Identification and Quantification of Both Methylation and Demethylation Biotransformation Metabolites of 5-Demethylsinensetin in Rats

Abstract

5-Demethylated polymethoxyflavones (5-OH PMFs) are the most unique monodemethylated PMFs with relatively low polarities and are proved to possess better anticancer and anti-inflammatory effects than their respective permethoxylated ones. However, their detailed in vivo metabolic fates have not been fully studied. 5-Demethylsinensetin (5-OH Sin), being one of the 5demethylated citrus PMFs, was used in the present research to investigate its biotransformation in pharmacokinetics and excretion in rats. The results showed that 5-OH Sin was mostly accumulated in the large intestine, indicating its poor absorption in the small intestine. In addition, 5,3′-didemethylsinensetin and 5,4′-didemethylsinensetin were identified as two dominated metabolites of 5-OH Sin, and the C-3′ position of 5-OH Sin was more facile to be demethylated in systemic circulation. Moreover, other than demethylation reactions, the methylation transformation of 5-OH Sin and its metabolites were also observed and quantified, suggesting that the bidirectional biotransformation between 5-OH Sin and its parent compound, Sin, occurred under in vivo conditions.

Synthetic pathways of sinensetin and derivatives as an alternate source in biological activity study

“…Therefore, in the characterization of 5-demethylsinsensetin metabolites, the chemical synthesis of potential 5demethylsinensetin metabolites, such as 5,3′-didemethylsinensetin (24a, eupatorin), 5,4′didemethylsinensetin (24b, cirsilineol) and 5,3′,4′-tridemethylsinensetin (24c, cirsiliol) was the direct one-step 5-demethylation (Figure 6) from the prepared B-ring demethylated sinensetin (16a, 16b or 16c) illustrated in Figure 4. In detail, 5-demethylation of 3′-demethylsinensetin (16a), 4′-demethylsinensetin (16b) and 3′,4′-didemethylsinensetin (16c) yielded eupatorin (24a), cirsilineol (24b) (Wang et al, 2022) and cirsiliol (24c), respectively. Previously, benzyl ethers were employed for the protection of hydroxy group at the C-4′ position, but it complicated cirsilineol synthesis (Matsuura et al, 1973).…”

“…Thus, 5-demethylsinensetin and its metabolites were synthesized through a single-step, i.e. hydrochloric acid hydrolysis reaction (Wang et al, 2022). Overall, the syntheses of B ring demethylated derivatives of 5demethylsinensetin were achieved with one step reaction in high yields, which could be also introduced to the similar derivatization of 5-demethylated PMFs.…”