Acting on actin: The mechanism of action of amphidinolide X and amphidinolide J, two relatively small cytotoxic macrolides, has been elucidated. They do not target microtubules and intermediate filaments. The effects observed in A549 and PtK2 cells and the in vitro interaction with actin monomer (G-actin) indicate that these macrolides behave as actin-assembly inhibitors.

Mechanism of Action of the Cytotoxic Macrolides Amphidinolide X and J

1. Chiara Trigili¹,
2. Benet Pera¹,
3. Dr. Marion Barbazanges²,
4. Prof. Dr. Janine Cossy²,
5. Dr. Christophe Meyer²,
6. Dr. Oriol Pineda³,
7. Dr. Carles Rodríguez-Escrich³,
8. Prof. Fèlix Urpí³,
9. Prof. Dr. Jaume Vilarrasa^3,*,
10. Dr. J. Fernando Díaz^1,* and
11. Dr. Isabel Barasoain^1,*

DOI: 10.1002/cbic.201100042

Author Information

1. 1Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid (Spain), Fax: (+34) 915360432
2. 2Laboratoire de Chimie Organique, ESPCI, CNRS, 75231 Paris 05 (France)
3. 3Departament de Química Orgànica, Facultat de Química, Universitat de Barcelona, Diagonal 647, 08028 Barcelona (Spain)

Email: Prof. Dr. Jaume Vilarrasa (jvilarrasa@ub.edu), Dr. J. Fernando Díaz (i.barasoain@cib.csic.es), Dr. Isabel Barasoain (fer@cib.csic.es)

^*Departament de Química Orgànica, Facultat de Química, Universitat de Barcelona, Diagonal 647, 08028 Barcelona (Spain)

Trigili, C., Pera, B., Barbazanges, M., Cossy, J., Meyer, C., Pineda, O., Rodríguez-Escrich, C., Urpí, F., Vilarrasa, J., Díaz, J. F. and Barasoain, I. (2011), Mechanism of Action of the Cytotoxic Macrolides Amphidinolide X and J. ChemBioChem, 12: 1027–1030. doi: 10.1002/cbic.201100042

Corrected by:Corrigendum: Corrigendum: Mechanism of Action of the Cytotoxic Macrolides Amphidinolide X and J
Vol. 12, Issue 9, 1293, Version of Record online: 9 JUN 2011
http://onlinelibrary.wiley.com/doi/10.1002/cbic.201100042/abstract

Others

Total Synthesis by Alkene Metathesis: Amphidinolide X (Urpí /Vilarrasa),

To assemble the framework of the cytotoxic macrolide Amphidinolide X (3), Fèlix Urpí and Jaume Vilarrasa of the Universitat de Barcelona devised (Org. Lett. 2008, 10, 5191. DOI: 10.1021/ol8021676) the ring-closing metathesis of the alkenyl silane 1. No Ru catalyst was effective, but the Schrock Mo catalyst worked well.

Total Synthesis of Amphidinolide X & Y

Fürstner

A. Fürstner, E. Kattnig, O. Lepage, J. Am. Chem. Soc. 2006, 128, 9194-9204.
DOI: 10.1021/ja061918e

Another pair of amphidinolides in the bag, Fürstner et al. have completed the synthesis of X (the only member of the series with an even-numbered macrocycle) and Y using a powerful iron catalysed process. Both products (as with most of the family) are cytotoxic, and contain the heavily functionalised THF moiety. This allowed the group to create an intermediate common to both campaigns, starting from a simple epoxide produced from an Sharpless epoxidation.

Treatment of this with n-propyl grignard and catalytic quantities of the iron catalyst generated the allene in a 8:1 dr (this system has been used by the group in other work; see: DOI: 10.1246/cl.2005.624, DOI: 10.1021/ja027190t, DOI: 10.1002/anie.200460504, plus further examples cited in the paper). The allene was then cyclised with silver nitrate and calcium carbonate, returning the DHP, which was augmented to the desired THF via bromoesterification.
This portion of the natural product was coupled using an alkyl Suzuki reaction to the rest of the molecule in both cases, along with macrolactonisation to furnish the major ring system. In amphidinolide Y, a boron-mediated aldol reaction was used to create the 1,4 anti relationship between a pair of hydroxyls in the C1 - C12 fragment, in a 4:1 dr. Inseparable at this point, they carried the mixture through to a diastereoselective methyl grignard addition.

The desired aldol product reacted diastereoselectively with the grignard following the 1,2-anti chelate-cram model, whereas the undesired aldol product reacted with far less control. This section of the synthesis is quite intriguing, and is discussed in far more detail in the paper, which is a truly excellent read.


Figure 1: Scheme 1. (A) Sharpless asymmetric epoxidation of allylic alcohols 1 mediated by Ti(IV)-diethyltartrate (DET) catalyst with alkyl hydroperoxide as terminal oxidant leading to enantioenriched epoxides 2. (B) Preferential attack of the oxygen atom as a function of the stereochemistry of the DET chiral ligand. (C) Schematic representation of the dimeric active catalytic species 3.


Figure 10: Scheme 10. Structure of amphidinolide X 35 and details of the SAE step.

PAPER

http://onlinelibrary.wiley.com/doi/10.1002/anie.200900865/abstract




PAPER


http://onlinelibrary.wiley.com/doi/10.1002/chem.200802069/abstract
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Guaianolide

 SL guaianolide (11,13-dehydrocompressanolide). 





DEPT spectrum (CDCl 3 , 75.5 MHz) of the guaianolide. 


 Mass spectra recorded in the positive MS E mode for guaianolide and parthenolide (500.0 μg mL -1 ) of the dichloromethane fraction of the





COSY spectrum (CDCl 3 , 300 MHz) of the guaianolide







HMBC correlation spectrum (CDCl 3 , 300 MHz) of the guaianolide. 






