NEW 7-HYDROXY-1,3-DIAZBICYCLO[3.3.0]OCTANE DERIVATIVES - EVALUATION OF THEIR IN-VITRO IMMUNOMODULATING EFFECTS

In order to improve the water solubility of some previously reported i mmunoactive dioxothiadiazabicyclo[3.3.0]octanes, we synthesized a seri es of new diazabicyclo[3.3.0]octanols from the trans-4-hydroxy-L-proli ne methyl ester in two steps. Acylation of the ester with an isocyanat e or an isothiocyanate under the appropriate conditions afforded N-acy lated derivatives exclusively. Then through a cyclization process in t he presence of sodium methylate, bicyclic derivatives were obtained, m ost of them as a mixture of two diastereomers which were separated by column chromatography. A mitogenic stimulation assay using the T-cell mitogen phytohemagglutinin was performed with human peripheral blood l eukocytes in the presence of the different synthesized compounds and w ith levamisole as reference. Several compounds showed marked stimulant effects on the proliferation of lymphocytes as compared to levamisole , but no correlation could be established between molecular configurat ion and stimulation or inhibition effects on proliferation.