Mini-Reviews in Organic Chemistry - Volume 11, Issue 3, 2014

Triterpenoids are nature-derived compounds, broadly distributed in plant kingdom in a free form as well as in a form of numerous glycosides. The complex structures of triterpenoids chiefly involve squalene derivatives, lanostanes, cycloartanes, dammaranes, euphanes, tirucallanes, tetranortriterpenoids, quassinoids, lupanes, oleananes, friedelanes, ursanes, hopanes, serratanes and another less known groups. These compounds present interesting and perspective subject for experiments, chemical and biological as well. As it is known from literature data, triterpenoids and their saponins with respect to their multitude pharmacological activities could be involved in several areas such as chemistry, medicine and pharmacology, biomedicine and agrochemical sciences. The special structure of triterpenic skeletons allows to perform numerous chemical transformations in order to obtain many new derivatives with pharmacological activity. Taking under consideration the above data, chemistry, biology and pharmacology of triterpenoids and their saponins appear to be riped for revisiting. Therefore, this special issue aims to review the advances in triterpenoids science during the last decade. Carcinomas are probably the second leading cause of death in humans, so scientists intense their research upon the development of new biological sources with antitumor activity. Medicinal plants are now the most promising sources of new potent substances in cytotoxic drug development. As Csuk presented in his work, such compound of anticancer activity is glycyrrhetinic acid, obtained e.g. from liquorice, known as sweetwood (Glycyrrhiza glabra) and some derivatives obtained from this triterpenic acid. Antitumor activity also exhibits, as presented by Paduch and Kandefer-Szerszeń, other triterpenes, such as: asiatic acid, betulinic acid, boswellic acid, lupeol, oleanolic acid or ursolic acid and their analogs and derivatives. These compounds exhibit a cytotoxicity against a variety of tumor cell lines comparable to some clinically used drugs. Most of them also have important antiviral properties, especially anti-HIV activity, which makes them potentially useful additives to current anti-HIV therapy. Another group of triterpenoids with anticancer and antiviral activity is limonoids family, belonging to tetranortriterpenoids. As Pękala and co-workers present, limonoids are a very valuable group of triterpenoids because of a wide spectrum of biological properties, such as cytotoxic, antimalarial, anti-inflammatory, antifeedant, antiviral, neuroprotective, antimicrobial, antibacterial, antifungal and other activities. Limonoids present rich variety of structures: until 2011, about 1300 limonoids with more than 35 carbon frameworks had been isolated from four families (Meliaceae, Rutaceae, Simaroubaceae, and Cneoraceae). The unique structural features of these terpenoids have attracted continuous attention of chemists and pharmacologists. Triterpenoids often occur as ingredients of daily diet or of herbal products used for therapeutic purposes. These phytochemicals occur in nature in free form or as glycosylated compounds, known as saponins, due to their characteristic foaming properties. Pharmacological activities of saponins are very broad and include numerous directions of action which were discussed in many works. Podolak and Janeczko summarize pharmacological properties of natural, non-glycosylated triterpenoids, that were reported over the last five years. The work discusses e.g. antimicrobial, cytotoxic, anti-inflammatory, antinociceptive, antidiabetic, hepatoprotective, wound healing and other activities of triterpenoids, focusing on less known compounds. Plants remain as the most viable source of triterpenoid saponins. As plants are the source of pharmacologically active saponins and free triterpenoids, it is obvious that the development of new methodologies to improve saponin yields is a significant issue. As Yendo et al. state in their work current challenges to improve triterpenoid saponin production including a better understanding of the signal transduction pathways leading to their accumulation, isolation and heterologous expression of biosynthetic genes, as well as structural and modeling studies of biosynthetic enzymes and their catalytic mechanisms. Some triterpenoids and their semi-synthetic derivatives can be identified as potential therapeutics against neurodegenerative diseases. Ruszkowski and Bobkiewicz-Kozlowska discuss the ability of celastrol, oleanolic acid, ursolic acid, asiatic