Research Progress on the Pharmacological Activity and Structural Modification of Sinomenine

Sinomenine is an isoquinoline alkaloid isolated from Qingfeng vine, a traditional Chinese medicine for the treatment of rheumatic diseases. In recent years, scholars at home and abroad have conducted in-depth research on its pharmacological effects, and found that it has anti-inflammatory, immune, analgesic, antihypertensive, anti-arrhythmic and other physiological activities. Clinically, its hydrochloride preparation is commonly used for the treatment of rheumatoid arthritis and arrhythmia, and has achieved good therapeutic effects.

Pharmacological effects of Sinomenine 

(1) Effect on the cardiovascular system

Sinomenine can affect heart function and has obvious anti-arrhythmic effects, and experiments have confirmed that Sinomenine can prolong LVET and QS2 during cardiac contraction in rabbits, and it is a blood concentration-dependent trend. The experimental results showed that Sinomenine had the effect of inhibiting the transmembrane current of Na+ and K+. The results of patch-clamp whole-cell recording showed that Sinomenine had concentration- and frequency-dependent blocking effects on INa and concentration-dependent blocking effect on Ca-L. 

(2) Effect on the central nervous system

Sinomenine has a significant stabilizing effect. Sinomenine can significantly inhibit the spontaneous activity and passive activity of animals, manifested as reduced activity, quiet, drooping eyelids, animal experimental studies have found that Sinomenine has a good effect on large, mouse opioid-dependent withdrawal symptoms, the inhibitory activity of enkephalin receptors is more than 75%, and it is not addictive. Qingfeng vine can produce obvious inhibitory and blocking effects on the inhibition and blocking effect of morphine-dependent isolated guinea pig ileum, and the higher the dose, the more obvious the inhibitory effect. It can significantly reduce the urge withdrawal symptoms and weight loss in morphine-dependent mice; Sinomenine can eliminate the conditional position preference for morphine production, and its mechanism of action is related to the reduction of central cAMP levels. It can also regulate the disorder of neurotransmitter levels in the brain of morphine-dependent rats, and reduce the sudden increase of monoamine neurotransmitters after withdrawal. These studies suggest that Sinomenine can be used not only for the treatment of opioid withdrawal symptoms, but also for the treatment of other drug dependence.

(3) Anti-inflammatory effect

Sinomenine has anti-inflammatory effects on chemical, proteinic, and bacterial inflammation, and Sinomenine tablets with Sinomenine as the main component can significantly reduce the number of twists in mice, and there is a good correlation between dose and inhibition rate. Sinomenine has obvious analgesic effect on experimental mice, and the mechanism may be that Sinomenine has the effect of inhibiting the synthesis and release of local PGE in inflammation. The therapeutic effect of Sinomenine on adjuvant arthritis and the effect of nitric oxide and related inflammatory mediators in the secondary validation area showed that the therapeutic effect of Sinomenine rheumatoid arthritis was related to its inhibition of cytokine activity in the local area of inflammation and the reduction of inflammatory mediator content, and the reduction of NO level by Sinomenine may be an important mechanism of anti-rheumatoid arthritis.

Synthesis and structural modification of Sinomenine derivatives

Sinomenine has low bioavailability and is rapidly metabolized in the body, resulting in its inability to exert its efficacy in time. Therefore, in recent years, the structure of Sinomenine has been modified and optimized, and the derivatives synthesized by structural modification have been studied more. Sinomenine is composed of hydrophenanthrene nucleus and ethylamine bridge, which is similar in structure to morphine and codeine, and its structure is shown in the figure below. The Sinomenine skeleton is composed of four rings: A, B, C, and D, wherein A ring is a benzene ring, B ring is a semi-chair six-membered ring connected to a ring, C ring is  a twisted chair six-membered ring with a α and β unsaturated ketone structure connected to B ring, and D ring is a nitrogen-containing chair six-membered ring below the B ring. 

Fig.1 Structure of Sinomenine (source reference [1]).

