Pyrimidinyl-arylpropionic acid derivatives: viable resources in the development of new antineoplastic agents

Abstract

Numerous studies have documented that various naturally derived ligands or synthetic non-thiazolidinediones (TZD) as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have shown moderate or potent antitumor activities, which is PPARgamma independent or partially dependent. However, the PPARgamma agonistic or glucose-lowering activity is ranked first more often than antitumor activity to determine promising novel PPARgamma agonists for potential clinical use. In this study, we hypothesized that there might exist some compounds with less PPARgamma agonistic activity but potent antitumor activity. Thereafter, we evaluated the PPARgamma agonistic and antitumor activity of a novel series of alpha-aryloxy-alpha-methylhydrocinnamic acid derivatives synthesized with the initial aim of developing novel PPARgamma agonists as hypoglycemic agents. MTT assay results revealed that several compounds were able to inhibit cell proliferation in a dose-dependent manner with IC(50) 12.7-29.7 microM, better than that of rosiglitazone (45.9-141 microM), although the PPARgamma agonistic activity of most compounds is much lower than rosiglitazone. Some compounds induced cell cycle arrest and apoptosis tested by Flow Cytometry. Oral administration of DH9 (100 mg/kg/d) for 21 days to BALB/c nude mice bearing xenografts including MGC-803, NCI-H460, HT-29 and OS-RC-2 cells significantly retarded tumor growth. DG8 and DJ5 showed benefits in some of the above four xenografts. Our findings demonstrate that these compounds have potent antitumor activity in vitro and in vivo and pyrimidinyl-arylpropionic acid derivatives might be viable resources in the development of new antineoplastic agents.

DH9, a novel PPARγ agonist suppresses the proliferation of ADPKD epithelial cells: An association with an inhibition of β-catenin signaling

“…Since long-term treatment with rosiglitazone is known to cause weight gain, fluid retention, and some of devastating side effects, we have designed and synthesized a new group of PPARγ agonists for the purpose of minimizing the problem. After extensive screening, we have identified DH9 as a candidate which did not cause the weight gain in mice after 21 days of treatment [8]. Comparing with rosiglitazone, DH9 was a much potent inhibitor of ADPKD cell proliferation, with a magnitude of difference of 6-fold over rosiglitazone.…”

“…Interestingly, however, we found that DH9 exhibits a stronger anti-tumor activity. DH9 treatment substantially improves general health status and survival and reduces tumor size in multiple-tumors-bearing mice [8].…”

“…Thus, it is essential to develop new agent with a better long-term safety profile. To this end, we have synthesized and tested a new α-aryloxy-α-methylhydrocinnamic acid derivative, DH9 [8]. Comparing with TZDs, DH9 has a moderate PPARγ activity.…”