acid, erythrodiol, and some triterpenoid saponins to protect the brain against neurodegeneration and neuroinflammation processes. The authors focus on triterpenoids as possible drugs to treat or slow the progression of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis and multiple sclerosis (MS). Further, pharmacological activities of naturally-derived triterpenenoids and some of their synthetic derivatives are discussed by Jeong and Bae, Jaworska-Paszel et al. and by Luo et al. The anti-inflammatory effect is a common property of many triterpenoids. Jeong and Bae discuss the anti-inflammatory property of several triterpenoids derived from natural sources and from chemical synthesis. These triterpenoids include avicins, boswellic acid, celastrol, diosgenin, escin, ginsenosides, glycyrrhizin, lupeol, oleanolic acid, platycodon D, saikosaponins, ursolic acid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), and some of their derivatives. Jaworska-Paszel et al. describe anti-inflammatory, antioxidative, antitumor, antileukemic, hepatoprotective, gastroprotective, cardioprotective and many other important pharmacological activities of oleanolic acid. Luo et al. focus on recent advances in enone and NOreleasing derivatives of oleanolic acid with anti-cancer activity. Other compounds exhibiting numerous pharmacological activities are betulin and betulinic acid, both with pentacyclic lupane-type skeleton. Betulin, betulinic acid and their derivatives have been studied in the last decades for their diversified pharmacological activities like anti-HIV, anticancer, antibacterial, anti-inflammatory and many others. In the last few years, great progress had been made on the synthesis and biological activity of triterpenoids derived from betulin and betulinic acid. Shi and co-workers discuss recent research and development in chemistry of betulin and betulinic acid and present recent modification within A-ring, E-ring, both, at the C-3 and at the C-28 position as well as at the C-30 position of betulin and betulinic acid. The authors also present methods of conjunction of the above triterpenes with drugs. Supercritical fluid extraction has been a widely studied green technology to obtain triterpenoids enriched extracts from various vegetable matrices. De Melo and co-workers discuss research advances regarding the supercritical fluid extraction of triterpenoids in terms of biomass sources, operating conditions and their optimization, and modeling. The authors provide overview concerning the recent works (both publications and patents) upon supercritical fluid extraction of plant material leading to triterpenoids with the most important experimental and/or theoretical information. Many families of bioactive natural products are usually extracted from numerous plant sources in low yields. Triterpenic acids belong to a group of the most often studied compounds, mainly because of their abundance in a large number of food and medicinal plants. Domingues et al. in their work present overview of the biogenetic origin of some triterpenic acids, on the analytical extraction and hyphenated methodologies (mainly GC-MS) used on their identification and quantification. The authors also present an overview of the major sources of some triterpenic acids, indicating their potential large scale production pathways, with especial emphasis on abundant agroforestry biomass residues. The future perspectives towards improved therapeutic strategies using these triterpenic acids are also discussed herein. The root bark of the Chinese medicine Tripterygium wilfordii contains a quinone methide triterpenoid - celastrol. Literature data presents, that celastrol is one of the most potent antitumor activity compounds among the natural triterpenoids. Salvador et al. discuss different mechanisms of antitumor activity of celastrol, such as abilities of inhibing proliferation, inducing apoptosis and suppressing invasion and metastasis of tumor cells. The authors also describe the anticancer property of semi-synthetic celastrol derivatives. As they noticed, the quinone methide moiety is required for its antitumor activity. I thank all the contributors or this special issue and hope that the progresses highlighted in the topics covered will inspire more research in this challenging area of organic synthesis. I thank Prof. Atta-ur-Raman for the kind invitation to be the Guest Editor of this issue and all the reviewers for their time and valuable comments. I also thank Ms. Hina Wahaj (Publications Manager, Bentham Science Publishers) for the help in organizing this issue.

