Synthesis, structure and conformation of natural products and analogues of biological importance

Research Group:

Head: Gerardo Burton

Senior Research Associates:

Pablo H. Di Chenna

Fernando J. Durán

Alberto A. Ghini

Rosana I. Misico

Adriana S. Veleiro

Posdocs and PhD students:

Lautaro Alvarez

Valeria Edelzstein

Mayra Y. Machado Rada

Evelyn Bonifazzi

Virginia Dansey

 


Topics:


Synthesis and structure-activity correlations of steroid hormone analogues

Steroid hormones influence a great variety of processes and cellular types in mammals. An area of interest in contemporary receptorology is the development of synthetic analogues specific for each of the five receptor classes. On the other hand, the development of specific antagonists of steroid hormones allows mechanistic studies on receptor-mediated processes, aids in medical diagnosis and allows the medical manipulation of endocrine related functions. Steroid hormones and some of their metabolites act on the brain at different receptor sites than those mentioned, e.g. brain cell membrane sites, opioid recptors, voltage gated calcium channels and neurotransmitter receptors (g-aminobutyric acid GABA and glutamate). Most of these neurosteroids and neuroactive steroids are allosteric agonists of the GABAA receptor modulating GABA-induced chloride flux in a similar way as barbiturates.

One of our goals, oriented to the search for antihormones, is the correlation of the structural characteristics of synthetic analogues of natural steroid hormones (e.g. conformation, steroid nucleus flexibility, relative orientation of functional groups) with their biological activity in vitro and in vivo (glucocorticoid, mineralocorticoid, progestagen, estrogenic and androgenic). A second goal is the search for new GABAA receptor agonists.

Our studies on structure-activity relationships are carried out in collaboration with Prof. Carlos P. Lantos and his research group (Biological Chemistry Department) and follow a biopharmacological approach. We have established a correlation between mineralocorticoid activity and flatness of the steroidal skeleton which resulted in the design and synthesis of 11,19-epoxyprogesterone, a strong mineralocorticoid comparable to aldosterone, which lacks the "typical" functional groups commonly associated with such activity. Another related synthetic analogue, 21-hydroxy-6,19-epoxyprogesterone, resulted in a highly specific antiglucocorticoid. For neuroactive steroids, 6,19-epoxy-4-pregnenolone was a potent anticonvulsivant in vivo. Several synthetic procedures have been developed for the preparation of a variety of steroidal analogues (including heterosteroids and C and D-homosteroids).

The most relevant results obtained are described in the following publications:

17(13-18)abeopregnanes. Synthesis of progesterone analogues. A. Ferrara, M. O. V. Benedetti, A. A. Ghini,G. Burton, J. Chem. Res., 276 (1993)

Sodium retaining activity of some natural and synthetic 21-deoxysteroids. G. Burton, M. Galigniana, S. de Lavallaz, A. L. Brachet-Cota, E. M. Sproviero, A. A. Ghini, C. P. Lantos, M. C. Damasco, Molecular Pharmacology, 47, 535 (1995)

A simple synthetic approach to 6-oxasteroids. Synthesis of 6-oxa-5b-pregnane-3,20-dione. D. Nicoletti, A. A. Ghini, A. L. Brachet-Cota, G. Burton, J. Chem. Soc. Perkin Trans. 1, 1089 (1995)

Ring expansion of fused cyclopropylketones. Synthesis of a 12(1318)abeopregnane. A. Ferrara, G. Burton, Tetrahedron Lett., 37, 929 (1996)

1H-1H long range couplings in fused cyclopropanes. NMR spectral assignment and conformation of 17,18-cyclosteroids. E. M. Sproviero, A. Ferrara, R. H. Contreras, G. Burton, J. Chem. Soc. Perkin Trans. 2, 933 (1996)

Oxidative cyclization of iodoketones. Synthesis of 6-oxa-5a-pregnane-3,20-dione. D. Nicoletti, A. A. Ghini, G. Burton, J. Org. Chem., 61, 6673 (1996)

21-Hydroxy-6,19-oxidoprogesterone. A novel synthetic steroid with specific antiglucocorticoid properties in the rat. G. P. Vicent, M. C. Monteserín, A. S. Veleiro, G. Burton, C. P. Lantos, M. D. Galigniana, Mol. Pharmacol., 52, 749 (1997)

Synthesis and GABAA receptor activity of 6-oxa-analogs of neurosteroids. D. Nicoletti, A. A. Ghini, R. Furtmuller, W. Sieghart, R. H. Dodd, G. Burton, Steroids, 65, 349 (2000)

