Antitumor agents. 4. Cytotoxicity and in vivo activity of helenalin esters and related derivatives

Lee, Kuo‐Hsiung; Meck, R.; Piantadosi, Claude A.; Huang, Eng‐Shang

doi:10.1021/jm00261a034

Cited by 60 publications

(43 citation statements)

References 2 publications

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“…The exocyclic ␣-methylene-␥-lactone was important for cytotoxic activity of analogs of sesquiterpene lactone helenalin (Lee et al, 1971(Lee et al, , 1973(Lee et al, , 1977Lee and Furukawa, 1972;Hall et al, 1978).…”

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory activity of extracts and 11,13-dihydrozaluzanin C from Gochnatia polymorpha ssp. floccosa trunk bark in mice

Piornedo

Souza

Stefanello

et al. 2011

Journal of Ethnopharmacology

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Section: Discussionmentioning

confidence: 99%

Anti-inflammatory activity of extracts and 11,13-dihydrozaluzanin C from Gochnatia polymorpha ssp. floccosa trunk bark in mice

Piornedo

Souza

Stefanello

et al. 2011

Journal of Ethnopharmacology

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“…A number of investigations have demonstrated the importance of an ester group in the cytotoxicity and antileukemic activity of compounds in certain classes ( , 1973Levy et al, 1983;Nagao et al, 1991). The specific role of the bioactivity of pyridine ring has been recognized and the introduction of some pyridine analogs into the molecules of drugs could result in new compounds that have significant biological activity compared with the parent compounds Straub et al, 1997;Bolognese et al, 2002;Tiwari et al, 2002;Kuo et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and biological evaluation of novel pyridine acid esters of podophyllotoxin and esters of 4′-demethylepipodophyllotoxin

Liu

Tian

2007

Med Chem Res

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Podophyllotoxin and related analogs present numerous challenges associated with optimal antitumor activity and severe unpredictable toxicity. In the course of our ongoing investigation of quantitative structure-activity relationships to find biorational antitumor drugs, two series of pyridine acid ester derivatives of podophyllotoxin and 4 0 -demethylepipodophyllotoxin have been prepared by reacting the corresponding pyridine acids with the hydroxyl group of podophyllotoxin and 4 0 -demethyl epipodophyllotoxin in the presence of dimethylaminopyridine (DMAP) and N,N-dicyclohexylcarbodiimde (DCC). The structures of the compounds were extensively characterized by using 1 H-nuclear magnetic resonance, mass spectroscopy, infrared, and elemental analysis and evaluated for their in vitro cytotoxicity on two neoplastic cell lines (P-388 murine leukemia, A-549 human lung carcinoma) using a MTT-based assay, the results indicated significantly higher efficacy of these compounds in comparison with the prototypical inhibitor etoposide. On the basis of the preliminary biological testing results, it suggested that the cytotoxic activity of OCH 3 at C-4 0 is more potent than that of its demethylated analogs and the podophyllotoxin substitution at C-4 may be optimal for synthesizing more potent cytotoxic compounds.

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“…Therefore, exposed thiol groups, such as cysteine residues in proteins, appear to be the primary targets of sesquiterpene lactones. Some sesquiterpene lactones, for example, helenalin, possess two alkylant structure elements which may be responsible for their remarkably high activity (5)(6)(7)(8). However, other factors, such as lipophilicity, molecular geometry, and the chemical environment of the target sulfhydryl may also influence the activity of sesquiterpene lactones (6).…”

mentioning

confidence: 99%

The Anti-inflammatory Sesquiterpene Lactone Helenalin Inhibits the Transcription Factor NF-κB by Directly Targeting p65

Lyß¹,

Knorre²,

Schmidt³

et al. 1998

Journal of Biological Chemistry

431

111

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The sesquiterpene lactone helenalin is a potent antiinflammatory drug whose molecular mechanism of action remains unclear despite numerous investigations. We have previously shown that helenalin and other sesquiterpene lactones selectively inhibit activation of the transcription factor NF-B, a central mediator of the human immune response. These drugs must target a central step in NF-B pathway, since they inhibit NF-B induction by four different stimuli. It has previously been reported that sesquiterpene lactones exert their effect by inhibiting degradation of IB, the inhibitory subunit of NF-B. These data contradicted our report that IB is not detectable in helenalin-treated, ocadaic acid-stimulated cells. Here we use confocal laser scanning microscopy to demonstrate the presence of IBreleased, nuclear NF-B in helenalin-treated, tumor necrosis factor-␣ stimulated cells. These data show that neither IB degradation nor NF-B nuclear translocation are inhibited by helenalin. Rather, we provide evidence that helenalin selectively alkylates the p65 subunit of NF-B. This sesquiterpene lactone is the first anti-inflammatory agent shown to exert its effect by directly modifying NF-B.

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Antitumor agents. 4. Cytotoxicity and in vivo activity of helenalin esters and related derivatives

Cited by 60 publications

References 2 publications

Anti-inflammatory activity of extracts and 11,13-dihydrozaluzanin C from Gochnatia polymorpha ssp. floccosa trunk bark in mice

Anti-inflammatory activity of extracts and 11,13-dihydrozaluzanin C from Gochnatia polymorpha ssp. floccosa trunk bark in mice

Design, synthesis, and biological evaluation of novel pyridine acid esters of podophyllotoxin and esters of 4′-demethylepipodophyllotoxin

The Anti-inflammatory Sesquiterpene Lactone Helenalin Inhibits the Transcription Factor NF-κB by Directly Targeting p65

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