A serious flaw of many chemotherapeutics employed now for the (post-surgery) treatment of malignant tumors is their high cytotoxicity against vital organs. In addition, tumor cells that survive chemotherapy often show pronounced drug resistance against a wide range of therapeutics. Recently, glycyrrhetinic acid derivatives derived from a cheap and easy-to-obtain natural product have attracted pharmacological interest. Many derivatives of glycyrrhetinic acid showed good to excellent cytotoxicity and inhibited the proliferation of a wide range of human tumor cells. They act predominantly by apoptosis, thus making them an interesting and even fascinating starting point for the development of selective, effective and safe antitumor active drugs.

Over the last two decades, extensive research on compounds isolated from fruits, vegetables, cereals, herbs and medicinal plants has revealed that triterpenoids possess important pharmacological properties. Among the group of triterpenoids, pentacyclic ones show wide range of extensively studied pharmacokinetics linked with anticancer and antiviral action. In the group of pentacyclic triterpenoids the most active against cancer development are asiatic acid (AA), betulinic acid (BetA), boswellic acid (BA), glycyrrhizin and 18β-glycyrrhetinic acid (GA), lupeol, oleanolic acid (OA) or ursolic acid (UA) and their analogs and derivatives. They exhibit a cytotoxic action against a variety of tumor cell lines comparable to some clinically used drugs. Most of them have also important antiviral properties, especially anti-HIV activity, which make them potentially useful additives to the current anti-HIV therapy. The literature concerning studies on both, anticancer and antiviral activities of pentacyclic triterpenes is reviewed.

Limonoids are chemically classified on the basis of the four rings, marked as A, B, C and D in the intact triterpene nucleus with various oxidative modifications. The structural variations of limonoids found in Rutaceae species are lesser than in species of Meliaceae. Limonoids isolated from the plant family Meliaceae are more complex with very high degree of oxidation and structural rearrangements. Limonoids family exhibits a wide spectrum of biological properties, such as cytostatic, antimalarial, anti-inflammatory, antifeedant, antiviral, neuroprotective and a number of other activities like antimicrobial acitivity.

Triterpene compounds constitute one of the major groups of plant secondary metabolites. They often occur as ingredients of daily diet or of herbal products used for therapeutic purposes. Each year many pharmacological activities of these compounds are described. This mini-review summarizes pharmacological properties of natural, non-glycosylated triterpenoids, that were reported over the past five years, with special emphasis on antimicrobial, antidiabetic and antiinflammatory effects.

Saponins are ubiquitous plant natural products, essentially involved in plant defense against biotic stresses, with numerous pharmaceutical and agricultural applications. The common precursor for triterpenoid saponins is squalene (30 carbon molecule) which, via cationic intermediates, is oxidized to 2,3-oxidosqualene. After cyclization, the basic triterpenoid cyclic structure undergoes oxidation by monoxygenases and glycosylations of hydroxyl groups. Chemical synthesis of saponins essentially recapitulates the main biosynthetic steps. However, to date, plants are the most viable source of these molecules. Jasmonic or salicylic acid, as well as their respective methylated derivatives, are important signaling molecules in the responses culminating in triterpenoid saponin production. The current challenges to improve triterpenoid saponin production include a better understanding of the signal transduction pathways leading to their accumulation (with emphasis on late enzymes and “master” regulatory transcription factors), isolation and heterologous expression of biosynthetic genes, and structural and modeling studies of biosynthetic enzymes and their catalytic mechanisms.

Terpenoids and especially triterpenoids are the largest and the most diverse group of naturally occurring organic compounds. Its diversity plays very important role in new chemical entities activity screening against different disorders. Some of these compounds and their semi-synthetic derivatives can be identified as potential therapeutics against neurodegenerative diseases and were widely studied in the last few years. Celastrol, oleanolic acid, ursolic acid, asiatic acid, erythrodiol, and some triterpenoid saponins have the ability to protect the brain against neurodegenerative and neuroinflammatory processes. This review article is focused on triterpenoids as possible drugs to treat or slow the progression of neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s Disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS).

Evidence suggests that discovery of anti-inflammatory agents is driven by the search for bioactive compounds from natural products and synthetic chemicals. Triterpenoids are a wide-spread group of natural products and a polycyclic secondary metabolite in many terrestrial plants. In addition, their anti-inflammatory activity and action as immunomodulators has been demonstrated in many studies. Because of their various advantages, triterpenoids are used as a platform or target of drug development in wide-range applications against inflammatory diseases. Therefore, the modification of a variety of triterpenoids in structure from the natural origin has been done for optimization of bioactivity, and some semisynthetic analogs are suggested to be potent anti-inflammatory triterpenoids. The aim of this review is to illustrate the anti-inflammatory effects of several triterpenoids originating from natural products and chemical synthesis, and to analyze the structural activities and relationships between the different types of triterpenoids. These triterpenoids include avicins, boswellic acid, celastrol, diosgenin, escin, ginsenosides, glycyrrhizin, lupeol, oleanolic acid, platycodon D, saikosaponins, ursolic acid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), and their derivatives. This review provides a summary of recent advances of treiterpenoids and discusses further advances on the anti-inflammatory effect.

