The anti-inflammatory activity of boron derivatives in rodents.

Acyclic amine-carboxyboranes were effective anti-inflammatory agents in mice at 8 mg/kg x 2. These amine-carboxyboranes were more effective than the standard indomethacin at 8 mg/kg x 2, pentoxifylline at 50 mg/kg x 2, and phenylbutazone at 50 mg/kg x 2. The heterocyclic amine derivatives as well as amine-carbamoylboranes, carboalkoxyboranes, and cyanoboranes were generally less active. However, selected aminomethyl-phosphonate-N-cyanoboranes demonstrated greater than 60% reduction of induced inflammation. The boron compounds were also active in the rat induced edema, chronic arthritis, and pleurisy screens, demonstrating activity similar to the standard indomethacin. The compounds were effecive in reducing local pain and decreased the tail flick reflex to pain. The derivatives which demonstrated good anti-inflammatory activity were effective inhibitors of hydrolytic lysosomal, and proteolytic enzyme activities with IC(50) 50 values equal to (-6)M in mouse macrophages, human leukocytes, and Be Sal osteofibrolytic cells. In these same cell lines, the agents blocked prostaglandin cyclooxygenase activity with IC(50) values of (-6)M. In mouse macrophage and human leukocytes, 5' lipoxygenase activity was also inhibited by the boron derivatives with IC(50) values of 10(-6)M. These IC(50) values for inhibition of these enzyme activities are consistent with published values of known anti-inflammatory agents which target these enzymes.

The hypolipidemic activity of metal complexes of amine carboxyboranes in rodents.

The metal complexes of amine-carboxyborane including copper, chromium, zinc, calcium amd cobalt were effective hypolipidemic agents lowering both serum cholesterol and triglyceride levels significantly in mice at 8 mg/kg/day, I.P. after 16 days. The agents reduced acetyl CoA synthetase, ATP-dependent citrate lyase, acyl CoA cholesterol acyl transferase, sn-glycerol-3-phosphate acyl transferase activities of rat liver and small intestinal mucosa after 14 days treatment. The neutral cholesterol ester hydrolase activity was elevated by the agents in both tissues. The metal complexes altered lipid levels in the bile of rats after treatment as well as the bile acid composition after 14 days administration, orally. The agents blocked enterohepatic absorption of cholesterol from rat isolated intestinal loops.

Relationship of hypolipidemic and antineoplastic activities of tricyclohexyl- and triphenylphosphine boranes, carboxyboranes, cyanoboranes, and related derivatives.

A series of tricyclohexyl- and triphenylphosphine boranes, carboxyboranes and cyanoboranes were synthesized. These compounds have potent hypolipidemic effects, antineoplastic and antiinflammatory activities in rodents. Furthermore, they demonstrated potent cyctotoxicity against standard human tissue culture lines. The compounds which afforded the best hypolipidemic activity, i.e. greater than 40% reduction of serum cholesterol and triglyceride levels, were diphenyl-(4-methylphenyl)-phosphine borane and triphenylphosphine carboxyborane. Other derivatives demonstrated more potent antineoplastic activity against the Ehrlich ascites carcinoma growth including triphenylphosphine cyanoborane, 2-amino-4-methyl-pyridine cyanoborane and 2-amino-pyridine cyanoborane. Most of the derivatives showed good activity against murine L1210 lymphoid leukemia, Tmolt3 human leukemia, uterine HeLaS cells, and human glioma cell growth. Select compounds were active against colon adenocarcinoma, KB nasopharynx, lung bronchogenic and osteosarcoma cell growth. Tricyclohexyl- and triphenylphosphine boranes and the carboxy derivatives of the latter borane demonstrated good antiinflammatory activity.

Hypolipidaemic activity in rodents of boron analogs of phosphonoacetates and cyanoborane adducts of dialkyl aminomethylphosphonates.

