Diterpenes as lead molecules against neglected tropical diseases

Nowadays, neglected tropical diseases (NTDs) are reported to be present everywhere. Poor and developing areas in the world have received great attention to NTDs. Drug resistance, safety profile, and various challenges stimulate the search for alternative medications. Plant‐based drugs are viewed with great interest, as they are believed to be devoid of side effects. Diterpenes, a family of essential oils, have showed attractive biological effects. A systematic review of the literature was carried out to summarize available evidences of diterpenes against NTDs. For this, databases were searched using specific search terms. Among the 2338 collected reports, a total of 181 articles were included in this review. Of them, 148 dealt with investigations using single organisms, and 33 used multiple organisms. No mechanisms of action were reported in the case of 164 reports. A total of 93.92% were related to nonclinical studies, and 4.42% and 1.66% dealt with preclinical and clinical studies, respectively. The review displays that many diterpenes are effective upon Chagas disease, chikungunya, echinococcosis, dengue, leishmaniasis, leprosy, lymphatic filariasis, malaria, schistosomiasis, and tuberculosis. Indeed, diterpenes are amazing drug candidates against NTDs. Copyright © 2016 John Wiley & Sons, Ltd.     

Diterpenes and Their Derivatives as Potential Anticancer Agents

As therapeutic tools, diterpenes and their derivatives have gained much attention of the medicinal scientists nowadays. It is due to their pledging and important biological activities. This review congregates the anticancer diterpenes. For this, a search was made with selected keywords in PubMed, Science Direct, Web of Science, Scopus, The American Chemical Society and miscellaneous databases from January 2012 to January 2017 for the published articles. A total 28, 789 published articles were seen. Among them, 240 were included in this study. More than 250 important anticancer diterpenes and their derivatives were seen in the databases, acting in the different pathways. Some of them are already under clinical trials, while others are in the nonclinical and/or pre‐clinical trials. In conclusion, diterpenes may be one of the lead molecules in the treatment of cancer. Copyright © 2017 John Wiley & Sons, Ltd.     

Anti‐Schistosoma mansoni effects of essential oils and their components

Schistosoma mansoni is endemic in 55 countries around the world. S. mansoni is a water‐borne parasite of humans belonging to the group of blood flukes. Generally, schistosomiasis is treated with praziquantel, which results in frequent treatment failures and reinfections. Essential oils have diverse biological effects, including antimicrobial, antiprotozoal and antiparasitic. This review aimed at summarizing available in vitro, in vivo and clinical trials showing evidence and mechanisms of actions of essential oils and their derivatives acting against S. mansoni. The findings suggest that a number of essential oils and/or their components act against S. mansoni. Essential oils and/or their derivatives may be one of the potential sources of antischistosomal drugs.     

Anti‐obesity effect of plant diterpenes and their derivatives: A review

Obesity is a medical condition in which excess body fat is accumulated by a combination of excessive food intake, lack of physical activity, and genetic susceptibility. Obesity increases the risk of various diseases and conditions, including cardiovascular diseases, diabetes, cancer, and depression. This review focuses on most recent reports pertaining to the antiobesity activity of plant‐derived diterpenes in different databases. For this, a search (until August 2019) was conducted in the PubMed and Science Direct databases with the following keywords: “plant diterpenes” or “plant diterpenoids” paired with “obesity” or “antiobesity effects.” Overall, 729 references that used the aforementioned keywords were selected, among which 34 articles have been included in this review. Results from this search suggest that a number of diterpenes and their derivatives have been found to exert antiobesity effects through various mechanisms, such as overweight reduction or modification of body mass index, protein‐tyrosine phosphatase 1B inhibition, lipase activity inhibition, antiadipogenesis effect, among others. Carnosic acid, carnosol and the derivatives of abietic acid, steviol, and andrographolide are examples of important antiobesity diterpenes and their derivatives. Of note, plant‐derived diterpenes may be potential candidates for managing obesity and obesity‐related diseases and disorders in human and other animals.     

