Synthesis and antitumor activity of puupehedione and related compounds

Barrero, Alejandro F.; Álvarez-Manzaneda, Enrique; Chahboun, Rachid; Cortés, Manuel; Armstrong, Verónica

doi:10.1016/s0040-4020(99)00992-8

Cited by 77 publications

(67 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As we have previously established, 3 the oxidative process involves ring opening and subsequent cyclization to obtain 1a and 1b in the same 1:4 relative proportion, independent of the C-8 epimeric ratio for the starting methylenedioxy derivatives.…”

mentioning

confidence: 57%

“…1 Puupehedione (1a) was isolated from a sponge of the order Verongida and was characterized as a metabolite featuring a sesquiterpene unit joined to a shikimate-derived moiety. 2 The cytotoxic activity of 1a and its synthetic, non-natural, 8-epimer 1b was assayed against the cell lines P-338, A-549, 3 and the most active compound was found to be 8-epipuupehedione (1b).The syntheses previously reported for 1a and 1b 3,4 were based on electrophilic cyclization of suitable intermediates to the respective dihydrobenzopyrans as methylenedioxy derivatives (2a and 2b), followed by oxidative cleavage of the methylenedioxy moiety. As we have previously established, 3 the oxidative process involves ring opening and subsequent cyclization to obtain 1a and 1b in the same 1:4 relative proportion, independent of the C-8 epimeric ratio for the starting methylenedioxy derivatives.…”

mentioning

confidence: 99%

See 1 more Smart Citation

An Efficient Stereoselective Synthesis of Cytotoxic 8-Epipuupehedione

et al. 2003

Self Cite

View full text Add to dashboard Cite

An efficient and highly stereoselective synthesis of cytotoxic 8-epipuupehedione (1b) was achieved starting from natural (-)-drimenol (6). The key step to obtain stereoselectivity was the simultaneous demethylation and oxidation of the dihydrobenzopyran methoxy derivatives 10a and 10b.Marine sponges are recognized as a rich source of structurally unique and biologically active terpenoids. 1 Puupehedione (1a) was isolated from a sponge of the order Verongida and was characterized as a metabolite featuring a sesquiterpene unit joined to a shikimate-derived moiety. 2 The cytotoxic activity of 1a and its synthetic, non-natural, 8-epimer 1b was assayed against the cell lines P-338, A-549, 3 and the most active compound was found to be 8-epipuupehedione (1b).The syntheses previously reported for 1a and 1b 3,4 were based on electrophilic cyclization of suitable intermediates to the respective dihydrobenzopyrans as methylenedioxy derivatives (2a and 2b), followed by oxidative cleavage of the methylenedioxy moiety. As we have previously established, 3 the oxidative process involves ring opening and subsequent cyclization to obtain 1a and 1b in the same 1:4 relative proportion, independent of the C-8 epimeric ratio for the starting methylenedioxy derivatives.Our strategy here involves nucleophilic addition of the organolithium derived from 5 to drim-7-en-11-al (7), 5 easily available from natural (-)-drimenol (6) 6,7 (Figure 1). The aromatic synthon 5 was prepared in high yield from 3,4-dimethoxybenzaldehyde (Figure 2). Addition of aldehyde 7 to the aryllithium derived from 5, and subsequent deprotection of the silyl ether, afforded 8/9 in a ratio of 3:1 ( 1 H and 13 C NMR). Acid-mediated cyclization of the mixture gave 10a and 10b in a ratio of 1:3. Simultaneous demethylation and oxidation of the epimeric dihydrobenzopyrans 10a(C 8 -Me R ) and 10b(C 8 -Me ) with AgO-HNO 3 8 led to o-quinones 1a and 1b (1:3). A further straightforward route was studied. Direct treatment of the condensation product with acid, without previous deprotection of the tert-butyldimethylsilyl ether, afforded 10a and 10b in a ratio 1:8.Simultaneous demethylation-oxidation of the mixture gave the epimeric 1a and 1b (1:8). The relative proportion was the same as that obtained for the dihydrobenzopyran methoxy derivatives, since the well-known reaction with AgO in acid medium 8 avoids ring opening, due to very fast oxidation. These results suggest that, under acidic conditions, the main product arises from attack on the less hindered R side, and the epimeric ratio seems to depend on the effective free nucleophilic group.The present work represents the shortest and most efficient synthesis for the highly bioactive 8-epipuupehedione (1b).

