Chemistry and Biology of Rocaglamides (= Flavaglines) and Related Derivatives from Aglaia Species (Meliaceae)

Ebada, Sherif S.; Lajkiewicz, Neil J.; Porco, John A.; Li‐Weber, Min; Proksch, Peter

doi:10.1007/978-3-7091-0748-5_1

Cited by 64 publications

(79 citation statements)

References 141 publications

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“…Flavagline synthesis remains a challenge as the compounds have two contiguous quaternary chiral centers and cis aryl groups on adjacent carbons of a strained cyclopentane ring. Since most of these efforts have already been reviewed, we will discuss only the most recent developments in this field [3,4,12].…”

Section: Synthesesmentioning

confidence: 99%

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Flavaglines: Potent Anticancer Drugs that Target Prohibitins and the Helicase eIF4A

et al. 2013

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Flavaglines are complex natural products that are found in several medicinal plants of Southeast Asia in the genus Aglaia; these compounds have shown exceptional anticancer and cytoprotective activities. This review describes the significance of flavaglines as a new class of pharmacological agents and presents recent developments in their synthesis, structure-activity relationships, identification of their molecular targets and modes of action. Flavaglines display a unique profile of anticancer activities that are mediated by two classes of unrelated proteins: prohibitins and the translation initiation factor eIF4A. The identification of these molecular targets is expected to accelerate advancement toward clinical studies. The selectivity of cytotoxicity towards cancer cells has been shown to be due to an inhibition of the transcription factor HSF1 and an upregulation of the tumor suppressor TXNIP. In addition, flavaglines display potent anti-inflammatory, cardioprotective and neuroprotective activities; however, the mechanisms underlying these activities are yet to be elucidated.

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Section: Synthesesmentioning

confidence: 99%

“…The chemistry and pharmacology of flavaglines has been the object of several reviews [3,4,9,10]. Over the last year, the pharmacological investigation of the flavaglines greatly increased, in particular with the identification of their molecular targets.…”

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confidence: 99%

Flavaglines: Potent Anticancer Drugs that Target Prohibitins and the Helicase eIF4A

et al. 2013

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“…The Aglaia genus of the Meliaceae family of angiosperms has garnered much attention as a source of novel therapeutic agents, as many Aglaia species are utilized in traditional medicines to treat respiratory diseases and inflammation [138]. In addition, extracts from Aglaia sp have been reported to possess tumor-suppressing properties since the 1970s [139].…”

Section: Rocaglatesmentioning

confidence: 99%

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

Chu

Pelletier

2015

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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“…To measure the time resolved gene responses to Roc-A, RNA was isolated from Roc-A-treated (50 nM) normal T and Jurkat T cells at t 5 [0, 1,2,3,4,6,8,10,14,20,28,36] and t 5 [0. 5,1,2,3,4,5,6,7,8,10,12,14,16,20,24,28,32,36] hr, respectively. The quality of total RNA was controlled with an Agilent 2100 Bioanalyzer (Agilent Technologies GmbH, Berlin, Germany).…”

Section: Rna Preparation and Dna Microarray Analysismentioning

confidence: 99%

“…A number of Roc compounds have been shown to possess potent inhibitory effects on tumor growth in vitro and in vivo in animal models with IC 50 concentrations at the nM range (for reviews 6,7 ). Roc-mediated inhibition of proliferation was first found to be associated with inhibition of protein synthesis in 1998.…”

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confidence: 99%

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

et al. 2013

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Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over-expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide-A (Roc-A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1-S phase. Roc-A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc-A can induce a rapid degradation of Cdc25A by activation of the ATM/ATRChk1/Chk2 checkpoint pathway. However, Roc-A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc-A by a time-resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc-A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc-A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy.In normal cells, the cell division cycle is tightly controlled. Cancer cells are characterized by deregulation in the cell division cycle, which is associated with increased DNA replication and elevated cellular proliferation. 1-3 Therefore, targeting the cancer cell cycle machinery has been considered to be a rational strategy for cancer treatment. 4 Cell division is governed by cyclin dependent kinases (CDKs) that are tightly regulated by cyclins and CDK inhibitors (CDKIs). Tumor-associated cell cycle defects often show alterations in CDK expression or/and activity. 2 Typically, CDK4 and CDK6 that are crucial for G1 checkpoint control are often over-expressed in many malignancies. 2,3 Evidence shows that deregulation of CDK4 and CDK6 activity is associated with a wide variety of tumors. 2 Moreover, elevated expressions of the cell division cycle 25 (Cdc25) phosphatases, in particular, the isoform Cdc25A, which is essential for cell cycle transitions of G1-S and S-G2, has been shown in different cancers and their over-expression often correlates with more aggressive disease and poor prognosis. 1,5 Recently, genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. 2 Thus, targeting the activities of CDK2, CDK4 and CDK6 may be a promising approach for cancer treatment.Rocaglamides (Roc; 5 Flavaglines), derived from the traditional Chinese medicinal plant Aglaia, are a group of naturally occurring herbal chemicals. A number of Roc compounds have been shown to possess potent inhibitory effects on tumor growth in vitro and in vivo in animal models with IC 50 concentrations at the n...

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Chemistry and Biology of Rocaglamides (= Flavaglines) and Related Derivatives from Aglaia Species (Meliaceae)

Cited by 64 publications

References 141 publications

Flavaglines: Potent Anticancer Drugs that Target Prohibitins and the Helicase eIF4A

Flavaglines: Potent Anticancer Drugs that Target Prohibitins and the Helicase eIF4A

Targeting the eIF4A RNA helicase as an anti-neoplastic approach

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

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