Amine Carboxyboranes Research Articles

Recent developments in the synthesis of bioactive boron-containing compounds

Boron-containing compounds which possess unique and attractive properties have recently received increasing attention in organic, material and medicinal chemistry. Specifically, they have displayed interesting and useful biological activities, which promoted a great deal of interest in their synthetic approaches. This digest covers the recent developments of synthetic methods towards bioactive boron-containing compounds, with selected examples including peptidyl boronates/boronic acids, benzoxaboroles, benzoxaborines, benzodiazaborines, amine cyanoboranes and amine carboxyboranes.

ROS-mediated carbon monoxide and drug release from drug-conjugated carboxyboranes.

Elevated levels of reactive oxygen species (ROS) are associated with several detrimental diseases. Therefore, using this condition for selective treatments could be a great advantage in fighting these disorders. Here, we present amine carboxyboranes as a class of molecules for therapeutic CO gas generation and for delivering drug molecules in the presence of ROS. Our findings indicate amine carboxyboranes to be very slow CO releasers at physiological pH and temperature without any inducers but generate CO faster when reacted with a non-radical ROS (H2O2). Furthermore, a radical ROS (˙OH) dramatically expedites the production of CO from amine carboxyboranes. A decomposition profile shows the release of the amine group during the decarbonylation process from drug-conjugated carboxyboranes. This suggests that the carboxyborane moiety can be a useful tool for the delivery of amine-containing drugs to disease sites which display abundant ROS levels.

Synthesis of biologically active boron-containing compounds.

Boron-containing compounds which possess unique and attractive properties have received increasing attention from the pharmaceutical industry and academia recently. They have shown interesting and useful biological activities, including antibacterial, antifungal, antiparasitic, antiviral, and anti-inflammatory activities. In this review, the synthetic strategies for various boron-containing compounds, including peptidyl boronic acids, benzoxaboroles, benzoxaborines, benzodiazaborines, amine carboxyboranes, and amine cyanoboranes are summarized. Representative structures of each structural class and recently developed biologically active boron-containing compounds are used as examples in this review.

Nonmetallic carbon monoxide releasing molecules (CORMs).

Carbon monoxide (CO) is a gasotransmitter that plays important roles in regulating cell functions and has shown therapeutic effects in clinic studies. CO releasing molecules (CORMs), which allow controlled release of CO in physiological conditions, have been intensively studied in the past decade. While most CORMs are metal complexes, several nonmetallic CORMs have also been developed and most of them were reported in recent years. The major advantages of nonmetallic CORMs are potentially low toxicity and easy modification for property tuning. Syntheses, CO-release mechanisms, biological behaviors, and physicochemical properties of these nonmetallic CORMs are reviewed here. The first part of this short review covers the nonmetallic CORMs that do not require irradiation to release CO, which includes methylene chloride, CORM-A1 and its derivatives, amine carboxyboranes, and bimolecular CORMs. The second part focuses on the CORMs that release CO under irradiation (PhotoCORMs) including unsaturated cyclic diketones, xanthene carboxylic acids, meso-carboxy BODIPYs, and hydroxyflavones. Future prospects are discussed at the end of this review.

α‐Aminoboronic Acids, Amine Cyanoboranes, Amine Carboxyboranes and Their Derivatives

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Pharmacologically Active Boranes

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Pharmacologically active boranes

Abstract Novel methods are described for the preparation of alkyldimethylamine cyanoboranes and β-hydroxylalkyldimethylamine cyanoboranes by C-lithiation of trimethylamine cyanoboranes followed by reaction with alkyl halides, aldehydes, and ketones. Lithiation of the monobromo derivatives of amine cyanoboranes led to the synthesis of the first examples of diborane derivatives of amine cyanoboranes. Bromo derivatives of amine cyanoboranes and amine carboxyboranes have been synthesized by new simple and efficient methods. Amine fluorocyanoboranes and amine fluorocarboxyboranes, new classes of compounds, have been prepared from the bromo precursors by fluorine/bromine exchange using fluorinating reagents such as AgF and Et3N.3HF. Eight different derivatives of oxazaborolidines were synthesized and evaluated for their affect on Streptococcus mutans viability, adhesion, and biofilm formation using 3[H]-thymidine labeled bacteria, and fluorescent stained bacteria. This is the first reported antibacterial activity of this class of compounds. The minimal inhibitory concentration (MIC) values ranged from 0.26 to 10 mM. Structure-activity relationship was observed. The B-butyl moiety of the oxazaborolidines contributed an anti-adhesion effect for all derivatives, while its effect diminished when the boron atom was incorporated in a fused heterocyclic ring. The B-phenyl group induced bacterial adhesion in all tested compounds. In a separate study for boronated saccahrides and enzymatic inhibition, the complex formation between N-butylboronic acid and a series of monosaccharides was investigated by 1H, 13C, and 11B NMR spectroscopy and gas chromatography-mass spectrometry (GC-MS). Then, a series of boronic acid compounds with protease inhibition properties were prepared. The effect of added mono-, di-, and polysaccharides on the inhibitory activity of these compounds was studied. Potassium organotrifluoroborates were found to be reversible competitive inhibitors of α-chymotrypsin and trypsin. Based on 19F NMR, it was speculated that they inactivate the enzymes as a result of the formation of hydrogen bonds between fluorine atoms of the inhibitors and the serine protease.