Antiamoebic and Antigiardial Activity of Clerodane Diterpenes from Mexican Salvia Species Used for the Treatment of Diarrhea

Terpenoids from Salvia species have been identified to possess biological properties as antiprotozoal agents. Here, we evaluated the antiamoebic and antigiardial activities of 14 known clerodane and modified clerodane‐type diterpenes isolated from five Mexican Salvia species against Entamoeba histolytica and Giardia lamblia, and analyzed the effects of the functionalities in decalin ring or in the whole clerodane framework to visualize the structural requirements necessary to produce an antiprotozoal activity. Among these, linearolactone was the most active clerodane diterpene against both protozoa with IC₅₀ values of 22.9 μM for E. histolytica and of 28.2 μM in the case of G. lamblia. In this context it may be a lead compound for the development of novel therapeutic agent for the treatment of diarrhea and dysentery. The remaining diterpenes assayed showed moderate to weak activity against both protozoa. These findings give support to the use of Salvia species in the traditional medicine from México for the treatment of diarrhea. Copyright © 2015 John Wiley & Sons, Ltd.     

Antibacterial diterpenes from the leaves and seeds of Juniperus excelsa M. Bieb

Two diterpenes from Juniperus excelsa, obtained by bioautography-guided isolation technique, were found to possess significant antibacterial activity in a two-fold serial dilution assay. (+)-Ferruginol (abieta-8,11,13-triene-12-ol) (1) and (?)-sandaracopimeric acid (isopimara-8(14), 15-diene-18-oic acid) (2) exhibited significant activity against Bacillus subtilis, Staphylococcus aureus and Streptococcus durans, while their corresponding 3β-hydroxy derivatives [(hinokiol (3) and 3β-hydroxysandaracopimeric acid (4), also isolated from J. excelsa)] were found to be inactive. (+)-Ferruginol, in addition, demonstrated strong activity against Mycobacterium smegmatis, M. intracellulare, M. xenopi and M. cheloni. The minimum inhibitory concentrations were determined for all compounds isolated from the active bioautographic zones, and were compared to those of the standard antibiotics chloramphenicol and streptomycin sulphate.     

中国南海软珊瑚Sinularia flexibilis中西松烷型二萜的研究

 目的对中国南海软珊瑚(Sinularia flexibilis)中的西松烷二萜类成分进行研究,从中寻找有抗肿瘤活性的次生代谢产物。方法采用多种色谱手段进行分离纯化,通过理化性质和光谱分析确定化合物结构。通过抗肿瘤活性筛选方法,研究西松烷二萜的抗肿瘤活性。结果共分离得到4个西松烷二萜类化合物,其结构分别确定为:(1R,13S,12S,9S,8R,5S,4R)-9-Acetoxy-5,8:12,13-diepoxy-cembr-15(17)-en-16,4-olide(1),sinulariolide(2),dihydroflexibilide(3),flexibilide(4)。结论化合物3对所选肿瘤细胞株(BGC-823)显示中等的抑制活性。     

番荔枝属植物树皮中二萜类成分的HPLC-ELSD分析

 目的建立一种HPLC-ELSD分析方法,测定不同产地、不同种番荔枝属植物树皮中4种贝壳杉烷型二萜的含量。方法采用Agilent ZORBAX 80A Extend-C₁₈柱,0.3%冰醋酸溶液(A)-乙腈(B)梯度洗脱[0～40 min,60%～0%(A);40%～100%(B)],流速0.6 mL·min^-1,蒸发光散射检测器(ELSD)。结果4种贝壳杉烷型二萜与相邻杂质能较好分离,理论塔板数按16α-hydro-19-acetoxy-ent-kauran-17-oic acid(Ⅲ)计算不低于49 000。贝壳杉烷型二萜成分以海南产圆滑番荔枝中含量最高。结论该方法精密度高、分离效果好,分析准确,适合于该属植物中二萜类成分的含量测定;不同产地、不同种植物中各成分均存在一定的差别。     

Structure-activity relationship of in vitro antiviral and cytotoxic activity of semisynthetic analogues of scopadulane diterpenes.

Fourteen semisynthetic compounds derived from the natural scopadulane-type diterpenes thyrsiflorin A (4), B (5), and C (6), including several precursors, have been examined in vitro for their antiherpetic activity against Herpes simplex virus type II (HSV-2) and cytotoxicity against two human tumor cell lines. Four of these compounds showed moderate antiherpetic activity, but none of them exhibited a significant cytotoxicity against the cell lines used. Some structure-activity relationships have been identified for the antiviral activity in these scopadulane derivatives as well as important structural features for the cytotoxic activity.     

