Research progress has been made in the new drug system of alkaloids

In recent years, the Kunming Institute of Botany, Chinese Academy of Sciences, has made a series of progress in the research of new drug system of sconce leaf alkaloids
.
In 2019, scientific researchers completed the IIa clinical trial of total alkaloids from the leaves of the lamp , demonstrating its preliminary clinical effectiveness
.
Subsequently, the Kunming Institute of Botany assisted the company to complete the pilot production of three batches of qualified total alkaloids from the leaves of the lamp, and published the following papers on the research of the leaves of the lamp:

Pharmacological efficacy study : Dr.
Zhao Yunli of the Kunming Institute of Botany and others revealed that the alkaloids of sconce leaf can significantly inhibit the replication of H1N1, RSV and HSV-1 viruses and the growth of beta-hemolytic streptococcus in vitro; 12.
5 mg/kg is less effective for H1N1 The death protection rate of mice is 67%, and the lung weight index is reduced by 54%; the death protection rate of 400mg/kg in mice infected with beta-hemolytic streptococcus is 40% (Natural Products and Bioprospecting 2021)
.
In further cooperation with the Guangzhou Medical University team, it was found that the alkaloids of the sconce leaf showed significant death protection in mice infected with the H1N1 influenza virus, effectively inhibiting the virus replication and the production of pro-inflammatory factors in the lungs of the mice; significantly reduced The proportion of monocyte-derived macrophages, dendritic cells, and neutrophils that infect the lungs of mice inhibits the depletion of alveolar macrophages
.
Cell signaling pathway analysis shows that Toll-like receptor 3 (TLR-3), retinoic acid-inducible gene protein I (RIG-I) and other mediated innate immune signaling pathways may be the key to improving the lung injury caused by influenza virus infection.
Target (Phytomedicine 2020, 77, 153272)
.
Zhao Yunli and others used porcine pancreatic elastase to induce a mouse emphysema model, and found that the alkaloids of the lamp table leaf can significantly reduce airway inflammatory factors (IL-1β, IL-11, MCP-1, MMP-12, TGF-β).
, VEGF), fibronectin, NF-κB and b-catenin (β-catenin) levels, significantly increase elastin content and B-lymphocyte tumor-2 gene (Bcl-2) expression, relieve airflow resistance, and reduce lung elasticity Retract and balance protease/anti-protease, inhibit excessive activation of alveolar macrophages (Journal of Ethnopharmacology 2020, 259, 112949)
.
Zhao Yunli and other studies have found that the alkaloids of sconce leaf can reduce the salivation sugar chain antigen (KL-6), lactate dehydrogenase, transforming growth factor-β (TGF-β), hydroxyproline (Hydroxyproline) and Oxidative stress such as type I collagen and malondialdehyde can inhibit lung inflammation, thereby significantly improving lung lesions.
Inhibiting the expression of matrix metalloproteinase-1 and transforming growth factor-β is the main mechanism of treatment for pulmonary fibrosis ( Journal of Ethnopharmacology 2021, 267, 113506)
.

