Anticonvulsant activities of α-asaronol ((E)-3'-hydroxyasarone), an active constituent derived from α-asarone.

BACKGROUND: Epilepsy is one of chronic neurological disorders that affects 0.5-1.0% of the world's population during their lifetime. There is a still significant need to develop novel anticonvulsant drugs that possess superior efficacy, broad spectrum of activities and good safety profile. METHODS: α-Asaronol and two current antiseizure drugs (α-asarone and carbamazepine (CBZ)) were assessed by in vivo anticonvulsant screening with the three most employed standard animal seizure models, including maximal electroshock seizure (MES), subcutaneous injection-pentylenetetrazole (PTZ)-induced seizures and 3-mercaptopropionic acid (3-MP)-induced seizures in mice. Considering drug safety evaluation, acute neurotoxicity was assessed with minimal motor impairment screening determined in the rotarod test, and acute toxicity was also detected in mice. RESULTS: In our results, α-asaronol displayed a broad spectrum of anticonvulsant activity (ACA) and showed better protective indexes (PI = 11.11 in MES, PI = 8.68 in PTZ) and lower acute toxicity (LD50 = 2940 mg/kg) than its metabolic parent compound (α-asarone). Additionally, α-asaronol displayed a prominent anticonvulsant profile with ED50 values of 62.02 mg/kg in the MES and 79.45 mg/kg in the sc-PTZ screen as compared with stiripentol of ED50 of 240 mg/kg and 115 mg/kg in the relevant test, respectively. CONCLUSION: The results of the present study revealed α-asaronol can be developed as a novel molecular in the search for safer and efficient anticonvulsants having neuroprotective effects as well as low toxicity. Meanwhile, the results also suggested that α-asaronol has great potential to develop into another new aromatic allylic alcohols type anticonvulsant drug for add-on therapy of Dravet's syndrome

Improved process for pilot-scale synthesis of danshensu ((±)-DSS) and its enantiomer derivatives

A pilot-scale process has been developed for green and scalable synthesis of (±)-?-(3,4-dihydroxyphenyl) lactic acid ((±)-DSS) and their two important derivatives, namely, (±)-IDHP [(±)-isopropyl 2-hydroxy-3-(3,4-dihydroxyphenyl)propanoate] and (±)-DBZ [(±)-bornyl 2-hydroxy-3-(3,4-dihydroxyphenyl)propanoate]. Subsequent hydrogenation has been carried out by employing Raney Ni as catalyst. The improved process results in higher yields of 47.5% for (±)-DBZ and 49.2% for (±)-IDHP compared to the initial process with a yield of 12% for (±)-DBZ and 18% for (±)-IDHP in our original medicinal chemistry route. Furthermore, kilograms of optical DBZ [(?)-S-DBZ and (+)-R-DBZ, >99% ee] and IDHP [(?)-S-IDHP and (+)-R-IDHP, >99% ee] have been produced by chiral high-performance liquid chromatography in good yield (>84%)

Improved Process for Pilot-Scale Synthesis of Danshensu ((±)-DSS) and Its Enantiomer Derivatives

A pilot-scale process has been developed for green and scalable synthesis of (±)-β-(3,4-dihydroxy­phenyl) lactic acid ((±)-DSS) and their two important derivatives, namely, (±)-IDHP [(±)-iso­propyl 2-hydroxy-3-(3,4-di­hydroxy­phenyl)­propano­ate] and (±)-DBZ [(±)-bornyl 2-hydroxy-3-(3,4-di­hydroxy­phenyl)­propano­ate]. Subsequent hydrogenation has been carried out by employing Raney Ni as catalyst. The improved process results in higher yields of 47.5% for (±)-DBZ and 49.2% for (±)-IDHP compared to the initial process with a yield of 12% for (±)-DBZ and 18% for (±)-IDHP in our original medicinal chemistry route. Furthermore, kilograms of optical DBZ [(−)-<i>S</i>-DBZ and (+)-<i>R</i>-DBZ, >99% ee] and IDHP [(−)-<i>S</i>-IDHP and (+)-<i>R</i>-IDHP, >99% ee] have been produced by chiral high-performance liquid chromatography in good yield (>84%)

Discovery of anti-inflammatory dihydroxylated phenolic acids in patients with severe cardiac symptoms and conditions associated with inflammation and hypoxia

Our initial studies detected elevated levels of 3,4-dihydroxyphenyllactic acid (DHPLA) in urine samples of patients with severe cardiac symptoms when compared with healthy subjects. In view of the reported anti-inflammatory properties of DHPLA and related dihydroxylated phenolic acids (DPAs), we embarked on a multi-centre investigation to establish the possible pathophysiological significance and therapeutic implications of these findings. Chinese and Caucasian patients with severe cardiac symptoms and those being treated for conditions associated with inflammation (WBC ≥ 10×109/L or hsCRP ≥ 3.0 mg/L) and/or hypoxia (PaO2 ≤ 75 mmHg) were enrolled, their urine samples were analyzed by HPLC, HPLC-MS, GC-MS and biotransformation assays. DHPLA was detected in urine samples of patients, but undetectable in healthy volunteers. Dynamic monitoring of inpatients undergoing treatment showed their DHPLA levels declined in proportion to their clinical improvement. Proteus vulgaris and P. mirabilis were significantly more abundant in DHPLA-positive patients’ fecal samples than healthy volunteers. In culture, these bacteria were capable of reversible interconversion between DOPA and DHPLA. Furthermore, porcine and rodent organs were able to metabolize DOPA to DHPLA and related phenolic acids. The elevated levels of DHPLA in these patients suggest anti-inflammatory DPAs are generated de novo as part of a human’s defense mechanism against disease. Given that DHPLA isolated from Radix Salvia miltiorrhizae has multi-dimensional pharmacological activities, these data demonstrate not only scientific basis of the ethnopharmacological uses of this medicinal plant but also highlight the therapeutic potential of endogenous, natural or synthetic DPAs and their derivatives in humans