Antiviral and immunomodulatory activities of synthetic stigmastane analogs

MICHELINI, F.M.; RAMÍREZ, J.A.; MOLINARI, A.; GALIGNANA, M.; GALAGOVSKY, L.R.; ALCHÉ, L.E.

Mendoza

Congreso; XLVIII Reunión Anual de Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular; 2012

The stigmastane analog (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound 1) displays antiviral activity in vitro against Herpes Simplex Virus Type 1 (HSV-1). The compound also significantly diminishes proinflammatory cytokines production in inflammatory cells. The 3-keto group and the double bond in r4 in the steroid A ring provide the molecule with structural similarities to that of corticosteroids. In order to improve the immunomodulatory activity of this molecule, we designed new stigmastane analogs, keeping the (22S,23S)-22,23-dihydroxylated side chain of the steroidal structure, responsible of the antiviral activity, and introducing an additional double bond in r1 and/or a fluorine atom in the molecule, structural features known to improve the anti-inflammatory activity of steroidal drugs. The presence of the r1-4 ceto in the stigmastane structure reduced anti HSV-1 activity and did not improve the immunomodulatory effect of the compound. However, a fluorine atom in C6 enhanced both antiviral and immunosuppressive activities of the new compounds, since they were more effective than compound 1 to reduce virus yields in epithelial cells infected with HSV-1 and cytokine production in inflammatory cells, as determined by virus yield reduction assays and ELISA, respectively. Radioligand binding assays and reporter gene induction assays showed that the stigmastane analogs did not exhibit affinity for the glucocorticoids and mineralocorticoid receptors. The compounds would be exerting their effect through a mechanism of action different from that of commercial anti-inflammatory steroidal drugs.