Three diterpenes from Leonurus japonicus houtt protect primary cultured rat cortical cells from glutamate‐induced toxicity

To examine the cytoprotective effects of Leonurus japonicus Houtt, its protection against the glutamate‐induced toxicity in primary cortical cultured neurons was tested. In order to clarify the cytoprotective mechanism(s) of this observed effect, isolation was performed to seek and identify active fractions and components. By such fractionation, three known diterpenes – prehispanolone (1), leojaponin (2) and iso‐preleoheterin (3) – were isolated from the methanol extracts from the air‐dried L. japonicus. Among these three compounds, leojaponin (2) exhibited significant cytoprotective activities against glutamate‐induced toxicity, exhibiting cell viability of about 50%, at concentrations ranging from 0.1 μm to 10 μm . Therefore, the cytoprotective effect of L. japonicus might be due to the inhibition of glutamate‐induced toxicity by the diterpenes it contains. Copyright © 2010 John Wiley & Sons, Ltd.     

Assessment of the efficacy of quwenling as a mosquito repellent

Quwenling is a mosquito repellent product made in China from lemon eucalyptus. It was tested in the laboratory against. Anopheles gambiae in comparison with two commercial products containing 20–22% deet. The numbers of mosquitoes coming to bite in 30 s with successive increments of dosage of each product applied to human skin or to a cotton sleeve were compared with the numbers of bites with untreated controls. The ED₅₀, ED₉₀ and ED₁₀₀ values indicated that Quwenling was somewhat less potent than the deet products. The performance of the three products against British wild mosquitoes did not differ significantly.     

Antiviral effect of flavonoids on the dengue virus

In the present study we analysed the possible antiviral effect on dengue viruses of different flavonoids extracted and identified at the Chemistry Institute, UNAM, from the Mexican plants Tephrosia madrensis, Tephrosia viridiflora and Tephrosia crassifolia. The flavonoids glabranine and 7-O-methyl-glabranine presented 70% inhibition on the dengue virus at a concentration of 25 microM, while methyl-hildgardtol A, hildgardtol A and elongatine had no effect on viral growth. Our results show that glabranine and 7-O-methyl-glabranine isolated from Tephrosia s.p. exert a dose-dependent inhibitory effect in vitro on the dengue virus.     

蓝萼香茶菜二萜类物质对乳腺癌癌前病变肝郁肾虚证模型大鼠的干预作用

目的:通过加热回流的方法提取蓝萼香茶菜中二萜类物质,测定其含量,研究二萜类物质对乳腺癌癌前病变肝郁肾虚证模型大鼠的干预作用及其作用机制。方法:雌性SD大鼠随机分层分组为正常组、枸橼酸他莫昔芬片组、模型组、蓝萼组。除正常组外其他各组均用二甲基苯蒽(DMBA)结合慢性不可预见应激行为制备乳腺癌癌前病变肝郁肾虚证模型,造模结束后,观察记录各组大鼠的生物表征变化及病理变化验证模型。蓝萼组给予二萜类提取物水溶液5 mg·kg-1灌胃,正常组和模型组给予蒸馏水10 m L·kg-1灌胃,各组均连续灌胃30 d。30 d后,记录各组大鼠肉眼可见肿瘤的发生情况;腹腔取血,使用酶联免疫吸附试验(ELISA)试剂盒检测血清中雌二醇(E2),孕激素(P)水平;采集乳腺织织,用苏木素-伊红(HE)染色观察乳腺组织病理学变化,实时荧光定量PCR(Real-time PCR)及蛋白免疫印迹法(Western blot)检测乳腺组织血管内皮生长因子(VEGF),趋化因子受体4(CXCR4)mRNA及蛋白表达水平。结果:提取得干燥品质量2.162 g,干燥品中二萜类质量分数为26.35%。与模型组比较,蓝萼组血清中E2,P水平明显降低(P0.05),乳腺组织中VEGF,CXCR4蛋白及mRNA表达水平均明显降低(P0.05)。结论:蓝萼香茶菜二萜类物质有可能通过抑制VEGF,CXCR4蛋白及mRNA表达,抑制血管生成和趋化因子受体表达,调节大鼠激素水平,从而抑制大鼠乳腺癌癌前病变癌变的发生。     

