Adventures in bridgehead substitution chemistry: synthesis of polycyclic polyprenylated acylphloroglucinols (PPAPs)

Simpkins, Nigel S.

doi:10.1039/c2cc37914g

Cited by 35 publications

(22 citation statements)

References 34 publications

(42 reference statements)

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“…Gambogic acid, a caged xanthone from Garcinia hanburyi , has been tested in vitro and in vivo as a novel anticancer agent that inhibits cell proliferation, angiogenesis, and metastasis 23 - 25 . The PPAPs have been used in antiseptics, antidepressants, and antibiotics for centuries and their mimics also show fascinating biological activities 26 , 27 . For instance, oblongifolin C (OC), a PPAP purified from G. yunnanensis Hu, can activate a mitochondrial apoptotic pathway in human cervical cancer cells 28 .…”

Section: Introductionmentioning

confidence: 99%

The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

et al. 2014

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Metabolic stress induces autophagy as an alternative source of energy and metabolites. Insufficient autophagy in nutrient-deprived cancer cells would be beneficial for cancer therapy. Here, we performed a functional screen in search of novel autophagy regulators from natural products. We showed that oblongifolin C (OC), a natural small molecule compound extracted from Garcinia yunnanensis Hu, is a potent autophagic flux inhibitor. Exposure to OC results in an increased number of autophagosomes and impaired degradation of SQSTM1/p62. Costaining of GFP-LC3B with LysoTracker Red or LAMP1 antibody demonstrates that autophagosome-lysosome fusion is blocked by OC treatment. Furthermore, OC inhibits lysosomal proteolytic activity by altering lysosomal acidification and downregulating the expression of lysosomal cathepsins. Importantly, OC can eliminate the tolerance of cancer cells to nutrient starvation. Starvation dramatically increases the susceptibility of cancer cells to OC-induced CASP3-dependent apoptosis in vitro. Subsequent studies in xenograft mouse model showed that OC has anticancer potency as revealed by increased staining of cleaved CASP3, LC3 puncta, and SQSTM1, as well as reduced expression of lysosomal cathepsins. Combined treatment with OC and caloric restriction potentiates anticancer efficacy of OC in vivo. Collectively, these data demonstrated that OC is a novel autophagic flux inhibitor and might be useful in anticancer therapy.

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Section: Introductionmentioning

confidence: 99%

The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

et al. 2014

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“…Polycyclic polyprenylated acylphloroglucinols (PPAP) are family of natural products that possess a wide range of different important biologic activities, most of these compounds have a characteristic bicyclo[3.3.1]nonane-2,4,9-trione core structure, decorated with prenyl or geranyl side chains and an additional acyl group (5). When the structural similarities between the PPAPs are considered, the broad spectrum of biologic activities exhibited by these compounds is particularly striking (6).…”

Section: Introductionmentioning

confidence: 99%

Cambogin Induces Caspase-Independent Apoptosis through the ROS/JNK Pathway and Epigenetic Regulation in Breast Cancer Cells

Shen

Xie

Wang

et al. 2015

Molecular Cancer Therapeutics

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Cambogin is a polycyclic polyprenylated acylphoroglucinol (PPAP) from the Garcinia genus, which has been used traditionally for cancer treatment across Southeastern Asia. In this study, we found that cambogin inhibited breast cancer cell proliferation and induced cell apoptosis in vitro. Cambogin induced the activation of the caspase-independent mitochondrial apoptotic pathway, as indicated by an increase in the ratio of Bax/Bcl-2 and the nuclear translocation of apoptosis inducing factor (AIF). Two-dimensional gel electrophoresis and mass spectrometry revealed that the expression of proteins involving in the radical oxygen species (ROS) pathway was among the most affected upon cambogin treatment. Cambogin enhanced cellular ROS production, and induced the activation of the ASK1-MKK4/MKK7-JNK/SAPK signaling pathway. Pretreatment with ROS scavenger N-acetylcysteine (NAC), an antioxidant, or the JNK inhibitor SP600125 was able to restore cell viability in the presence of cambogin. Importantly, cambogin treatment led to the activation of activating transcription factor-2 (ATF-2) and the trimethylation of histone H3K9 in the activator protein 1 (AP-1) binding region of the Bcl-2 gene promoter. Finally, cambogin exhibited a potential antitumor effect in MCF-7 breast cancer xenografts without apparent toxicity. Taken in conjunction, the present study indicates that cambogin can induce breast adenocarcinoma cell apoptosis and therefore represents therapeutic potential for cancer treatment.

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“…[5][6][7] More recently, a number of remarkable studies on natural products and total synthesis of PPAPs have made these compounds class a hot topic in the related scientific communities. [8][9][10][11][12] H. attenuatum choisy, a member of the genus of Hypericum, is widely distributed in China. It has been used in traditional Chinese medicine for the treatment of numerous disorders, such as haemostasia, analgesia, and stimulation of lactation.…”

Section: Introductionmentioning

confidence: 99%

Two new adamantyl-like polyprenylated acylphloroglucinols from Hypericum attenuatum choisy

Zhu

et al. 2015

Tetrahedron Letters

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Adventures in bridgehead substitution chemistry: synthesis of polycyclic polyprenylated acylphloroglucinols (PPAPs)

Cited by 35 publications

References 34 publications

The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

The natural compound oblongifolin C inhibits autophagic flux and enhances antitumor efficacy of nutrient deprivation

Cambogin Induces Caspase-Independent Apoptosis through the ROS/JNK Pathway and Epigenetic Regulation in Breast Cancer Cells

Two new adamantyl-like polyprenylated acylphloroglucinols from Hypericum attenuatum choisy

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