Relationship of Chemical Structure to <i>in Vitro</i> Anti-inflammatory Activity of Tirucallane Triterpenoids from the Stem Barks of <i>Aphanamixis grandifolia</i>

Abstract

A series of tirucallane triterpenoids isolated from the stem barks of Aphanamixis grandifolia were assessed for their anti-inflammatory activity, exhibiting from weak to strong anti-inflammatory activity, by testing their inhibitory effects on nitric oxide (NO) production and tumor necrosis factor-α (TNF-α) level in lipopolysaccharide (LPS) induced RAW264.7 murine macrophages. To explore the relationship between the structures and anti-inflammatory activity, a vast pool of molecular descriptors for each isolate were calculated. Genetic algorithms (GA) or simulated annealing (SA) based partial least squares (GA-PLS and SA-PLS) algorithms identified some important descriptor combinations, which were correlated with both sets of the anti-inflammatory data by partial least squares 2 (PLS2) method. S-Plot was used to visualize the descriptor influence in the PLS2 model, disclosed five most important molecular descriptors, nOHt, RDF150m, lip_vio-lation, Mor32m and JhetZ.Key words Aphanamixis grandifolia; tirucallane triterpenoid; anti-inflammatory activity; nitric oxide; tumor necrosis factor-α; structure-activity relationship Inflammation is a normal and crucial response of the organism to various stimuli including physical damage, ultra violet irradiation, microbial invasion and immune reactions, playing a pivotal role in host defense.1,2) While inflammatory cascades may cause pain, tissue damage, and a wide range of human acute and chronic inflammatory diseases, such as chronic asthma, rheumatoid arthritis and multiple sclerosis, and psoriasis.3) Many of these diseases with increasing incidence rate are particularly debilitating to the patient's functional capacity and quality of life.Macrophages have vital functions in maintaining body homeostasis, as well as in inflammatory processes, which are endowed with the ability to release a variety of mediators including the free radical nitric oxide (NO), 4) one of the most versatile regulator in the immune system. 5) Overproduction of NO can exacerbate inflammation, playing an important role in the pathogenesis of several chronic and systemic inflammation diseases, such as rheumatoid arthritis. 6,7)Tumor necrosis factor-α (TNF-α), one of the most important pro-inflammatory cytokines, is also massively produced by the activated macrophages and monocytes at local sites of inflammation.8) Its excessive production further triggers the secretion of other inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) and thereby aggravates the inflammation in many autoimmune/inflammatory diseases. 9-11)Exposure to major anti-inflammatory agents, such as corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), is known to increase substantially the risk of serious side effects.3,12) Therefore, there is an unmet medical need for new treatment strategies, which could be possibly filled by rational phytopharmaceuticals with a favorable benefit/risk ratio. Recent investigations into the anti-inflamm...

Limonoids from the Fruits of Aphanamixis polystachya (Meliaceae) and Their Biological Activities

“…The anti-inflammatory activities of compounds 1 – 25 were evaluated by testing their inhibitory activities against lipopolysaccharide (LPS) induced nitric oxide (NO) production in mouse macrophage cell line, RAW264.7, bought from the Chinese Academy of Science Cell Bank (Shanghai, China). The level of NO was determined using the NO kit according to the previously described protocol …”

“…The level of NO was determined using the NO kit according to the previously described protocol. 18 Fungicide Assays. Compounds 1−25 were evaluated against several pathogens on leaf-piece assays, 19 at the rate of 200 and 60 ppm for Phytophthora infestans on tomato, and 100 ppm for Septoria tritici on wheat and Uromyces viciae-fabae on bean.…”

Least Absolute Shrinkage and Selection Operator-Based Prediction of the Binding Constant of p-Sulfonatocalix[6]/[8]arenes with Alkaloids

“…36 Descriptors of radial distribution function (RDF) encoded the size and shape of the molecules, which were obtained by RDFs centered on different interatomic distances. RDF150m can be interpreted as the mass distribution of finding an atom in a spherical volume of certain radius at 15.0 Å 37,38 that contributed positively to K alkaloids-SC6A . E1m and Km denote the first component accessibility directional WHIM index/ weighted by relative mass and K global shape index/weighted by relative mass, respectively.…”