Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities

Karen Liby, Tadashi Honda, Charlotte R. Williams, Renee Risingsong, Darlene B. Royce, Nanjoo Suh, Albena T. Dinkova-Kostova, Katherine K. Stephenson, Paul Talalay, Chitra Sundararajan, Gordon W. Gribble, Michael B. Sporn

Research output: Contribution to journalArticle

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Abstract

Betulinic acid (BA), a pentacyclic triterpene isolated from birch bark and other plants, selectively inhibits the growth of human cancer cell lines. However, the poor potency of BA hinders its clinical development, despite a lack of toxicity in animal studies even at high concentrations. Here, we describe six BA derivatives that are markedly more potent than BA for inhibiting inducible nitric oxide synthase, activating phase 2 cytoprotective enzymes, and inducing apoptosis in cancer cells and in Bax/Bak-/- fibroblasts, which lack two key proteins involved in the intrinsic, mitochondrial-dependent apoptotic pathway. Notably, adding a cyano-enone functionality in the A ring of BA enhanced its cytoprotective properties, but replacing the cyano group with a methoxycarbonyl strikingly increased potency in the apoptosis assays. Higher plasma and tissue levels were obtained with the new BA analogues, especially CBA-Im [1-(2-cyano-3-oxolupa-1,20(29)-dien-28-oyl)imidazole], compared with BA itself and at concentrations that were active in vitro. These results suggest that BA is a useful platform for drug development, and the enhanced potency and varied biological activities of CBA-Im make it a promising candidate for further chemoprevention or chemotherapeutic studies.

Original languageEnglish
Pages (from-to)2113-2119
Number of pages7
JournalMolecular Cancer Therapeutics
Volume6
Issue number7
DOIs
Publication statusPublished - 1 Jul 2007

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Pentacyclic Triterpenes
Plant Bark
Apoptosis
Betula
betulinic acid
Chemoprevention
Nitric Oxide Synthase Type II
Neoplasms
Fibroblasts
Cell Line
Enzymes
Growth
Pharmaceutical Preparations
Proteins
imidazole
In Vitro Techniques

Cite this

Liby, Karen ; Honda, Tadashi ; Williams, Charlotte R. ; Risingsong, Renee ; Royce, Darlene B. ; Suh, Nanjoo ; Dinkova-Kostova, Albena T. ; Stephenson, Katherine K. ; Talalay, Paul ; Sundararajan, Chitra ; Gribble, Gordon W. ; Sporn, Michael B. / Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 7. pp. 2113-2119.
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abstract = "Betulinic acid (BA), a pentacyclic triterpene isolated from birch bark and other plants, selectively inhibits the growth of human cancer cell lines. However, the poor potency of BA hinders its clinical development, despite a lack of toxicity in animal studies even at high concentrations. Here, we describe six BA derivatives that are markedly more potent than BA for inhibiting inducible nitric oxide synthase, activating phase 2 cytoprotective enzymes, and inducing apoptosis in cancer cells and in Bax/Bak-/- fibroblasts, which lack two key proteins involved in the intrinsic, mitochondrial-dependent apoptotic pathway. Notably, adding a cyano-enone functionality in the A ring of BA enhanced its cytoprotective properties, but replacing the cyano group with a methoxycarbonyl strikingly increased potency in the apoptosis assays. Higher plasma and tissue levels were obtained with the new BA analogues, especially CBA-Im [1-(2-cyano-3-oxolupa-1,20(29)-dien-28-oyl)imidazole], compared with BA itself and at concentrations that were active in vitro. These results suggest that BA is a useful platform for drug development, and the enhanced potency and varied biological activities of CBA-Im make it a promising candidate for further chemoprevention or chemotherapeutic studies.",
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Liby, K, Honda, T, Williams, CR, Risingsong, R, Royce, DB, Suh, N, Dinkova-Kostova, AT, Stephenson, KK, Talalay, P, Sundararajan, C, Gribble, GW & Sporn, MB 2007, 'Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities', Molecular Cancer Therapeutics, vol. 6, no. 7, pp. 2113-2119. https://doi.org/10.1158/1535-7163.MCT-07-0180

Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities. / Liby, Karen; Honda, Tadashi; Williams, Charlotte R.; Risingsong, Renee; Royce, Darlene B.; Suh, Nanjoo; Dinkova-Kostova, Albena T.; Stephenson, Katherine K.; Talalay, Paul; Sundararajan, Chitra; Gribble, Gordon W.; Sporn, Michael B.

In: Molecular Cancer Therapeutics, Vol. 6, No. 7, 01.07.2007, p. 2113-2119.

Research output: Contribution to journalArticle

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T1 - Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities

AU - Liby, Karen

AU - Honda, Tadashi

AU - Williams, Charlotte R.

AU - Risingsong, Renee

AU - Royce, Darlene B.

AU - Suh, Nanjoo

AU - Dinkova-Kostova, Albena T.

AU - Stephenson, Katherine K.

AU - Talalay, Paul

AU - Sundararajan, Chitra

AU - Gribble, Gordon W.

AU - Sporn, Michael B.

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Y1 - 2007/7/1

N2 - Betulinic acid (BA), a pentacyclic triterpene isolated from birch bark and other plants, selectively inhibits the growth of human cancer cell lines. However, the poor potency of BA hinders its clinical development, despite a lack of toxicity in animal studies even at high concentrations. Here, we describe six BA derivatives that are markedly more potent than BA for inhibiting inducible nitric oxide synthase, activating phase 2 cytoprotective enzymes, and inducing apoptosis in cancer cells and in Bax/Bak-/- fibroblasts, which lack two key proteins involved in the intrinsic, mitochondrial-dependent apoptotic pathway. Notably, adding a cyano-enone functionality in the A ring of BA enhanced its cytoprotective properties, but replacing the cyano group with a methoxycarbonyl strikingly increased potency in the apoptosis assays. Higher plasma and tissue levels were obtained with the new BA analogues, especially CBA-Im [1-(2-cyano-3-oxolupa-1,20(29)-dien-28-oyl)imidazole], compared with BA itself and at concentrations that were active in vitro. These results suggest that BA is a useful platform for drug development, and the enhanced potency and varied biological activities of CBA-Im make it a promising candidate for further chemoprevention or chemotherapeutic studies.

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