Antiviral potential of medicinal plants against HIV,HSV, influenza,hepatitis, and coxsackievirus: A systematic review

Viral infections are being managed therapeutically through available antiviral regimens with unsatisfactory clinical outcomes. The refractory viral infections resistant to available antiviral drugs are alarming threats and a serious health concern. For viral hepatitis, the interferon and vaccine therapies solely are not ultimate solutions due to recurrence of hepatitis C virus. Owing to the growing incidences of viral infections and especially of resistant viral strains, the available therapeutic modalities need to be improved, complemented with the discovery of novel antiviral agents to combat refractory viral infections. It is widely accepted that medicinal plant heritage is nature gifted, precious, and fueled with the valuable resources for treatment of metabolic and infectious disorders. The aims of this review are to assemble the facts and to conclude the therapeutic potential of medicinal plants in the eradication and management of various viral diseases such as influenza, human immunodeficiency virus (HIV), herpes simplex virus (HSV), hepatitis, and coxsackievirus infections, which have been proven in diverse clinical studies. The articles, published in the English language since 1982 to 2017, were included from Web of Science, Cochrane Library, AMED, CISCOM, EMBASE, MEDLINE, Scopus, and PubMed by using relevant keywords including plants possessing antiviral activity, the antiviral effects of plants, and plants used in viral disorders. The scientific literature mainly focusing on plant extracts and herbal products with therapeutic efficacies against experimental models of influenza, HIV, HSV, hepatitis, and coxsackievirus were included in the study. Pure compounds possessing antiviral activity were excluded, and plants possessing activity against viruses other than viruses in inclusion criteria were excluded. Hundreds of plant extracts with antiviral effect were recognized. However, the data from only 36 families investigated through in vitro and in vivo studies met the inclusion criteria of this review. The inferences from scientific literature review, focusing on potential therapeutic consequences of medicinal plants on experimental models of HIV, HSV, influenza, hepatitis, and coxsackievirus have ascertained the curative antiviral potential of plants. Fifty‐four medicinal plants belonging to 36 different families having antiviral potential were documented. Out of 54 plants, 27 individually belong to particular plant families. On the basis of the work of several independent research groups, the therapeutic potential of medicinal plants against listed common viral diseases in the region has been proclaimed. In this context, the herbal formulations as alternative medicine may contribute to the eradication of complicated viral infection significantly. The current review consolidates the data of the various medicinal plants, those are Sambucus nigra, Caesalpinia pulcherrima, and Hypericum connatum, holding promising specific antiviral activities scientifically proven through studies on experimental animal models. Consequently, the original research addressing the development of novel nutraceuticals based on listed medicinal plants is highly recommended for the management of viral disorders.     

Pimarane‐type Diterpenes Obtained by Biotransformation: Antimicrobial Properties Against Clinically Isolated Gram‐positive Multidrug‐resistant Bacteria

The present study describes the antimicrobial activity of five pimarane‐type diterpenes obtained by fungal biotransformation against several nosocomial multidrug‐resistant bacteria. Among the investigated metabolites, ent‐8(14),15‐pimaradien‐3β‐ol was the most active compound, with very promising minimal inhibitory concentration values (between 8.0 and 25.0 µg mL^?1). Time‐kill assays using this metabolite against Staphylococcus aureus (HCRP180) revealed that this compound exerted its bactericidal effect within 24 h at all the evaluated concentrations (8.0, 16.0, and 24.0 µg mL^?1). When this metabolite was associated with vancomycin at their minimal bactericidal concentration values, the resulting combination was able to drastically reduce the number of viable strains of S. aureus within the first 6 h, compared with these chemicals alone. The checkerboard assays conducted against this microorganism did not evidence any synergistic effects when this same combination was employed. In conclusion, our results point out that ent‐8(14),15‐pimaradien‐3β‐ol is an important metabolite in the search for new effective antimicrobial agents. Copyright © 2012 John Wiley & Sons, Ltd.     

