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Lanostane Tetracyclic Triterpenoids as Important Sources for Anti‐Inflammatory Drug Discovery

IntroductIon Inflammation is a protective response of the human body to various harmful stimuli, including physical trauma, noxious chemicals, and microbes. The inflammatory reaction is initiated by a series of harmful exogenous and endogenous signals resulting from mechanically, chemically, or biologically induced tissue damage.[1] Inflammation is closely related to the occurrence and development of many major diseases and is mainly characterized by local redness, swelling, pain, edema, and temperature increase caused by reactions of the vascular system. Failure to resolve recurrent acute events of inflammation may lead to chronic inflammatory diseases, such as arthritis,[2] colitis,[3] or asthma,[4] which are associated with irreversible tissue damage and increased risk for the development of cardiovascular disease,[5] cancers,[6] rheumatoid arthritis (RA),[7] and osteoporosis.[8] Chronic inflammation includes severe inflammatory autoimmune diseases,[9] which can lead to severe tissue damage. During chronic inflammatory states, pro‐inflammatory cytokines such tumor necrosis factor‐α (TNF‐α),[10] interleukin (IL)‐6,[11] and IL‐1β persist for long periods.[12] Inflammation is caused by a prolonged immune response, consisting of pro‐inflammatory macrophages, microglia, and neutrophils,[13] together with cytokines Lanostane Tetracyclic Triterpenoids as Important Sources for Anti‐Inflammatory Drug Discovery

released from other cell types, such as endothelial cells, oligodendrocytes, and fibroblasts. [14] The reaction mechanism of inflammatory diseases forms a complex network of relationships. Many enzymes and factors in cell signaling pathways are involved, such as nuclear factor (NF)-κB, [15] mitogen-activated protease (p38MAPk), [16] matrix metalloproteinases, [17] and γ-interferon [18] and the STAT nuclear protein family [19] that play a crucial role in the growth hormone signaling pathway. In general, drug treatment can ameliorate inflammatory responses by blocking the production or release of inflammatory mediators. Clinical treatment of inflammation uses three major types of drugs, nonsteroidal anti-inflammatory drugs, [20] steroidal anti-inflammatory drugs, and traditional Chinese medicine. [21][22][23] Lanostane triterpenoids are a type of tetracyclic triterpenic acids whose skeletons contain one to three carboxyl groups. Natural lanostane-type triterpenoids are common in fungi and marine organisms and occur in higher plants, but so far are mainly isolated from the families Ganodermataceae, Polyporaceae, and Schisandraceae. Compounds isolated from these sources showed pharmacologically diverse activities, including anti-inflammatory, anti-tumor, cytotoxicity, anti-bacterial, and analgesia, among others.
This review systematically summarizes all previously isolation and synthesis work performed with lanostane triterpenoids and discusses the anti-inflammatory effects of lanostane triterpenoids. This review can serve as a reference for future research on the lanostane triterpenoids.

InflammatIon-related dIseases
Inflammation is a complicated biological interaction that arises in response to a series of injuries caused by physical trauma, noxious chemical stimuli, or microbiological toxins. Clinically, many diseases are associated with inflammation., including RA, neurodegenerative diseases, liver and lung inflammation, cardiovascular diseases, cancer, and colitis.
RA is a common chronic disease, in which the failure of spontaneous resolution of inflammation causes the disease to persist in patients throughout their lives. [24,25] Extensive investigations of the pathogenetic mechanisms of inflammation and autoimmunity, and the resulting increased understanding of cytokine networks and cellular players in RA, have led to the development of agents that block TNF-α, IL-1, and IL-6 [26] signaling, or target pathogenic cells such as B cells [27] and osteoclasts. [28] Bari summarized recent insights into the roles of mesenchymal stem cells (MSCs) in RA and discussed the potential to harness the immunomodulatory properties of MSCs for the treatment of RA. [29] Numerous studies have shown that fibroblast-like synoviocytes (FLS) are significant contributors to joint inflammation in RA. [30] Brandstetter's research identified that the inactivation of forkhead box O3 (FOXO3) results from TNF-α-induced downregulation of phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1). Reduced PI3KIP3 results in increased phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway activity in FLS. This finding provides novel insights into the molecular mechanism underlying TNF-driven inflammatory diseases. [31] Neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease are related to neuroinflammation and most commonly occur in the elderly. Their pathogenesis is related to microglia-mediated neuroinflammation. Many inflammatory factors, such as IL-1β and TNF-α, are detected in neurodegenerative disease patients. [9] Numerous studies have suggested that neuroinflammation plays an essential role in neurodegenerative disorders. Toll-like receptor 4 (TLR4) is an important pattern recognition receptor expressed in microglia and is responsible for microglial activation. [32] Nair et al. reported that the DNA damage-linked inflammatory cascade is mediated by expression-level changes in G protein-coupled receptors and can be targeted to counteract inflammation during anticancer therapies as well as aging. [33] Inflammation is also associated with various diseases. It can suppress pro-inflammatory cytokine production, including TNF-α, IL-1β, and IL-6 via inhibition of the NF-κB pathway, and lead to chronic obstructive pulmonary disease. [34] The previous study showed that TLRs play critical roles in liver inflammation. [35,36] Inflammation is also a significant cause of disease in patients with colitis. Singh et al. [37] found that the conditional deletion of HDAC2 in CD4 + T cells results in elevated IL-17 expression and causes severe colitis in a mouse model. The identification of the Ubc9/ROR-γt/HDAC2 axis that governs IL-17 expression may open new avenues for the development of therapeutic measures for inflammatory disorders. [37] However, the development of fibrosis and inflammation may not be interlinked with inflammatory bowel diseases elucidated by Hünerwadel et al. [38] lanostane-type trIterpenoIds Triterpenes comprise a large number of compounds which, according to the diverse features of their skeletons, can be classified as acyclic, mono-, bi-, tri-, tetra-, and pentacyclic triterpenes. [39] More than 20,000 triterpenes have been discovered in nature, many of them occurring in their free form, while others occur as glycosides (saponins) or other combinations. [40] Triterpenoids are compounds of wide occurrence and structural diversity that have gained attention for their pharmacological activities. [41] Since 1985, Connolly and Hill have annually reviewed newly isolated triterpenoids from the plant kingdom. [42] The most studied triterpenes are tetracyclic triterpenes such as lanostanes, protostanes, tirucallanes, cucurbitanes, meliacanes, cycloartanes, dammaranes, and euphanes and pentacyclic triterpenes including ursanes, gammaceranes, lupanes, oleananes, and hopanes. [43,44] Among numerous inhibitory activities of such derivatives, inhibition of tumor promotion, inflammation, and lipid peroxidation are the most significant.