1. Structural modification of A-ring

The A ring of Sinomenine is a benzene ring, and there are 1 methoxy group and 1 hydroxyl group attached to the 3 and 4 positions, respectively. Most of the modifications for the A-ring are concentrated in the more active 1 and 4 positions, and some modifications occur in the 2 and 3 positions, but they are relatively rare. Some scholars have synthesized three derivatives of Sinomenine by chemical methods, including 4-methoxymetomenine, 1-bromomethinine and 10-dehydro-3-keto-memenine, using Sinomenine as raw material. Under the condition of p-toluenesulfonic acid as a catalyst, Sinomenine and tetrahydropyrrole are reacted in toluene to generate 5-(N-pyrrolidyl)Sinomenine, which is then acylated and acidically hydrolyzed at low temperature, and finally 4-acetoxy-5-Acetylthininine derivative. Using Sinomenine or denitromethylmemenine as raw materials, a diSinomenine derivative can be obtained by connecting a carbon-carbon method at the A ring 1 position, and the derivative showed good biological activity in pharmacodynamic tests. Using Sinomenine as raw material, the Heck reaction and the 1,3 dipole cycloaddition reaction at the A ring 1 position can introduce halogens, carbon-carbon double bond substituents or isozoline heterocycles, and these derivatives have good anti-inflammatory activity. 

Using Sinomenine as raw material, 1-ethyl-(3-dimethylaminopropyl)carboyldiimide hydrochloride (EDC), palmitate (PA) and 4-dimethylaminopyridine () were added sequentiallyDM AP), room temperature reaction to complete. Finally, 4-hydroxy-palmitate Sinomenine compound can be obtained, and the same concentration of Sinomenine and Sinomenine 4-hydroxy-palmitate were injected into lipopolysaccharide-induced endotoxemia mice, and it was found that Sinomenine 4-hydroxy-was injectedPalmitate mice showed an improvement in survival. Seven derivatives were successfully synthesized by the more common acylation and etherification of the 4-position phenolic hydroxyl group, and the activity of these seven derivatives was detected by mouse writhing body and rat plantar swelling model, and the results showed that the activity of some derivatives was better, but the synthetic yield was low, and the free phenolic hydroxyl group was easy to be oxidized and more easily decomposed when it entered the body, so it was necessary to increase the dosage. 

After a comprehensive analysis of the natural structure of Sinomenine and its derivatives and their previous modifications, a series of derivatives were synthesized by introducing 1,2,3-triazole or substituted benzyl at the 4th position, and the lipopolysaccharide-induced NF-κB activity was tested, and some of the activities were found to be better than those of Sinomenine. According to the properties and characteristics of Mannich base compounds, the Mannich reaction was carried out with Sinomenine hydrochloride, aldehydes and amines as raw materials. Two new derivatives of 1-position substitution were synthesized, and then further exchanged with aromatic amines and morpholine to obtain 1 new compound and 8 derivatives, and the anti-inflammatory activity of mice with xylene-induced oricula inflammation was screened, and some derivatives were found to have good pharmacological effects. By the  Mitsunobu reaction to modify Sinomenine by the Mitsunobu reaction, five new derivatives of 4-X benzylmemenine compounds were obtained by reacting with memenine hydrochloride and benzyl alcohol as raw materials in an ice bath, and then further reduced by 4-X benzylmemenine and lithium aluminum tetrahydrochloride to obtain five reduced 4-X benzylmemenine compounds, and finally by ACE-Cl demethylation, one 4-X benzylmemenine demethylated compound was obtained. Pharmacodynamic experiments were carried out on 10 of them, and it was found that two of the derivatives were superior to Sinomenine in terms of toxicity and activity. 