Oleanolic acid (OA) is a pentacyclic triterpenoid compound naturally found in plant kingdom. OA possesses several biological activities, which make it an interesting compound for scientists working in the field of pharmacy and new drugs design and development. The compound exhibits anti-inflammatory and anti-oxidative effects in vitro and in vivo, which probably determine its dual function - cytoprotective and cytotoxic/cytostatic activity. In this study, we focused on the presentation of molecular mechanisms of the compound’s action to emphasize its multifunctional character. Due to multiple pharmacological properties of the triterpenoid, it could be used to prevent the majority of the most common diseases of civilization i.e. cancer, cardiovascular diseases, atherosclerosis or diabetes. However, because of its relatively weak activity it may serve as a starting material for the synthesis of more potent chemical compounds.

Betulin, betulinic acid and their derived compounds are important pentacyclic lupane-type triterpenoids and exhibit diversified pharmacological activities like anti-HIV, antitumor, antimycotic, anti-inflammatory, antioxidant and immunomodulatory activities. Many new methods for the synthesis of potentially valuable betulin derived triterpenoids with potent bioactivity have been largely reported in the past few years. In this review, we will present the progress made on the synthesis of novel structural triterpenoids with excellent chemical or biological activity that have appeared from 2006 to 2012.

Oleanolic acid (OA) is a natural pentacyclic triterpenoid acid with diverse biological activities including antiinflammation, suppression of tumor promotion, protection of the liver against toxic injury, and induction of differentiation. However, the potency of OA as an anti-cancer agent is relatively weak. Therefore, remarkable progress has been made in the modification of OA to improve its anti-cancer activity over the past few years. This paper reviews the progress mainly on anti-cancer activity of enone derivatives and nitric oxide (NO)-releasing derivatives of OA over the last decade.

Supercritical fluid extraction (SFE) has been a widely studied green technology to obtain triterpenoids (TTs) enriched extracts from various vegetable matrices. This review covers research advances regarding the SFE of TTs, with emphasis on biomass sources, operating conditions and their optimization, and modeling. As in other applications of the supercritical technology, carbon dioxide is the common solvent adopted, being generally modified with small amounts of cosolvents (e.g. ethanol, methanol) to increase TTs solubility, as many of these molecules are polar. The operating conditions reported for the SFE of TTs from biomass lie between 40 and 90°C, 100 and 500 bar, and 0 and 5 wt. % of modifier. An extensive list of relevant works in this field is also provided, where the most important experimental and/or theoretical information is presented. Exploitation is also addressed through a compilation of registered patents on TTs extraction and purification, particularly on strategies to concentrate these compounds after organic solvent or supercritical carbon dioxide extraction. In the whole, there is a research and intellectual property basis to support further industrial attempts to implement processes combining SFE and purification technologies for TTs production.

This review aims to provide an overview of the biogenetic origin of triterpenic acids (with particular emphasis on ursolic, oleanolic and betulinic acids), on the analytical extraction and hyphenated methodologies (mainly GC-MS) used on their identification and quantification, followed by an overview of the major sources of these components, indicating their potential large scale production pathways, with especial emphasis on abundant agroforestry biomass residues. The biological activity of ursolic, oleanolic and betulinic acids is described, focusing on their antitumoral potential as modulators of growth inhibitory signals, evasion of apoptosis and angiogenesis. The future perspectives towards improved therapeutic strategies using these triterpenic acids are also herein discussed.

Celastrol is a quinone methide triterpenoid extracted from the root bark of the Chinese medicine Tripterygium wilfordii with the most potent antitumor activity among the natural triterpenoids. Celastrol has the abilities to inhibit proliferation, induce apoptosis and suppress invasion and metastasis of tumor cells. Structure and activity analysis based on celastrol semi-synthetic derivatives revealed that the quinone methide moiety is required for its antitumor activity. The heat shock protein HSP90 chaperone machinery and NF-κB signaling are two principal pathways targeted by celastrol. The optimization of solubility and identification of tumor specific targets is required for further developing celastrol and its derivatives as clinically useful anticancer agents.