Total synthesis of phenanthroindolizidine alkaloids (±)-antofine, (±)-deoxypergularinine, and their dehydro congeners and evaluation of their cytotoxic activity

Su, Chung Ren; Damu, Amooru G.; Chiang, Po Cheng; Bastow, Kenneth F.; Morris‐Natschke, Susan L.; Lee, Kuo Hsiung̀; Wu, Tian Shung

doi:10.1016/j.bmc.2008.04.032

Cited by 42 publications

(29 citation statements)

References 18 publications

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“…The ketone group at C-11 in j changes the tertiary amine in the indolizidine nucleus to an amide, decreasing the electron density at nitrogen-atom which may be important in the electrostatic interaction with the target. Such a finding is in agreement with the previous reports that C-9 amide structures of various phenanthroindolizidines were much less potent in cancer cell growth assays [8] , [47] . Other synthetic intermediates, h and i , also confirmed this conclusion and displayed significantly reduced activities.…”

Section: Resultssupporting

confidence: 93%

Synthesis, Biological Evaluation and Mechanism Studies of Deoxytylophorinine and Its Derivatives as Potential Anticancer Agents

Ren

et al. 2012

PLoS ONE

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Previous studies indicated that (+)-13a-(S)-Deoxytylophorinine (1) showed profound anti-cancer activities both in vitro and in vivo and could penetrate the blood brain barrier to distribute well in brain tissues. CNS toxicity, one of the main factors to hinder the development of phenanthroindolizidines, was not obviously found in 1. Based on its fascinating activities, thirty-four derivatives were designed, synthesized; their cytotoxic activities in vitro were tested to discover more excellent anticancer agents. Considering the distinctive mechanism of 1 and interesting SAR of deoxytylophorinine and its derivatives, the specific impacts of these compounds on cellular progress as cell signaling transduction pathways and cell cycle were proceeded with seven representative compounds. 1 as well as three most potent compounds, 9, 32, 33, and three less active compounds, 12, 16, 35, were selected to proform this study to have a relatively deep view of cancer cell growth-inhibitory characteristics. It was found that the expressions of phospho-Akt, Akt, phospho-ERK, and ERK in A549 cells were greater down-regulated by the potent compounds than by the less active compounds in the Western blot analysis. To the best of our knowledge, this is the first report describing phenanthroindolizidines alkaloids display influence on the crucial cell signaling proteins, ERK. Moreover, the expressions of cyclin A, cyclin D1 and CDK2 proteins depressed more dramatically when the cells were treated with 1, 9, 32, and 33. Then, these four excellent compounds were subjected to flow cytometric analysis, and an increase in S-phase was observed in A549 cells. Since the molecular level assay results of Western blot for phospho-Akt, Akt, phospho-ERK, ERK, and cyclins were relevant to the potency of compounds in cellular level, we speculated that this series of compounds exhibit anticancer activities through blocking PI3K and MAPK signaling transduction pathways and interfering with the cell cycle progression.

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Section: Resultssupporting

confidence: 93%

Synthesis, Biological Evaluation and Mechanism Studies of Deoxytylophorinine and Its Derivatives as Potential Anticancer Agents

Ren

et al. 2012

PLoS ONE

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“…C9-Keto analogs, amide structures of various phenanthroindolizidines and phenanthroquinolizidines, have also been found to be much less potent in cancer cell growth assays [31, 34, 63]. …”

Section: Mechanism Of Actionmentioning

confidence: 99%

Phenanthroindolizidines and Phenanthroquinolizidines: Promising Alkaloids for Anti-Cancer Therapy

Chemler¹

2009

CBC

131

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The phenanthroindolizidine and phenanthroquinolizidine alkaloids, typified by tylophorine and cryptopleurine, are a family of plant-derived small molecules with significant therapeutic potential. The plant extracts have been used in herbal medicine and the isolated compounds have displayed a range of promising therapeutic activity such as anti-ameobicidal, anti-viral, anti-inflammatory and anti-cancer activity. Despite their therapeutic protential, no compounds in this class have fully passed clinical trials. Drawbacks include low in vivo anti-cancer activity, central nervous system toxicity and low natural availability. A number of biological effects of these compounds, such as protein and nucleic acid synthesis suppression, have been identified, but the specific biomolecular targets have not yet been identified. Significant effort has been expended in the synthesis and structure-activityrelationship (SAR) studies of these compounds with the hope that a new drug will emerge. This review will highlight important contributions to the isolation, synthesis, SAR and mechanism of action of the phenanthroindolizidine and pheanthroquinolizidine alkaloids.

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“…The 12 different PA analogues were synthesized primarily based on previous reports ( 9 ). The 12 PA analogues contain the same phenanthrene ring with different functional groups at different positions.…”

Section: Methodsmentioning

confidence: 99%

In vitro anticancer effects of two novel phenanthroindolizidine alkaloid compounds on human colon and liver cancer cells

Liu

Zhang

et al. 2017

Molecular Medicine Reports

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Malignant cancer is one of the most serious diseases threatening the health of human beings. Natural plant alkaloids exhibit multiple biological functions, including inhibition of cell proliferation, and may have potential anticancer activity. However, most natural alkaloids may not be suitable for human therapies owing to instability, poor dissolubility and potential side effects. To improve their anticancer activity and drug effect, the present study aimed to develop new alkaloid derivatives, the phenanthroindolizidine alkaloid compounds, and evaluated their potential antitumor effects on human cancer cells in vitro. Among the several newly synthesized analogues of phenanthroindolizidine alkaloids (PAs), the compounds YS306 and YS206 exhibited an increased growth inhibition activity on HepG2 liver cancer cells and on HCT116 and HT29 colon cancer cells, with half-maximal inhibitory concentrations in the micromolar range. YS206 and YS306 (5 µg/ml) both significantly induced cell cycle arrest at the G2/M phase and notably decreased cell distribution at the G0/G1 and S phase. In addition, these two molecules significantly inhibited cancer cell migration, as analyzed by the wound-healing and Transwell assays. However, neither YS306 nor YS206 exhibited observable effects on apoptosis. Therefore, chemical structure modifications of natural PAs based on anticancer activity assessments may be feasible in the development of new cancer chemotherapeutic agents.

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Total synthesis of phenanthroindolizidine alkaloids (±)-antofine, (±)-deoxypergularinine, and their dehydro congeners and evaluation of their cytotoxic activity

Cited by 42 publications

References 18 publications

Synthesis, Biological Evaluation and Mechanism Studies of Deoxytylophorinine and Its Derivatives as Potential Anticancer Agents

Synthesis, Biological Evaluation and Mechanism Studies of Deoxytylophorinine and Its Derivatives as Potential Anticancer Agents

Phenanthroindolizidines and Phenanthroquinolizidines: Promising Alkaloids for Anti-Cancer Therapy

In vitro anticancer effects of two novel phenanthroindolizidine alkaloid compounds on human colon and liver cancer cells

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