Novel Antidiabetic and Hypolipidemic Agents. 5. Hydroxyl versus Benzyloxy Containing Chroman Derivatives

Abstract

Several thiazolidinediones having chroman moieties were synthesized and evaluated for their euglycemic and hypolipidemic activities. Some of the analogues having an aminoalkyl group as a linker between the chroman ring and 4-[5-(2,4-dioxo-1, 3-thiazolidinyl)methyl]phenoxy moiety seem to be better than troglitazone. In vitro transactivation assays of PPARgamma have been carried out with these glitazones to understand their molecular mechanism. For the first time we have found that some of the unsaturated thiazolidinediones are superior to their saturated counterpart in the in vivo assay. A more potent thiazolidinedione analogue than troglitazone is reported. Pharmacokinetic studies have shown that protection of the OH group in the chroman moiety leads to a decrease in metabolism, thereby resulting in a superior pharmacological profile.

Design and Synthesis of Biotinylated Troglitazone as an Active Affinity Probe

“…On the other hand, it has been reported that protection of the hydroxyl group in the chroman ring of TGZ with benzyl retains its euglycemic and hypolipidemic activities in vivo. 19 This fact, together with the observation that tocopherol moiety alone does not induce physiological response similar to TGZ in HCT-116 cells, 10 suggests that the modification of the hydroxyl group in the chroman moiety would be well tolerated. To ensure a large conformational freedom of the bioactive TGZ motif, a poly(ethylene glycol) (PEG) linker with rational length was introduced to link it with the biotin tag.…”

“…20 Preparation of the probe was commenced with (R/S)-Trolox. 19 Reduction of the carboxyl acid group with LiAlH 4 yielded 1, which was then attached with the PEG linker to give 2. Reaction of 2 with 4-fluorobenzaldehyde afforded 3 with low yield, owing to partially denatured KOBu-t. Aldol reaction of 3 with thiazolidine-2,4-dione gave 4, which was reduced with MeOH-Mg to furnish 5 as a mixture of two diastereomer pairs (2R-5R/2S-5S and 2R-5S/2S-5R).…”

“…The solid was removed by filtration and the filtrate concentrated under reduced pressure to give a brown gum (190 mg, 93.6%), which was used in the next step without further purification. 19 …”

Synthesis and Antihyperglycemic Activity of Erythrose, Ribose and Substituted Pyrrolidine Containing Thiazolidinedione Derivatives

“…Thiazolidinediones have been shown to improve insulin sensitivity/glucose utilization in animal model and to enhance insulin sensitivity in human. [26][27][28][29] But, it was assumed that troglitazone has the hepatotoxicity [30][31][32] due to the enterohepatic circulation of the metabolites, that is quinone moiety.In order to prevent this and to discover novel compounds which have the ability to increase glucose utilization, we focused our attention on the modification of chroman moiety to erythrose, ribose and substituted pyrrolidine group. As a result of our efforts, in this paper, we describe the synthesis and the in vitro glucose utilization activity.…”

“…Thiazolidinediones have been shown to improve insulin sensitivity/glucose utilization in animal model and to enhance insulin sensitivity in human. [26][27][28][29] But, it was assumed that troglitazone has the hepatotoxicity [30][31][32] due to the enterohepatic circulation of the metabolites, that is quinone moiety.…”