Study of glucocorticoid activity of 21-hemisuccinate-6,19-OP. An oxygen bridge analog.

LAUTARO D. ALVAREZ, ADRIANA S. VELEIRO, CARLOS P. LANTOS, ADALÍ PECCI Y GERARDO BURTON.

Rosario

Simposio; XLII Reunión Anual; 2006

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

STUDY OF GLUCOCORTICOID ACTIVITY OF 21-HEMISUCCINATE-6,19-OP, AN OXYGEN BRIDGE ANALOG.   (1) Alvarez, L. D.; (1) Veleiro, A.; (2) Lantos, C. P.; (2,3) Pecci, A.; (1) Burton, G.   (1) Dto. Qca Orgánica, FCEN-UBA (2) Dto. de Qca Biológica, FCEN-UBA. (3) LEGMA, IFIBYNE-CONICET. E-mail: lalvarez@qo.fcen.uba.ar   According to the overall conformation as the three-dimensional structure and spatial distribution of charges, glucocorticoid molecules exhibit a bent skeleton as a consequence of the degree of curvature at the A/B junction of the respective structure. In our approach rigidly bent analogue with some specific anti-glucocorticoid activities was obtained by a 6,19 oxygen bridge introduced in a pregnane structure(21-OH-6,19-OP). This compound devoids affinity at receptoral level for both mineralocorticoid and progesterone receptor. In order to enhance polarity and water solubility we synthesized the esther derivative 21-hemisuccinate-6,19-OP. This new compound has demonstrated to be a highly potent antiapoptotic agent, according to DNA fragmentation and FICT-Annexin V assays when it is co-administrated in combination to dexamethasone in thymocyte primary cultures. However, this compound not only is not able to block dexamethasone induced MMTV-luciferase reporter gene but also it significantly potenciates at its lowest concentration the glucocorticoid action of dexamethasone.