Evaluation of the antiprotozoal activity of neo‐clerodane type diterpenes from Salvia polystachya against Entamoeba histolytica and Giardia lamblia

Chia (Salvia polystachya Ort., Lamiaceae) is frequently used in Mexican traditional medicine to treat dysentery. In this study the main neo‐clerodane diterpenes (polystachynes A, B and D, as well as linearolactone) were isolated from the aerial parts of chia, and their antiprotozoal activities toward Entamoeba histolytica and Giardia lamblia trophozoites were evaluated in vitro. Linearolactone was the most potent antiamoebic and antigiardial compound with IC₅₀ values of 22.9 μM for E. histolytica and 28.2 μM for G. lamblia. Polystachynes A, B and D, showed moderate antiprotozoal activity against both protozoans with IC₅₀ values ranging from 117.0 to 160.6 μM for E. histolytica and from 107.5 to 134.7 μM for G. lamblia. These data suggest that linearolactone may play an important role in the antidiarrhoeal activity of S. polystachya. Copyright © 2009 John Wiley & Sons, Ltd.     

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??Dengue fever is one of the most important vector-borne human diseases caused by mosquito vector Aedes aegypti and Aedes albopictus. Dengue virus can cause dengue fever, dengue hemorrhagic fever and dengue shock syndrome. There are no approved drugs for the treatment of dengue disease so far. According to the mechanism of anti-dengue virus(anti-DENV) action, drugs under development for dengue disease can be divided into two categories:viral replication inhibitors and anti-cell factor pathway inhibitors. The former is further divided into DENV entry inhibitors, capsid protein inhibitors, NS3 protein inhibitors, NS5 protein inhibitors, and NS4B protein inhibitors; the latter is further divided into cell receptor inhibitors, lipid synthesis and metabolism inhibitors, and glucosidase inhibitors. The R&D of anti-DENV drugs is facing enormous challenges. Development of effective drugs which can be used for the treatment of four serotypes of dengue has a broad application prospect, and it will bring new hopes for dengue fever prevention and therapy.     

荆三棱顺式茋类化合物的结构修饰及抗炎活性

 目的 对荆三棱顺式茋类化合物进行结构修饰及体外抗炎活性评价。方法 分别运用甲基化、乙酰化、去甲基化反应对荆三棱中新的顺式茋类化合物sciryagarol I(1)进行结构修饰。采用噻唑蓝(MTT)法考察化合物1及其结构修饰物3~5和荆三棱中另一新顺式茋类化合物sciryagarol II(2)对RAW264.7细胞活力的影响。以脂多糖(LPS)与Pam3csk4分别诱导RAW264.7细胞炎症模型,运用酶联免疫吸附法(ELISA )法检测化合物1~5对细胞释放炎性因子肿瘤坏死因子-ɑ与白细胞介素-6(IL-6)的影响。结果 通过¹H-NMR和HRESI-MS确定修饰物3~5的结构;化合物1,2 和5能显著抑制由LPS或Pam3csk4诱导的RAW264.7细胞释放的炎性因子肿瘤坏死因子-ɑ和白细胞介素-6。结论 修饰物3~5皆为新化合物,顺式茋类化合物的抗炎作用强度与其结构上的酚羟基数目有一定关系。     

Labdane‐type diterpenes from Hedychium gardnerianum with potent cytotoxicity against human small cell lung cancer cells

Seven labdane‐type diterpenes, coronarin E, coronarin A, yunnancoronarin A, yunnancoronarin B, hedyforrestin B, villosin, and hedyforrestin C were isolated from the rhizome of Hedychium gardnerianum and evaluated for cytotoxic activity against human small cell lung cancer (NCI‐H187) and non‐cancerous Vero cells. The results showed that villosin exhibited potent cytotoxic activity with IC₅₀ of 0.40 μM, which was higher than that of the drug ellipticine (IC₅₀ 1.79 μM). Moreover, ellipticine was very toxic to Vero cells (IC₅₀ 7.47 μM) whereas the toxicity of villosin was undetectable at concentration lower than 166.42 μM. The results have indicated that the lactone ring is essential for high cytotoxic activity and that the presence of a hydroxyl group at the 6 or 7 position causes decrease in activity. The very high cytotoxicity against the NCI‐H187 cells and the exceptionally high selectivity index (>416) of villosin suggested that this compound may be used as a potential lead molecule for antitumor therapeutic development. Copyright © 2009 John Wiley & Sons, Ltd.