Aphadilactones A–D, Four Diterpenoid Dimers with DGAT Inhibitory and Antimalarial Activities from a Meliaceae Plant

Liu, Jia; He, Xiu-Feng; Wang, Gaihong; Merino, Emilio F.; Yang, Sheng‐Ping; Zhu, Rongxiu; Gan, Li‐She; Zhang, Hua; Cassera, María B.; Wang, He-Yao; Kingston, David G. I.; Yue, Jian‐Min

doi:10.1021/jo402340h

Cited by 43 publications

(39 citation statements)

References 36 publications

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“…30,31 Sixteen compounds exhibited IC 50 values below 100 nM, eight compounds showed mid to high nanomolar IC 50 values (100–860 nM), eight compounds were in the micromolar range, and the others were inactive at 25 μ M, which was the highest concentration tested (Table 5). Fifteen of the compounds that exhibited IC 50 values below 100 nM were tested for mammalian cytotoxicity toward normal embryonic lung tissue (WI-38 cell line).…”

Section: Resultsmentioning

confidence: 99%

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Nanomolar Antimalarial Agents against Chloroquine-Resistant Plasmodium falciparum from Medicinal Plants and Their Structure–Activity Relationships

Zhou

Dalal³

et al. 2016

J. Nat. Prod.

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Inspired by the discovery of the antimalarial drug artemisinin from a traditional Chinese medicine (TCM), a natural product library of 44 lindenane-type sesquiterpenoids was assessed for activities against the Dd2 chloroquine-resistant strain of the malaria parasite Plasmodium falciparum. These compounds were mainly isolated from plants of the Chloranthus genus, many species of which are named “Sikuaiwa” in TCM and have long been used to treat malaria. The compounds consisted of 41 sesquiterpenoid dimers and three monomers, including the twelve new dimers 1–12 isolated from C. fortunei. The results showed that 16 dimers exhibited potent antiplasmodial activities (<100 nM); in particular, compounds 1, 14 and 19 exhibited low nanomolar activities with IC50 values ranging from 1 to 7 nM, which is comparable to the potency of artemisinin, and selectivity index values toward mammalian cells greater than 500. A comprehensive structure-activity relationship (SAR) study clearly indicated that three functional groups are essential and two motifs can be modified.

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Section: Resultsmentioning

confidence: 99%

“…30–31 Artemisinin was used as a positive control. Parasite growth was normalized to untreated controls in the presence of DMSO.…”

Section: Methodsmentioning

confidence: 99%

Nanomolar Antimalarial Agents against Chloroquine-Resistant Plasmodium falciparum from Medicinal Plants and Their Structure–Activity Relationships

Zhou

Dalal³

et al. 2016

J. Nat. Prod.

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“…Furthermore, the development of purification and structural elucidation methods, especially preparative HPLC and high resolution NMR, makes it now possible to identify compounds at trace amounts. Chiral HPLC dramatically accelerated the isolation of stereoisomers, especially those with complex structures like diterpenoid dimers [7][8][9]. In recent years, ECD calculations have been widely used to determine the absolute configurations of diterpenoid dimers [7,[9][10][11].…”

Section: Dgatmentioning

confidence: 99%

Naturally Occurring Diterpenoid Dimers: Source, Biosynthesis, Chemistry and Bioactivities

et al. 2016

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Diterpenoid dimers are rare in nature and mainly found in higher plants including the families Acanthaceae, Annonaceae, Asteraceae, Calceolariaceae, Chrysobalanaceae, Cupressaceae, Euphorbiaceae, Fabaceae, Lamiaceae, Liliaceae, Meliaceae, Rhizophoraceae, Taxaceae, Velloziaceae, and Zingiberaceae. In addition, a few diterpenoid dimers have been also reported from fungi (Psathyrellaceae), liverworts (Scapaniaceae), and a gorgonian (Gorgoniidae). They feature a wide variety of structures due to different core skeletons, linkage patterns, substituents, and configurations. Accordingly, diterpenoid dimers exhibit a broad range of bioactivities, including cytotoxic, anti-inflammatory, antimicrobial, antimalarial, and antifouling properties, which have attracted more and more research interests in the past decades. This review with 176 metabolites from 109 references provides a comprehensive and up-to-date overview of the source, biosynthesis, structure, synthesis, and bioactivities of diterpenoid dimers.

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“…XN enhances apoB degradation owing to a lack of lipidation of the lipoprotein particle caused by the insufficient transfer of newly synthesized TG from the microsomal membrane to the active lumenal pool via DGAT and MTP activity. [96] [73] Through the screening of DGAT inhibitors from natural resources, the brown alga Pachydictyon coriaceum, which is distributed in California, China, Japan, Korea, and Taiwan, was identified as an active species, and diterpene dictyol E and hydroxyisocrenulatin ( Figure 4) were isolated by chromatographic analysis for the treatment of obesity and type II diabetes.…”

Section: Dgat Inhibitors Of Plant Originmentioning

confidence: 99%

“…According to Liu et al, alphadilactone C represents a new structural scaffold and is a promising candidate for a DGAT-1 inhibitor. [96]…”

Section: Dgat Inhibitors Of Plant Originmentioning

confidence: 99%

Therapeutic Strategies for Metabolic Diseases: Small‐Molecule Diacylglycerol Acyltransferase (DGAT) Inhibitors

et al. 2014

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Metabolic diseases such as atherogenic dyslipidemia, hepatic steatosis, obesity, and type II diabetes are emerging as major global health problems. Acyl-CoA:diacylglycerol acyltransferase (DGAT) is responsible for catalyzing the final reaction in the glycerol phosphate pathway of triglycerol synthesis. It has two isoforms, DGAT-1 and DGAT-2, which are widely expressed and present in white adipose tissue. DGAT-1 is most highly expressed in the small intestine, whereas DGAT-2 is primarily expressed in the liver. Therefore, the selective inhibition of DGAT-1 has become an attractive target with growing potential for the treatment of obesity and type II diabetes. Furthermore, DGAT-2 has been suggested as a new target for the treatment of DGAT-2-related liver diseases including hepatic steatosis, hepatic injury, and fibrosis. In view the discovery of drugs that target DGAT, herein we attempt to provide insight into the scope and further reasons for optimization of DGAT inhibitors.

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Aphadilactones A–D, Four Diterpenoid Dimers with DGAT Inhibitory and Antimalarial Activities from a Meliaceae Plant

Cited by 43 publications

References 36 publications

Nanomolar Antimalarial Agents against Chloroquine-Resistant Plasmodium falciparum from Medicinal Plants and Their Structure–Activity Relationships

Nanomolar Antimalarial Agents against Chloroquine-Resistant Plasmodium falciparum from Medicinal Plants and Their Structure–Activity Relationships

Naturally Occurring Diterpenoid Dimers: Source, Biosynthesis, Chemistry and Bioactivities

Therapeutic Strategies for Metabolic Diseases: Small‐Molecule Diacylglycerol Acyltransferase (DGAT) Inhibitors

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