Bone-targeting glycol and NSAIDS ester prodrugs of rhein: Synthesis, hydroxyapatite affinity, stability, anti-inflammatory, ulcerogenicity index and pharmacokinetics studies

Although rhein and NSAIDs are potent anti-inflammatory drugs, their use has been limited by the high incidence of gastrointestinal erosions and the necessity to deliver the drug to specific sites of target organ. Using the prodrug approach, a series of rhein–NSAIDs prodrugs containing anthraquinone bone-targeting moiety were synthesized by linking rhein with NSAIDs through glycol ester. The target compounds demonstrated significant capability of binding to HAP and were hydrolytically activated in physiological conditions. Hybrid rhein–NSAIDs prodrugs exhibited significant anti-inflammatory activity, moreover, the tested compounds were also found to possess less degree of ulcerogenic potential. Our pharmacokinetic studies of 7e demonstrated this prodrug is a potential candidate for a slower and sustained release form of rhein.

Graphical abstractUsing the prodrug approach, a novel series of rhein–NSAIDs ester prodrugs containing anthraquinone bone-targeting moiety were synthesized by linking rhein with NSAIDs through glycol ester.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Using the prodrug approach, novel rhein–NSAIDs prodrugs were synthesized. ► The target compounds demonstrated significant capability of binding to HAP. ► Hybrid rhein–NSAIDs prodrugs exhibited significant anti-inflammatory activity. ► The tested compounds were found to possess less degree of ulcerogenic potential. ► PK studies showed 7e is a slower and sustained release form of rhein.