Toxicological research : In cooperation with Yunnan Institute of Materia Medica, the acute toxicity of the total alkaloids from the leaves of the lampstand was measured by the LD50 of ICR mice by intragastric administration and the approximate lethal dose of Beagle dogs (Beagle)
.
Studies have shown that the acute toxicity median lethal dose (LD50) of the total alkaloids from the stilbola leaves in mice is 5.
48 g/kg.
bw, and the maximum tolerable dose (LD0) in mice is 2.
2 g/kg.
bw
.
Beagle dogs (Beagle) 4.
0 g/kg.
bw of total alkaloids from the leaves of the lampstand were given once orally, and no animal died during the observation period (Natural Products and Bioprospecting 2020, 209-220)
.
SD rats were given 3 doses of total alkaloids from the leaves of the sconces by intragastric administration for 13 weeks.
The animals in each group were able to move freely, their coats were shiny, and were generally in good condition.
Histopathological examination showed no changes in histomorphology related to the administration, suggesting that the leaves of the sconces.
Total alkaloids below 50 times the clinically planned dose are non-toxic doses
.
Continuous oral administration of 3 doses of total alkaloids from stilt leaves to beagle dogs for 13 weeks, withdrawal and recovery for 4 weeks, no abnormality in the inspection of all indicators, suggesting that total alkaloids from stilt leaves below 60 times the clinically proposed dose is a safe dose range (Natural Products and Bioprospecting 2020, 77-88)
.
Three doses of total alkaloids from the leaves of the lampae were given by single intragastric administration, and there was no obvious change in general behavioral activities, and no significant effect on the coordinated movement of mice.
There was no significant difference in sleep rate of animals in each group compared with the vehicle control group; 3 A single dose administered to beagle dogs via the duodenum has no significant effect on the cardiovascular and respiratory systems; the number of colonies of Salmonella typhimurium did not exceed the reference value range of the number of spontaneous regression colonies, suggesting the results of the reversion test It is negative; the aberration rate of Chinese hamster lung fibroblasts (CHL) is less than 5%, indicating that there is no chromosomal aberration; it does not cause the increase of the micronucleus rate of the mouse bone marrow polychromatic erythrocytes and the decrease of the PCE/(PCE + NCE) ratio , Suggesting no mutagenic effect (Natural Products and Bioprospecting 2020, 119-129)
.

Phytochemical research : Dr.
Wei Xin and others discovered two new indole alkaloids, their structure has a rare C17 norbrocine molecular skeleton and brucine C-16/19 furan ring, the hydrogen on the benzene ring in the molecule It can be exchanged for deuterium in deuterated methanol without a catalyst.
This is the first natural product of CH self-activation reported (Tetrahedron Letters 2020, 61, 151894)
.
Researchers from Yunnan University have discovered two novel triterpenoids Alstoscholarinoids A and B with rearranged skeletons, a new skeleton triterpenoid with 6/6/6/7/5 ring system rearrangement and C-28 reduction, and rare The 6/6/5/6/6/6 ring system and a unique C28→C11 lactone ring (Organic Letters 2021)
.

Phase I clinical trial : In a randomized, double-blind, placebo-controlled phase I tolerance clinical trial conducted in cooperation with experts from West China Hospital, a single-dose trial of 8 dose groups and a continuous multiple dose of 2 doses test, observe vital signs and physical examination, including blood, urine and stool; biochemical indicators of liver and kidney function; twelve-lead ECG; upper abdominal ultrasound, combined with follow-up of any adverse event occurred / adverse reactions and Combined medication, no obvious adverse reactions were found in clinical trial results (Pharmaceutical Biology 2021) .
In cooperation with experts from Beijing Xiyuan Hospital, we carried out a phase I clinical pharmacokinetic and safety trial with a randomized, open, cross-over trial design.
In addition to further evaluation of its tolerability, all subjects were fully exposed to 4 doses.
Exposure of more than 10 active compounds and 35 metabolic compounds (main metabolic pathways) at 12 time points .
The overall exposure status of the active ingredient group in human blood drugs was obtained, the high-exposure medicinal components were determined, and the pharmacokinetic parameters of the high-exposure medicinal compounds were calculated .
Through the clinical pharmacokinetic test of the total alkaloids from the leaves of the lamp, it revealed the correlation of the subjects' dose-time-exposure for a variety of medicinal ingredients, and the exposure of a variety of medicinal molecules in the human body objectively supported the lamp.
The material basis of total leaf alkaloids for the treatment of respiratory diseases with multiple targets and multiple aspects (Phytomedicine 2019, 61, 152828) .

Researcher Luo Xiaodong’s research team takes phytochemistry as the core, and the research results have enriched the structural groups of natural products, and provided novel and diverse molecules for pharmacological research, which has attracted widespread attention.
Among them, 6 "sandrines" are used as Hot off the press in Introduced by Natural Products Reports; 14 "Landrine bases" were fully synthesized by chemists
.
The team has published more than 40 research papers on the resources, chemistry, pharmacology and pharmacokinetics, process and safety of the sconce tree, and clinical research, and published more than 40 papers on the research of a single plant species, which supports the innovation and transfer value of scientific and technological achievements of the new drug shuangtai
.
(Bioon.
com)