Abstract
Novel daidzein napsylates (DD4 and DD5) were synthesized by microwave irradiation, according to structural modification of daidzein (DAI) using the principle of pharmacokinetic transformation. The pharmacological properties of DD4 and DD5 were evaluated via high performance liquid chromatography (HPLC) and calculated based on the drug design software ChemAxon 16.1.18. The cell uptake changes of DD4 and DD5 were investigated to analyse the structure–property relationship. The metabolisms of DD4 and DD5 were analysed by HPLC-mass spectrometry in human aortic vascular smooth muscle cells (HAVSMCs) and their possible metabolic pathways were inferred in vivo. The results showed that the solubility of DD4 and DD5 was increased by 2.79 × 105 and 2.16 × 105 times compared to that of DAI, separately, in ethyl acetate. The maximum absorption rates of DD4 and DD5 were enhanced by 4.3–4.5 times relative to DAI. Preliminary studies on metabolites of DD4 and DD5 in HAVSMCs showed that DD4 and DD5 were hydrolysed into DAI under the action of intracellular hydrolase in two ways, ester hydrolysis or ether hydrolysis. Then, DAI was combined with glucuronic acid to form daidzein monoglucuronate under the action of uridine diphosphate (UDP)-glucuronidase. Meanwhile, it was also found that metabolite M5 of DD5 could undergo glucuronidation under the action of UDP-glucuronosyltransferase and competitive sulphation under the action of sulphotransferase to produce its sulfate conjugate M7. Analysis of structure–property relationships indicated that the absorption and utilization of drugs is closely relative to the physical properties and could be improved by adjusting the liposolubility. The pharmaceutical properties were optimized comprehensively after DAI was modified by naphthalene sulphonate esterification. This indicates that this kind of derivatives may have relatively good absorption and transport characteristics and biological activities in vivo. The research on biological activities of the new derivatives (DD4 and DD5) is ongoing in our laboratory.
Highlights
Daidzein (DAI, 40, 7-dihydroxyisoflavone) is a secondary metabolite in soya beans that (i) plays an important role in (a) the treatment of a variety of cancers [1] and (b) the prevention of cardiovascular disease [2], (ii) has hypoglycaemic activity [3], (iii) exerts anti-oxidation and anti-inflammatory effects [4] and positive effects on cerebral ischaemic injury [5], and (iv) has other important physiological functions
Ysuda et al [6] reported that orally administered DAI was absorbed from the small intestine and metabolized in combination with glucuronide and sulphuric acid under the action of uridine diphosphate (UDP)-glucuronidetransferase and sulphotransferase in the liver
Xu et al [7] found that daidzein-7-glucuronic acid conjugate, daidzein-7sulphuric acid conjugate and daidzein-7-glucuronic acid-4’-sulphuric acid conjugate were the major forms after multiple intragastric administration of DAI in the plasma of rats
Summary
Daidzein (DAI, 40, 7-dihydroxyisoflavone) is a secondary metabolite in soya beans that (i) plays an important role in (a) the treatment of a variety of cancers [1] and (b) the prevention of cardiovascular disease [2], (ii) has hypoglycaemic activity [3], (iii) exerts anti-oxidation and anti-inflammatory effects [4] and positive effects on cerebral ischaemic injury [5], and (iv) has other important physiological functions. Ysuda et al [6] reported that orally administered DAI was absorbed from the small intestine and metabolized in combination with glucuronide and sulphuric acid under the action of uridine diphosphate (UDP)-glucuronidetransferase and sulphotransferase in the liver. The products, glucuronide and sulphuric acid conjugate, were excreted through urine and bile, and underwent strong hepatointestinal circulation. This suggested that the combined metabolism was its main metabolic pathway. Qiu’s research [9] proved that it was rapidly absorbed and converted into daidzein-7-O-glucuronide by the first-pass metabolism after intragastric administration of DAI solution in rats and the absolute bioavailability calculated on the basis of free DAI was 12.8%. It is hoped that their pharmaceutical properties can be improved through changes in the structure in order to enhance their biological activity
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