show abstract

mentioning

confidence: 57%

mentioning

confidence: 99%

An Efficient Stereoselective Synthesis of Cytotoxic 8-Epipuupehedione

et al. 2003

Self Cite

View full text Add to dashboard Cite

show abstract

“…Based on these results, we selected another 11 structurally related compounds to study and compare their potential anti‐angiogenic activities. Puupehenone and related compounds have been reported to display a wide range of important biological functions including antiviral, antifungal, antimalarial and antitumor activities 9, 10, 11, 12…”

mentioning

confidence: 99%

Study of puupehenone and related compounds as inhibitors of angiogenesis

Castro

González-Iriarte

Barrero

et al. 2004

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Puupehenone, a sesquiterpene produced by certain sponges, was selected in the course of a blind screening for new potential inhibitors of angiogenesis. In our study, we compare the potential anti-angiogenic activities of puupehenone and another 11 related compounds that were either natural products from marine origin or their synthetic derivatives. The effects of these compounds were determined with cell growth and differentiation assays on bovine aorta endothelial cells. Our results show that these compounds are weak inhibitors to cell growth and are not selective for endothelial cells. However, contrary to cell growth, the differentiation of endothelial cells into tubular structures was completely inhibited by 7 of these compounds at concentrations equal or lower than 3 M. Three of these compounds, isozonarol, 8-epipuupehedione and 8 epi-9,11-dihydropuupehedione, completely inhibited the in vivo angiogenesis in the CAM assay at doses equal or lower than 30 nmol/egg. Further characterisation showed that these 3 terpenes also inhibited endothelial cell production of urokinase and invasion. One compound (8-epipuupehedione) inhibited endothelial cell migration in a dose-dependent manner. The anti-angiogenic properties of the selected compounds, the simplicity of their structures and the feasibility of their synthesis make them attractive drugs for further evaluation in the treatment of angiogenesis-related pathologies.

show abstract

“…Foetal bovine serum (FBS) was a product of Harlan‐Seralab (Belton, U.K.). 8‐Epipuupehedione was synthesized as previously reported [13], and provided to us by Instituto Biomar S.A. (León, Spain). Stock solution (10 mg/ml) was prepared in dimethyl sulfoxide (DMSO) and stored in aliquots at –20°C.…”

Section: Methodsmentioning

confidence: 99%

The anti‐angiogenic 8‐epipuupehedione behaves as a potential anti‐leukaemic compound against HL‐60 cells

Martínez‐Poveda

Quesada

Medina

2007

J Cellular Molecular Medi

View full text Add to dashboard Cite

We have previously reported that 8-epipuupehedione, a synthetic derivative of sesquiterpenes found in several kinds of sponges, is a potent inhibitor of angiogenesis. Here, we show that 8-epipuupehedione is also a potent anti- leukaemic compound, targeting three hallmarks of malignancy: proliferation, survival and extra-cellular matrix re-modelling. To fulfil this goal, we use the HL-60 promyeolocytic cells as our model system and the following experimental procedures: cell growth assay, Hoetsch staining, cell cycle analysis and DNA fragmentation, caspase 3 activity and zymographic assays. Our results show that this compound inhibits proliferation and has potent and specific pro-apoptotic effects on HL-60 promyelocytic cells, inducing their nuclei and DNA fragmentation, as well as caspase 3 activity activation. Furthermore, 8-epipuupehedione strongly inhibits matrix metalloproteinase-2 and urokinase production by HL-60 cells. These results suggest that 8-epipuupehedione could be an attractive drug for further evaluation in the treatment of leukemia.

show abstract

Synthesis and antitumor activity of puupehedione and related compounds

Cited by 77 publications

References 14 publications

An Efficient Stereoselective Synthesis of Cytotoxic 8-Epipuupehedione

An Efficient Stereoselective Synthesis of Cytotoxic 8-Epipuupehedione

Study of puupehenone and related compounds as inhibitors of angiogenesis

The anti‐angiogenic 8‐epipuupehedione behaves as a potential anti‐leukaemic compound against HL‐60 cells

Contact Info

Product

Resources

About