The amine-carboxyboranes and related derivatives have been shown to be potent anti-inflammatory and anti-osteoporosis agents. Their action in part appears to be mediated by the modulation of cytokines, e.g. TNFα or IL-1. Previous studies have demonstrated that LPS induced macrophages release of TNFα maximally at 60 to 90 min. and IL-1 from 5 to 8 hr. The amine-carboxyboranes reduced significantly the release of these cytokines but also blocked TNFα high affinity binding to UMR-106 receptor at 90 min. at 10 μM, and IL-1 high affinity binding at 5 hr. at 12.5 μM. In addition, the agents suppressed IL-8 binding to CHO K1 high affinity receptor at 24 hr. at 50 μM and IL-2 binding to HuT-8 receptors at 25 μM at 90 min. and 5 hr. Correlation of metabolic events associated with osteoporosis showed that at 90 min., when TNFα receptor binding was reduced by the agents, calcium uptake into UMR-106 cells was reduced at 10 μM as well as the acid and alkaline phosphatases, and the prostaglandin cyclo-oxygenase activities and adhesion of leukocytes and macrophages to UMR-106 cell monolayers. At 5hr. when the agents reduced IL-1 binding to UMR-106 receptors, calcitonin and 1,25-dihydrovitamin D3 binding was reduced by the agents as was acid and alkaline phosphatase, and 5′-lipoxygenase activities and white blood cell adhesion. At this time calcium uptake and proline incorporation was increased significantly by the agents. At later times e.g. 18-48 hr. calcium uptake was still increased, and NAG activity was inhibited in the presence of the agents. These effects may be related more to the inhibition of other cytokine receptor binding, e.g. IL-8. Thus, many of the observed metabolic effects of amine-carboxyboranes as antiosteoporosis agents can be correlated with their inhibition of cytokine high affinity binding to target cell receptors.

The amine-carboxyboranes anti-inflammatory agents were shown to block TNF α release at 90 min. and IL-1 release at 5 hr. from macrophages. The agenst competed with L929 fibroblasts high affinity receptors for endogenous cytokines which regulate the inflammation process. Blocking the TNFα receptor at 90 min. by the agents from 10 to 50  μΜ, resulted in lysosomal hydrolytic enzyme inhibition and lowering of prostaglandin synthesis as well as reductions in calcitonin high affinity receptor binding and calcium influx into the cells. IL-1 receptors when blocked by the agents at 5 hr. resulted in a reduction of NAG activity and leukotriene synthesis. An elevation of proline incorporation into collagen occurred at 90 min. and 24 hr. in the presence of the agents.

A series of polyphenolic-sulfonated compounds were observed to have potent anti-inflammatory activity and were protective against induced endotoxic shock in mice at 8 and 16 mg/kg, I.P. These agents proved to be potent elastase inhibitors in human leukocytes and J774-AI and IC-21 mouse macrophages as well as prostaglandin cyclo-oxygenase inhibitors in J774-AI macrophages. The compounds from 5 to 50 μM inhibited TNFα release from IC-21 macrophages and IL-1 release from mouse P388D1 macrophages induced by LPS. The binding of these cytokines to high affinity receptors on target cells, e.g. L929 fibroblasts and IL-2 in HuT78 T lymphoma cells, were also suppressed by the agents. These compounds blocked the adhesion of leukocytes and macrophages to the plasma membranes of L929 fibroblasts.

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