Structure–activity studies of phenanthroindolizidine alkaloids as potential antitumor agents

Gao, Wenli; Bussom, Scott; Grill, Susan P.; Gullen, Elizabeth A.; Hu, Youcai; Huang, Xueshi; Zhong, Sanbao; Kaczmarek, Conrad; Gutiérrez, Julio; Francis, Samson; Baker, David C.; Yu, Shi‐Shan; Cheng, Yung‐Chi

doi:10.1016/j.bmcl.2007.05.021

Cited by 77 publications

(62 citation statements)

References 23 publications

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“…17 (+)-S-Tylophorine (DCB-3500) was synthesized by Dr. David C. Baker's laboratory. 16 To analyze the structure-activity relationships of tylophora alkaloids, we first compared their cytotoxicity in HepG2, PANC-1, and CEM cells, followed by the procedures described previously. 6,16 (+)-(S)-tylophorine and (−)-(R)-tylophorine differ only in the absolute configuration of the chiral center at the 13a position, the (R)-configured compound led to an approximately 3~4-fold decrease in cytotoxicity ( Table 1).…”

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Structural analogs of tylophora alkaloids may not be functional analogs

Gao

Chen

Leung

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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Phenanthroindolizidine-based tylophora alkaloids have been reported to have potential antitumor, anti-immuno and anti-inflammatory activity. The structure-activity relationships of a series of tylophora alkaloids were studied to guide future drug design. Our results indicate that although these compounds are structural analogs, their potency of cytotoxicity, selectivity against NF-κB signaling pathway, and their inhibitory effects against protein and nucleic acid synthesis are different. Because they do not have an identical spectrum of targets, the studied compounds are structural, but may not be functional analogs. KeywordsTylophora alkaloids; Structure; activity relationship; Protein; DNA and RNA synthesis Tylophora alkaloids originate from various plants of the Asclepiadaceae family, such as Tylophora, that are native of India and Southeast Asia. 1 They have antitumor, 2-6 antiinflammatory, 7 anti-arthritis, 8 and anti-lupus activity in vivo. 9 Due to their diverse and potent pharmacological actions, they continue to be targets for synthesis, modification, structureactivity relationship (SAR) studies since their first isolation in 1935. 10 Their molecular mechanisms of action of antitumor and anti-inflammatory activity include: inhibitory effect on protein synthesis 2 and nucleic acid synthesis, 2,11 inhibitory effect on RNA transcription which are controlled by cyclic AMP response elements (CREs), activator protein-1 (AP-1) sites, and NF-κB binding sites, 6 and ability to suppress the expression of a subset of proteins, such as cyclin D1, cyclin B1 and CDK4. 12 Tylocrebrine, a positional isomer of tylophorine, was found in clinical trials to have intolerable central nervous system (CNS) side effects. To *Corresponding author. Yung-Chi Cheng: tel.: +1-203-785-7118; fax: +1-203-785-7129; e-mail: E-mail: yccheng@yale.edu. Note: Yung-Chi Cheng is a fellow of the National Foundation for Cancer Research. † These authors contributed equally to this work.Supplementary data Supplementary data associated with this article (Synthesis of phenanthrene-based tylophorine derivatives described in Scheme 1, synthesis of tylophora alkaloids exemplified in Scheme 2, IC 50s of the inhibitory effect of tylophora alkaloids and PBTs against endogenous NF-κB, CRE, AP-1 and GRE mediated transcription in HepG2 cells listed in Table S1) can be found, in the online version, at doi: xxxxxxx.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. offset such CNS side effects, a series of phenanthrene-based tylophorine derivatives (PBTs) with increased polarity was synthesized to limit the crossin...

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Structural analogs of tylophora alkaloids may not be functional analogs

Gao

Chen

Leung

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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“…identified a ribonucleoprotein complex containing caprin-1 as the molecular target of tylophorine to suppress tumor growth14. PBT-1, the tylophorine analog used in the study is a dibenzoquinoline derivative that lacks the important E ring directly related to activity and mode of action1516. In addition, the D ring of tylophorine to which biotin moiety was added may change the function of parental compounds on the basis of our previous structure–activity relationship study1516.…”

Section: Discussionmentioning

confidence: 99%

“…Ribonucleoprotein complex containing caprin-1 is associated with tylophorine and responsible for inhibiting translation14. We previously reported that structural analogs of tylophorine may not be functional analogs1516.…”

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Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70

Wang

Lam

Chen

et al. 2016

Sci Rep

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Tylophorine analog DCB-3503 is a potential anticancer and immunosuppressive agent that suppresses the translation of cellular regulatory proteins, including cyclin D1, at the elongation step. However, the molecular mechanism underlying this phenomenon remains unknown. This study demonstrates that DCB-3503 preferentially binds to heat shock cognate protein 70 (HSC70), which is a determinant for cyclin D1 translation by binding to the 3′-untranslated region (3′ UTR) of its mRNA. DCB-3503 allosterically regulates the ATPase and chaperone activities of HSC70 by promoting ATP hydrolysis in the presence of specific RNA binding motifs (AUUUA) of cyclin D1 mRNA. The suppression of cyclin D1 translation by DCB-3503 is not solely caused by perturbation of the homeostasis of microRNAs, although the microRNA processing complex is dissociated with DCB-3503 treatment. This study highlights a novel regulatory mechanism of protein translation with AUUUA motifs in the 3′ UTR of mRNA by HSC70, and its activity can be allosterically modulated by DCB-3503. DCB-3503 may be used to treat malignancies, such as hepatocellular carcinoma or breast cancer with elevated expression of cyclin D1.

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“…The alkaloids have a lot of potential as a medicine. Alkaloids can be used as antituberculosis [9], antitumor [10], antipyretic [11], antimicrobial, antimalarial, cytotoxic, and anti-HIV [12].…”

Section: Resultsmentioning

confidence: 99%

Identification Of The Secondary Metabolite Compounds From Cempedak Tree Leaves (Artocarpus Integer)

Hakim¹

2017

Proceedings of the 2nd Sari Mulia International Conference on Health and Sciences 2017 (SMICHS 2017)

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Objective: This study aims to identify the secondary metabolite compounds in Cempedak Tree Leaves (Artocarpus integer). Methode: Cempedak tree leaves are extracted using maceration method with chloroform solvent. Identification of secondary metabolite compounds using identification methods for flavonoid compounds, alkaloids, glycosides, tannins, terpenoids, and steroids. Results: The result for identified of secondary metabolite compounds on chloroform extract cempedak tree leaves were positively result for alkaloids and negative results for flavonoids, glycosides, tannins, terpenoids, and steroids. Conclusion: Chloroform extract of cempedak tree leaves only identified alkaloids

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Structure–activity studies of phenanthroindolizidine alkaloids as potential antitumor agents

Cited by 77 publications

References 23 publications

Structural analogs of tylophora alkaloids may not be functional analogs

Structural analogs of tylophora alkaloids may not be functional analogs

Tylophorine Analog DCB-3503 Inhibited Cyclin D1 Translation through Allosteric Regulation of Heat Shock Cognate Protein 70

Identification Of The Secondary Metabolite Compounds From Cempedak Tree Leaves (Artocarpus Integer)

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