Novel Resveratrol-Based Aspirin Prodrugs: Synthesis, Metabolism, and Anticancer Activity

Abstract

Regular aspirin use has been convincingly shown to reduce the risk of colorectal cancer. However, long-term use of aspirin leads to gastrotoxicity. Herein, we designed and synthesized a novel class of resveratrol-based aspirin prodrugs to simultaneously release aspirin and resveratrol to attenuate the side effects caused by aspirin. Prodrug RAH exerted enhanced anticancer activities which are better than a physical mixture of aspirin and resveratrol as well as each individually. Metabolism of RAH in mice showed that the majority of RAH is decomposed to release resveratrol and aspirin or salicylic acid either in the intestine or after absorption. Mechanistic studies demonstrate RAH inhibits cell cycle arrest through downregulation of cyclins and induces apoptosis by activation of caspase-3 in cancer cells. These findings highlighted the improved anticancer properties of resveratrol-based aspirin prodrugs. RAH may represent novel and safe alternatives of aspirin for the purpose of daily use in the future.

Gastroprotective [6]-Gingerol Aspirinate as a Novel Chemopreventive Prodrug of Aspirin for Colon Cancer

“…This observation could be due to the structural skeleton composed of 6G and ASA with higher anticancer properties than those of individuals, or 6G + ASA, similar to our previous findings on the combination of resveratrol and ASA25. AMS and MS failed to strengthen the anticancer activity of aspirin, suggesting that methyl ester makes little contribution to aspirin while gingerol ester is a specific building block of GAS for various beneficial physiological effects of aspirin.…”

“…5i′-p′). Meantime, we found SUA, another metabolite of ASA25, in the feces and urine samples (Fig. 5o′-p′).…”

“…5). The presence of gingerdiols, ( 3R,5S )-[6]-gingerdiol (M1) and ( 3S,5S )-[6]-gingerdiol (M2), in mice was evidenced by comparing MS/MS fragmentation patterns with published data in our previous studies (Table 1)2425. Under positive ESI mode, GAS was found to be almost intact in the stomach, partly hydrolyzed in the proximal intestine and then fully decomposed in the distal intestine to release 6G and ASA in 2 h after oral administration (Fig.…”

“…5m and n). On the other hand, SA, a major metabolite of ASA25, was abundant in the tissues of stomach and colon, plasma, feces, and urine under a negative ESI mode (Fig. 5i′-p′).…”

Design, synthesis and biological evaluation of hybrids of β-carboline and salicylic acid as potential anticancer and apoptosis inducing agents

“…Epidemiological studies suggested that the regular intake of aspirin was associated with a reduction in the incidence of malignancies, including colorectal, gastrointestinal, and lung cancer1718. Recent studies demonstrated that aspirin and its metabolite salicylic acid (SA), and their derivatives could induce apoptosis in several colorectal carcinoma cell lines19202122.…”