2. Structural modification of the B-ring

The structural transformation of the B-ring is mostly concentrated in the 10-position and 14-position. Some scholars used Sinomenine as raw material and methanol as solvent, added diacetoxyiodobenzene (DIB), and reacted to complete at room temperature to obtain two derivatives of 10 β-acetoxymedomenine and 10 β-methoxymetomenine. When the 14-position of Sinomenine was modified, the O-hydroxyl group or O-acyl Sinomenine was first oxidized to obtain a 14-hydroxy-O-methylSinomenine derivative, and then the 14-position hydroxyl group was acylated, and finally the product 14-acetoxy-O-methylmemenine was reduced. At the same time, the structure of A and B rings was modified, due to the existence of phenolic hydroxyl groups that are easily oxidized in Sinomenine, through a series of oxidation and conjugate addition reactions, a C-10 substituent group was introduced at the 10th position of B ring for modification, and TNF-α inhibition test was carried out on the derivative, and the results showed that when the substituent was AcOH3CO, the anti-inflammatory activity of the derivative was better. 

3. Structural modification of the C ring

The structural modification of Sinomenine C ring is mainly concentrated on the 6-bit, 7-bit and 7,8 double bonds. Sinomenine derivatives with pyrazine rings were obtained by reacting the hydrolysate of Sinomenine with 1,2-diaminyl compounds, and it was found that such derivatives had better immunomodulatory functions through cell experiments. The other method is to dissolve the hydrolysate of Sinomenine and aldehyde and ammonium acetate in ethanol and react at room temperature, which has a high yield and can be applied to industrial production. It was synthesized from orthodione-containing Sinomenine and confirmed through a series of activity experiments that embedding the rigid lipophilic drug-like monomer into the C ring of Sinomenine could improve its immunosuppressive activity. The structural modification of the C ring by the method of ring reduction can obtain the Sinomenine derivative with (+)-Cnormorphinan backbone. Firstly, the Mitsunobu methylation reaction was used for Sinomenine, and then the hydroxyl group of the A ring was modified to obtain the 4-position O-methylmedomenine, and then through acid hydrolysis (C-cyclodione derivative), boron hydration reaction oxidation ring opening (O-methylSinomenine dialdehyde derivative), aldol condensation [(+)-C-normorphinan] and other steps. Eventually, a series of Sinomenine derivatives can be obtained. Seven derivatives were obtained by structural modification of C-ring 6-position carbonyl, 7-position enylmethyl ether and 7,8-position double bond, and two of them were found to have good anti-inflammatory and analgesic activity by ear swelling method in croton oil mice. A class of Sinomenine derivative monomers or dimers can be generated by linking linkers (aliphatic, aromatic, polyethylene glycol, etc.) with an X-bond (ether, ester, amide, sulfonamide, amine). After activity testing, it was found that its anti-inflammatory activity is good, and it has a wide range of uses, which can be used for anti-rheumatism, immunosuppression and health care.

4. Structural modification of D-ring

The D-ring modification of Sinomenine is mostly concentrated at the 17th position N. Some scholars use the method of strong alkali reflux to make the ring of 17-position N, and then synthesize the  N-methyl substituted Sinomenine derivative. Some studies first protected the phenolic hydroxyl group in Sinomenine through a benzyl group, and then demethylated the 17-position N, and then linked different functional groups (hydrocarbon groups, sulfonyl groups, etc.) to N to synthesize a series of 17 Bit substituted Sinomenine derivative. A series of Sinomenine derivatives were synthesized by first removing the methyl group on N with cyanogen bromide, and then introducing various benzyl-substituted triazoles on N through affinity reaction and Click reaction. The synthesis method has a high yield, and is environmentally friendly and easy to handle, but after activity testing, it is found that its inhibition effect on NF-κB in vitro is worse than that of Sinomenine. 

Resources

[1]刘芝宏,黄玉兰,姜芳,等.青藤碱的合成及构效关系研究进展[J].广州化工,2017,45(06):48-52.

[2]李修政,赵庆杰,董家潇,等.青藤碱结构改造的研究进展[J].药学实践杂志,2018,36(03):204-209+214.

About author: 

Xiaonisha

Xiaonisha, a practitioner in food science and technology, graduated from the School of Food Science and Engineering in the South China University of Technology as a Master of Food Science, and now works at a large drug R&D company in China, engaging in R&D of nutritional food.