suppress proliferation of cancer cells.…”