synthetIc lanostane-type trIterpenoIds
Triterpenoids are natural products with thirty carbon atoms, biosynthetically derived from the cyclization of squalene. Lanostane triterpenoids are reported to possess various biological, pharmacological, or medicinal activities, including anti-inflammatory and anticancer effects. However, in many cases, the potency of these triterpenoids is relatively weak. At present, only a few studies have presented research on synthetic intact lanostane triterpenoids [ Figure 3]. Wada et al. [102] synthesized eight intact lanostane-type triterpenoids with various functional groups (-Cl,-Br,-OMe,-CHO,-CN,-COOH, and-COOMe) at the C-2 position, according to the substrate compound 3-oxolanost-9 (11)-en-24S, 25-diol isolated from Pinus luchuensis. All the derivatives showed DNA topoisomerase II inhibitory effects, with IC 50 values ranging from 1.86 to 149.97 µM. Seventeen intact lanostane-type triterpenoid derivatives, including 11 N-glycosides, were synthesized from the natural triterpenoid, lanosterol, by Ukiya et al. [103] Honda et al. revised and confirmed the regiochemistry of these isoxazoles and subsequently synthesized a new intact lanostane triterpenoid with a cyano-enone functionality in ring A from lanost-8-en-3-one. [104] Six compounds were synthesized from the intact lanostane-type tetracyclic triterpenoid of trametenolic acid B by Ding et al. [105] dIscussIon The lanostane triterpenoids are mostly isolated from fungi and higher plants, which are represented by more than thirty different species. This phytochemical investigation has identified 85 new compounds isolated from the family Schisandraceae, 56 new compounds in the family Ganodermataceae, and 48 new compounds have been identified from the family Polyporaceae. Twenty-one of these compounds exhibited Obtusifoliol, 4α, l4α-dimethyl-5α-ergosta-7,9(11),24(28 )-trien-3 β-ol, and gramisterol exhibited the most potent anti-inflammatory activity, with IC 50 values of 87.1, 363.1, and 204 nM, respectively. The anti-inflammatory mechanism was found to be mediated by the inhibition of pro-inflammatory cytokines, iNOS, and COX-2 expression via the regulation of the NF-κB signaling pathway. SARs showed that the activity of a ring-opened seco-lanostane skeleton is much better than an intact lanostane triterpenoid, and the compound structure can be modified to increase its activity effectively.
The triterpenoids are economically and medicinally important and include many species with a variety of uses, which is attractive for pharmacological researchers and pharmaceutical industries. In recent years, new chemical entities derived from natural products have gained importance in the search for therapeutic drugs. Lanostane-type triterpenoids are considered to be promising agents for the development of anti-inflammatory drugs, and their derivatives have been shown to have anti-inflammatory activities. There is increasing evidence that lanostane triterpenoid compounds are widely found in nature and are a rich resource for the discovery of anti-inflammatory drugs.

conclusIon
The lanostane tetracyclic triterpenoids represent a promising and growing platform for anti-inflammatory biologically active natural compounds whose potential currently has yet to be developed into drugs by the pharmaceutical industry. Some recently studied lanostane triterpenoids showed significant anti-inflammatory activity. At present, the mechanism of anti-inflammatory effects of some of these lanostane tetracyclic triterpenoids has already been explained from different aspects at the cellular and molecular level. However, the molecular mechanism of the anti-inflammatory effects of most lanostane tetracyclic triterpenoids is not sufficiently elucidated or comprehensive for the specific propagation of action, and research at the genetic level is still uncommon. We conclude that the systemic evaluation of the anti-inflammatory activities of these compounds in vivo and in vitro is still needed. We also anticipate further progress in improvements in the methods of isolation and identification of lanostane triterpenoids, which open the way to targeted pharmacological modeling and resulting synthetic modifications. Targeted delivery systems, structural modifications, and the mechanisms of action of these compounds are essential in the design of novel derivatives with reduced cytotoxicity, improved efficacy, and increased therapeutic index. Research and development of drugs based on these triterpenoids, therefore, would be a key program in research institutions and pharmaceutical companies.