Boron analogues of phosphonoacetates proved to be potent hypolipidaemic agents in rodents, lowering both serum cholesterol and triglyceride levels. (C2H5O)3PBH2COOCH3 proved to be the most effective agent in mice, lowering serum cholesterol 46% and serum triglycerides 54% after 16 days. (C2H5O)3PBH2COOH and Na+H+(C2H5O)2(-O)PBH2COO- caused greater than a 40% reduction in lipids. The cyanoborane adducts of aminomethylphosphonates were generally less effective; (C6H5O)2P(O)CH2NH2BH2CN was the most effective, lowering serum cholesterol 32% and serum triglycerides 43% after 16 days. The phosphonoacetates appeared to lower lipid concentrations by several mechanisms. First, they lowered the de novo synthesis of cholesterol and triglycerides in the liver. Second, they accelerated the excretion of lipids into the bile and faeces. Thirdly, they modulated LDL and HDL-cholesterol contents in a manner which suggests they reduced the deposition of lipids in peripheral tissues, and accelerated the movement of cholesterol from tissues (e.g. plaques) to the liver for excretion into the bile.

DNA interaction with metal complexes and salts of substituted boranes and hydroborates in murine and human tumor cell lines.

A series of metal complexes and sodium salts of substituted boranes and hydroborates was shown to have cytotoxicity in murine and human tumor screens. Most of these agents were active against the growth of L-1210, Tmolt3 and Hela-S3. Selected agents demonstrated activity against the growth of monolayer human cell lines derived from solid tumors. Interestingly, many of the compounds demonstrated even lower ED50 values in the solid tumor than the L-1210 leukemic screen. Four compounds, Cu2(m-CH3)3NBH2CO2)4.2(CH3)NBH2COOH (I), [Fe3O((CH3)3NBH2CO2)6(CH3OH)3]NO3.CH3CN (II), cis-[Co(en)2((CH3)3N.BH2CO2)2]Cl.2.5 H2O.0.5 CH3OH (V), and Na(CH3)3NBH2CO2.0.25 CH3OH (IX) were shown preferentially to inhibit DNA synthesis of L-1210 cells with only moderate inhibition of RNA and protein synthesis. In preliminary studies these agents effectively inhibited the activities of regulatory enzymes involved in the purine pathway and nucleoside kinases resulting in the suppression of d(NTP) pool levels. The boron derivatives also caused L-1210 DNA strand scission. These drugs may act together to inhibit DNA synthesis and induce cytotoxicity.

The cytotoxicity of amine-cyanoboranes, amine-cyanoalkylboranes and aminomethyl-phosphonate cyanoborane adducts against the growth of murine and human tissue culture cells.

The amine-cyanoboranes, the amine-cyanoalkylboranes and the aminomethyl-phosphonate-N-cyanoborane adducts proved to be active antineoplastic agents. These compounds were more effective against single cell cultured cell growth rather than solid tumors. The following amine-cyanoboranes, (CH3)2(C18H37)NBH2CN (5), (CH3)2NHBH[CH(CH3)2]CN (7) and (CH3)3NB(CN)2.CH3 (10), were the most active in vivo and in vitro. A related phosphine-cyanoborane was also very active in both in vivo and in vitro model screens. Of the amino-methyl-phosphonate-N-cyanoborane adducts, (CH3O)2.P(O)CH2N(C2H5)2BH2CN (13) proved to be the most active. The amine-cyanoalkylboranes had the poorest in vivo activity; the in vitro cytotoxicity, however, was similar to that of other cyanoboranes.

Antineoplastic activity of a series of boron analogues of alpha-amino acids.

A series of amine cyanoboranes, amine carboxyboranes, and boron analogues of alpha-amino acids have been investigated for antineoplastic activity against the growth of Ehrlich ascites cells. Additional studies demonstrated that the boron analogues inhibited DNA and RNA synthesis at 300 microM. The suppression of DNA synthesis of Ehrlich ascites cells correlated with the reduction of DNA polymerase, 5-phosphoribosyl-1-pyrophosphate amidotransferase, and dihydrofolate reductase activities afforded by the boron compounds. These derivatives did not suppress protein synthesis, thymidylate synthetase, or thymidine monophosphate kinase activities as previously reported for some boron antineoplastic agents.