Mechanism of action of the potent sodium retaining steroid 11,19-oxidoprogesterone. M. D. Galigniana, G. P. Vicent, G. Piwien-Pilipuk, G. Burton, C. P. Lantos, Mol. Pharmacol., 58, 58 (2000)

Rearrangements of 18-iodo and 20-iodopregnanes mediated by iodosyl derivatives. D. Nicoletti, A. A. Ghini, R. F. Baggio, M. T. Garland, G. Burton, J. C. S. Perkin Trans. 1, 1511 (2001)

Cleavage of cyclopropylketones mediated by alkylmercury(II) hydrides. P. H. Di Chenna, A. Ferrara, A. A. Ghini, G. Burton, J. C. S. Perkin Trans. 1, 227 (2002)

Synthesis and GABAA receptor activity of a 6,19-oxido analogue of pregnanolone. A. S. Veleiro, R. E. Rosenstein, C. O. Jaliffa, M. L. Grilli, F. Speroni, G. Burton, Bioorg. Med. Chem. Letters, 13, 343-346 (2003)

PhI=NSes mediated aziridination of 11-pregnene derivatives: Synthesis of 11,12-aziridino analogues of neuroactive steroids. P. H. Di Chenna, P. Dauban, A. A. Ghini, R. Baggio, M. T. Garland, G. Burton, R. H. Dodd, Tetrahedron, 59, 1009-1014 (2003)

6,19-Carbon-bridged steroids. Synthesis of 6,19-methanoprogesterone. M. Joselevich, A. A. Ghini, G. Burton, Org. Biomol. Chem., 1, 939-943 (2003)

Synthesis of C(1)-C(11) oxygen-bridged pregnanes. A. S. Veleiro, P. J. Taich, L. D. Alvarez, P. H. Di Chenna, G. Burton, Tetrahedron Lett., 46, 4235-4238 (2005)

6,19-Sulfur-bridged progesterone analogues with antiimmunosuppressive activity. A. S. Veleiro, A. Pecci, M. C. Monteserín, R. F. Baggio, M. T. Garland, C. P. Lantos, G. Burton, J. Med. Chem., 48, 5675-5683 (2005)

Synthesis of 6,19-sulfamidate bridged pregnanes. F. J. Durán, A. A. Ghini, P. Dauban, R. H. Dodd, G. Burton, J. Org. Chem., 70, 8613-8616 (2005)

Synthesis of 6-thia analogs of the natural neurosteroid allopregnanolone. F. J. Durán, A. A. Ghini, H. Coirini, G. Burton., Tetrahedron, 62, 4762-4768 (2006)

Synthesis of 6,19-cyclopregnanes. Constrained analogues of steroid hormones. P. H. Di Chenna, A. S. Veleiro, J. M. Sonego, N. R. Ceballos, M. T. Garland, R. F. Baggio and G. Burton, Org. Biomol. Chem., 5, 2453-2457 (2007)


Insecticides and feedant deterrants of natural origin related to the withanolides. Isolation, structural elucidation and synthesis

The withanolides are a group of C-28 steroidal lactones of which ca. 400 structures are known, including lactols, secoderivatives and related compounds. They are present in certain members of the Solanaceae, and receive their name from the plant Withania somnifera from which they were first isolated. Since we started the study of the withanolides in argentine Solanaceae, our group in collaboration with Prof. Juan C. Oberti (Universidad Nacional de Córdoba) has isolated and characterized ca. 100 new withanolide structures. Some ring D aromatic withanolides from Salpichroa origanifolia (structurally related to the nicandrenoids from Nicandra physalides) are feedant deterrants for larvae of Tenebrio molitor and Tribolium castaneum. The study of this activity in withanolides and synthetic analogues was carried out in collaboration with Dr. Graciela Mareggiani and Dr. Silvina Bado (Facultad de Agronomia). More recently we became interested in the selective phytotoxicity exhibited by some withanolides.

