1,2-Dihydro-1-hydroxy-2-(organosulfonyl)areno[d] [1,2,3]diazaborines 2 (arene = benzene, naphthalene, thiophene, furan, pyrrole) were synthesized by reaction of (organosulfonyl)hydrazones of arene aldehydes or ketones with tribromoborane in the presence of ferric chloride. The activities of 2 against bacteria in vitro and in vivo (Escherichia coli) were determined and structure-activity relationships are discussed. Included in this study are 2,3-dihydro-1-hydroxy-2-(p-tolylsulfonyl)-1H-2,1-benzazaborole+ ++ (3) and 1-hydroxy-1,2,3,4-tetrahydro-2-(p-tolylsulfonyl)-2,1-benzazabor ine (4) as well as the carbacyclic benzodiazaborine analogue 4-hydroxy-3-(p-tolylsulfonyl)isoquinoline (7). The nature of the active species is briefly discussed.

The possibility of improving the antibacterial activities of drugs normally excluded by Gram-negative bacteria with polymyxin B nonapeptide (PMBN) has been explored. In vitro, PMBN rendered clindamycin, erythromycin, novobiocin, rifampicin and vancomycin very active against a number of Gram-negative enteric bacteria. The drug also sensitized the previously resistant bacterial strains to human, mouse or guinea pig serum. However, parenterally administered PMBN failed to influence bacterial growth in chambers implanted into mice and guinea pigs. It was also ineffective in experimental septicaemia at a dose of up to 200 mg/kg or when combined with antibiotics with which it interacted synergistically in vitro.

The possibility of predicting the clinical effects of cytokines from in vitro data is discussed, using GM-CSF as an example. GM-CSF incubated with bone marrow cells has been shown to induce proliferation and colony formation, predominantly of the colony-forming unit granulocyte and granulocyte-macrophage types. Daily treatment of normal monkeys with GM-CSF resulted in transient neutropenia followed by neutrophilia. After withdrawal of GM-CSF the neutrophil levels returned to baseline. Predictably, GM-CSF administration results in accelerated neutrophil recovery in patients with chemotherapy-induced neutropenia. GM-CSF has also been shown to induce microbial killing by neutrophils and monocytes in vitro. This activity translated into a dose-related protection of GM-CSF-pretreated mice infected with lethal doses of micro-organisms. Interleukin-3 (IL-3) increases the cellularity of the bone marrow and GM-CSF can induce mobilization of bone marrow cells into the peripheral blood. Therefore, it was predicted and subsequently proved that a combination of these cytokines is synergistic, increasing the yields of peripheral blood progenitor cells which could be collected and then retransplanted into patients undergoing myeloablative chemotherapy. Monkeys injected with recombinant human IL-3 and GM-CSF had increased antibody titres to human IL-3 compared with monkeys given IL-3 alone, suggesting a potential use of GM-CSF which was not predicted from its in vitro results, that of vaccine adjuvancy.(ABSTRACT TRUNCATED AT 250 WORDS)

SDZ MRL 953, a new synthetic monosaccharidic lipid A, was investigated in vitro and in vivo for immunopharmacological activities. In experimental models of microbial infections, the compound was highly protective when it was administered prophylactically either once or three times to myelosuppressed or immunocompetent mice. The 50% effective doses of SDZ MRL 953 varied with the infectious agents and the route of its administration. In all cases, the 50% effective doses were about 103 times higher than those obtained with endotoxin from Salmonella abortus equi. SDZ MRL 953 was, however, less toxic than lipopolysaccharide by a factor of 104 to >7 x 105 times in galactosamine-sensitized mice. The compound was also an effective inducer of tolerance to endotoxin. Hence, repeated dosing with the compound induced a transient resistance (.1 week) to lethal challenges with endotoxin. In vitro, the compound was devoid of intrinsic antimicrobial activity, but it moderately induced the release of cytokines from monocytes and primed human neutrophils for the enhanced production of reactive oxygen metabolites in response to a soluble stimulus. The results presented here suggest that SDZ MRL 953 may be useful in a clinical setting for enhancing resistance to infections, particularly in patients undergoing myelosuppressive chemotherapy or irradiation, and for the prophylaxis of endotoxin shock.Lipopolysaccharides (LPS) are common constituents of cell walls of gram-negative bacteria. They can cause a whole array of pathophysiological effects and are also the most powerful immunostimulants known. It is generally accepted that the lipid A moiety, the terminal acylated P(1-6)glucosamine disaccharide-1,4'-diphosphates of endotoxin, is responsible for immunopharmacological activity and induction of endotoxicity, such as changes in leukocyte count, disseminated intravascular coagulation, and multiorgan failure leading to irreversible shock and death (5,21,25).Extensive studies have unsuccessfully addressed the possibility of harnessing the immunopharmacological activities of endotoxins by using various detoxifying approaches (17,20). The elucidation of the correct structure of lipid A (8, 26) and the subsequent success in the total synthesis of biologically active lipid A and analogs (9-12, 27) have rekindled interest in the possibility of separating the immunostimulatory and toxic moieties of endotoxin. Efforts to identify beneficial immunostimulatory lipid A derivatives have concentrated on synthetic analogs representing both the nonreducing (10-12) and reducing sugar moieties, such as lipids X and Y (15,27). Synthetic lipid A subunits of the nonreducing sugar moiety such as GLA-27 and GLA-60 were reported to activate B cells and macrophages and to induce release of mediators including gamma interferon and tumor necrosis factor (TNF) at nontoxic doses (for a review, see reference 5). The analogs were also found to be active in enhancing host resistance to microbial and viral infections in normal and myelosuppressed mice (5-7). Synth...

Lipid X, a precursor in the biosynthesis of lipid A, has been claimed to possess most of the immunostimulatory activity but none of the toxicity of endotoxin. However, recent work shows that synthetic lipid X can be contaminated with small amounts of N,O-acylated disaccharide-1-phosphate (H. Aschauer, A. Grob, J.