HMQC correlation spectrum (CDCl 3 , 300 MHz) of the guaianolide.





 13 C NMR spectrum (75.5 MHz, CDCl 3 ) of the guaianolide. 





1 H NMR spectrum (CDCl 3 , 300 MHz) of the guaianolide.

Journal of the Brazilian Chemical Society

Print version ISSN 0103-5053
On-line version ISSN 1678-4790

J. Braz. Chem. Soc. vol.14 no.5 São Paulo Sept./Oct. 2003

http://dx.doi.org/10.1590/S0103-50532003000500006 

Sesquiterpene lactones and other chemical constituents of Mikania hoehnei R.

Juliana S. Chaves; Dionéia C. R. de Oliveira^*

Departamento de Física e Química. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Via do Café s/n, 14040 903, Ribeirão Preto-SP, Brazil

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532003000500006

8b-hydroxyzaluzanin D (1). Colorless gum; C₁₇H₂₀O₅; IR n_max/cm^-1 (NaCl film): 3494 (OH alcohol), 1750 (g-lactone), 1730 (acetyl group), 1664 and 1641 (c=c double bonds); EI-MS, m/z (relative intensity in %): 262 [M⁺- ketene] (14), 91 (24), 43 [CH₃CO]⁺ (100); ¹H NMR (300 MHz, CDCl₃), see Table 1. ¹³C NMR, DEPT 135⁰ and HMQC (75 MHz, CDCl₃): 45.0 (d, C-1), 36.5 (t, C-2), 74.5 (d, C-3), 147.7 (s, C-4), 50.4 (d, C-5), 77.6 (d, C-6), 50.1 (d, C-7), 65.7 (d, C-8), 41.8 (t, C-9), 142.8 (s, C-10), 136.0 (s, C-11), 170.8 (s, C-12), 121.6 (t, C-13), 117.4 (t, C-14), 114.2 (t, C-15), 169.4 (s, C-1'), 21.2 (q, C-2').

Results and Discussion

The chromatographic fractionation of hexane, ethyl acetate and ethanol extracts yielded stigmasterol, b-sitosterol and campesterol, lupeyl acetate,²¹ b-sitosteryl and stigmasteryl glucopyranosides,²² benzil 2,6-dimethoxybenzoate,²³ luteolin,²⁴ kaempferol²⁴ and dehydrocostuslactone.^13,14 The structures were established by comparison of their spectroscopic properties (mainly IR, ¹H and ¹³C NMR) with those reported in the literature and in some cases by direct comparison with authentic samples.

Structure of the guaianolide 1 was deduced from the IR, MS, ¹³C and ¹H NMR spectra data and the stereochemistry was defined from the coupling constants' value J and nOe difference correlations. This lactone has been previously reported as a synthetic compound obtained in the controlled acetylation of the natural guaianolide Integrifolin (8-epi-desacylcynaropicrin).¹² The IR spectrum displayed bands at 1750 cm^–1 (g-lactone), at 1730 cm^–1 (acetyl group), at 3494 cm^-1 (hydroxyl group) and weak bands at 1664, 1641 cm^–1 (c=c double bonds).

Inspection of the ¹H NMR spectrum of compound 1 indicated several signals very close to those observed in Zaluzanin D¹⁵. The position and the stereochemistry (b-orientation) of hydroxyl group at C-8 were determined by nOe correlation (Figure 1). nOe's were observed between the H-8 (d 4.37) and H-13a (d 5.62), H-7 (d 2.98) and H-9b (d 2.61). In the same way, correlation of the H-3 (d 5.50) with H-2b (d 2.45) and H-15a (d 5.32) in the nOe spectrum confirmed the a-orientation of H-3 which was attached to the carbon atom which is linked to the acetate group, as previously defined as Zaluzanin D (compound 2).

Just as the NMR spectrum of 2, the NMR spectrum of guaianolide 1 exhibited two characteristic doublets at d 6.42 and 5.62 (J 3.8 and 3.2 Hz respectively) corresponding to hydrogens of H - 13a and H - 13b of an exocyclic methylene group conjugated with a g-lactone. The exocyclic methylene groups attached to C-10 and C-4 were characterized by two singlets at d 4.99 (H-14a), 5.10 (H-14b) and a pair of triplets (J 2.0 Hz) at d 5.32 (H-15a) and 5.52 (H-15b), respectively.

The stereochemistry cis of the ring junction at C-1 and C-5 was established by the coupling constant (J 8.3 Hz) between H-1 and H-5. In the case of 1b, 5a-trans- guaianolide, a value of 10.0 Hz or greater is expected according to that reported in the literature.^25,26 The lactone ring junction was confirmed to be trans (6b H, 7aH) by the large coupling constant (J ~ 3.0 Hz) of the H -13-a-methylene protons this is due to H-6/H-7 (J 8.9 Hz) coupling constant.¹⁶

All other signals were in agreement with the proposed structure of the guaianolide 1 (Table 1). Heteronuclear multiple quantum correlation ¹H – ¹³C (HMQC) allowed us to assign unambiguously the signals of all carbons.

Besides the importance chemosystematic,²⁷ sesquiterpene lactone posseses a wide spectrum of biological activity.²⁸ Zaluzanin C, Zaluzanin D and its derivatives have shown several biological activities, such as activity against the P 388 lymphocytic leukemia in vitro,^29,30 antifungal activity,^31,32 inhibitory activity on nitric oxide production and nuclear fator KB,³³ inhibitory activity on ethanol absorption.³⁴

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PORT LOUIS, port louis FOOD, MAURITIUS

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