The diversity of structural variations found in this family of compounds and the insecticidal and phytotoxic action of several of its members cannot be fully exploited in many cases, due to the small amounts available and seasonal variations in the plant composition. One of our goals is the chemical conversion of the most abundant withanolides into the least abundant ones, as well as into synthetic analogues that combine various "natural" functional modifications in a single structure

The most relevant results obtained are described in the following publication.:

A ring D aromatic withanolide from Salpichroa origanifolia. A. S. Veleiro, J. C. Oberti, G. Burton, Phytochemistry, 31, 935 (1992)

A phenolic withanolide from Jaborosa leucotricha. A. S. Veleiro, C. E. Trocca, G. Burton, J. C. Oberti, Phytochemistry, 31, 2550 (1992)

New withanolides from Salpichroa origanifolia. A. S. Veleiro, G. Burton, G. M. Bonetto, R. R. Gil, J. C. Oberti, J. Nat. Prod., 57, 1741 (1994)

Novel withanolides from Jaborosa sativa. G. M. Bonetto, R. R. Gil, J. C. Oberti, A. S. Veleiro, G. Burton, J. Nat. Prod., 58, 705 (1995)

New 19-hydroxywithanolides from Jaborosa leucotricha. R. Misico, J. C. Oberti, A. S. Veleiro, G. Burton, J. Nat. Prod., 59, 66 (1996)

Spiranic withanolides from Jaborosa runcinata and Jaborosa araucana. A. M. Cirigliano, A. S. Veleiro, G. M. Bonetto, J. C. Oberti, G. Burton, J. Nat. Prod., 59, 717 (1996)

Ring D aromatic ergostane derivatives from Salpichroa origanifolia. M. C. Tettamanzi, A. S. Veleiro, J. C. Oberti, G. Burton., Phytochemistry, 43, 461(1996)

16-Hydroxylated withanolides from Exodeconus maritimus. R. R. Gil, R. I. Misico, I. R. Sotes, J. C. Oberti, A. S. Veleiro, G. Burton, J. Nat. Prod., 60, 568 (1997)

New hydroxylated withanolides from Salpichroa origanifolia. M. C. Tettamanzi, A. S. Veleiro, J. C. Oberti, G. Burton, J. Nat. Prod., 61, 338 (1998)

7-Hydroxy withanolides from Datura ferox. A. M. Cirigliano, A. S. Veleiro, J. C. Oberti, G. Burton, J. Nat. Prod., 62, 1010 (1999)

Antifeedant activity of withanolides from Salpichroa origanifolia on Musca domestica. G. Mareggiani, M. I. Picollo, E. Zerba, G. Burton, M. C. Tettamanzi, V. Benedetti-Doctorovich, A. S. Veleiro, J. Nat. Prod., 63, 1113 (2000)

Withanolides from Salpichroa origanifolia. M. C. Tettamanzi, A. S. Veleiro, J. R. de la Fuente, G. Burton, J. Nat. Prod., 64, 783 (2001)

Spiranoid withanolides from Jaborosa odonelliana. A. M. Cirigliano, A. S. Veleiro, J. C. Oberti, G. Burton, J. Nat. Prod., 65, 1049-1051 (2002)

Response of Tribolium castaneum (Coleoptera, Tenebrionidae) to Salpichroa origanifolia withanolides. G. Mareggiani, M. I. Picollo, A. S. Veleiro, M. C. Tettamanzi, M. O. V. Benedetti-Doctorovich, G. Burton, E. Zerba, J. Agric. Food. Chem., 50, 104 (2002)

15,21-Cyclowithanolides from Jaborosa bergii. V. E. Nicotra, R. R. Gil, C. Vaccarini, J. C. Oberti, G. Burton, J. Nat. Prod., 66, 1471-1475 (2003)

Lethal and Sublethal Effects of Withanolides from Salpichroa origanifolia and analogues on Ceratitis capitata. S. Bado, G. Mareggiani, N. Amiano, G. Burton,  A. S. Veleiro, J. Agric. Food. Chem., 52, 2875-2878 (2004)

Phytotoxic Withanolides from Jaborosa rotacea. V. E. Nicotra, N. S. Ramacciotti, R. R. Gil, J. C. Oberti, G. E. Feresin, C. A. Guerrero, R. F. Baggio, M. T. Garland, G. Burton, J. Nat. Prod. 69, 783-789 (2006)

Withanolides with Phytotoxic Activity from Jaborosa caulescens var. caulescens and J. caulescens var. bipinnatifida. V. E. Nicotra, R. R. Gil, J. C. Oberti, G. Burton, J. Nat. Prod. 70, 808-812 (2007)

Withanolides from Jaborosa laciniata. A. M. Cirigliano, A. S. Veleiro, R. I. Misico, M. C. Tettamanzi, J. C. Oberti, G. Burton, J. Nat. Prod., in press (2007)

For a recent review:

Chemistry and bioactivity of withanolides from southamerican Solanaceae. A. S. Veleiro, J. C. Oberti, G. Burton, in Bioactive Natural Products (Part M), Ed. Atta-ur Rahman. Series Studies in Natural Products Chemistry, Vol. 32, Elsevier Science Publishers, Amsterdam. (2005) p. 1019-1052


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