Barbara Stanić

2,8-dithia-dibenzo〔e,h〕azulenes and their 8-oxa analogs: synthesis and anti-inflammatory activity

Synthesis of 2, 8-dithia-dibenzo[e, h]azulenes (III, X = S) and their 8-oxa analogs (III, X = O), 1 two novel classes of fused heterocyclic compounds, is described. Starting 11H-dibenzo[b, f]thiepin-10-one, 11H-dibenzo[b, f]oxepin- 10-one and its 2-chloro derivative (1a-c) were oxidized to 1, 2-diketones (2a-c) which subsequently reacted with 2, 2’ -dimethyl thiodiglycolate to form fused thiophene ring by Hinsberg cyclization reaction. Substituents at positions C(1) and C(3) were then further transformed in order to obtain aminoalkoxy derivatives 8-11. Structures of regioisomers 6c and 6d were elucidated using two-dimensional NMR techniques. All compounds with tetracyclic skeleton were tested in vitro for their anti-inflammatory activity.

Macrolactonolides: a novel class of anti- inflammatory compounds

A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17β-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.

Differing effects of two iron compounds on experimental arthritis, TNF-α levels and immune response in mice

The effects of ferric-sorbitol-citrate and ferric-citrate on the severity of experimental arthritis, TNF-alpha secretion and the immune status were examined in mice. Arthritis was induced by footpad injection of methylated BSA and intraperitoneal injection of Bordetella pertussis. Joint and footpad swelling were measured weekly by a caliper. TNF-alpha serum levels were measured by ELISA. The immune status was determined by the response of mouse lymphocytes to ConA in vitro and by the antigen-presenting cell assay. Experimental arthritis was aggravated by ferric-citrate, whereas ferric-sorbitol-citrate did not promote it. If applied to normal (non-arthritic) mice three times a week for 4 weeks, ferric-sorbitol-citrate stimulated isolated splenocytes to increase production of TNF-alpha, the function of antigen-presenting cells and lymphocyte proliferation in response to ConA in vitro. TNF-alpha production by cultured splenocytes was also stimulated. In mice with antigen-induced arthritis, iron compounds did not additionally stimulate TNF-alpha production. Thus, we have shown that ferric-sorbitol-citrate stimulated TNF-alpha production, antigen-presenting cell activity and cellular immune response. Development of antigen-induced arthritis and TNF-alpha production in arthritic mice were not stimulated.