ChemInform Abstract: Effects of Alkyl Amine Carboxyboranes on L1210 DNA Fragmentation and Nucleic Acid Metabolism.

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Effects of alkyl amine carboxyboranes on L1210 DNA fragmentation and nucleic acid metabolism.

Amine-carboxyboranes with varying alkyl chain lengths were observed to be potent cytotoxic agents inhibiting the growth of a number of histological types of murine, rat, and human tumors. These agents preferentially reduced L1210 DNA synthesis with marked inhibition of the activities of regulatory enzymes of the purine pathway. Other enzyme activities which were marginally reduced were DNA polymerase alpha, ribonucleoside reductase, dihydrofolate reductase, t-RNA polymerase, and nucleoside kinases. Pyrimidine nucleotide pools were not reduced but DNA strand scission occurred after 24 h incubation with the agents. The amine-carboxyboranes were not DNA topoisomerase II inhibitors at 100 microM. The agents did not cause DNA protein linked breaks themselves; nevertheless, VP-16 [etoposide] induced DNA protein linked breaks were increased two fold in the presence of the agents suggesting synergistic effects. The amine-carboxyboranes decreased protein kinase C mediated phosphorylation of L1210 topoisomerase II protein, potentially decreasing its enzymatic catalytic activity. Thus, the amine-carboxyboranes did not function like VP-16 in affording cleavable products but were synergistic with VP-16 in causing DNA fragmentation. The agents were also additive with VP-16 in reducing tumor cell number, soft-agar colony growth and DNA synthesis and in producing DNA strand scission.

Anti-Osteoporotic activity of metal complexes of amine carboxyboranes

Metal complexes of trimethylamine carboxyborane successfully suppressed calcium flux from both paired pup calvaria bones and rat UMR-106 osteosarcoma cultured cells over a 48 h period. These agents increased uptake of calcium into the cell cultures and accelerated [3H]proline incorporation into collagen. Copper and iron complexes of the trimethylamine carboxyborane were more potent compared with the cobalt and chromium complexes. The agents effectively reduced Iysosomal enzyme activity and also proteolytic enzyme activities of macrophages. Since macrophages invade the bone surface and assist in the demineralization and digestion of collagen, those agents may be potentially useful to retard diseases involving bone reconstruction. Influx of white blood cells and macrophages to sites of degradation most probably would be inhibited by the agents, based on sponge test observations in mice. Osteoporosis induced by ovariectomy was minimized by injections of tetrakis[u-(trimethylamine-boranecarboxylato)-bis(trimethylamine-carboxyborane)dicopper(II)] into rats at 3.5 mg kg−1 day−1 for 14 days. Bone volume, density, weight and calcium content returned to normal baseline control values. In addition, the copper complex returned serum calcium, serum parathyroid hormone (PTH) and vitamin D3 values to normal levels. One possible mode of action of these derivatives is the regulation of the production and release of chemical mediators initiating bone loss, e.g. tumor necrosis factor, TNF α and interleukins 11 or 11-2.

The anti-osteoporotic activity of amine-carboxyboranes in rodents

Amine-carboxyboranes have been shown to prevent osteoporosis and loss of bone mass in rodents. In vitro studies using CF1 mouse pup calvaria and rat UMR-106 osteosarcoma cells showed that amine-carboxyborane derivatives reduced significantly the loss of intracellular calcium into the growth medium from 10(-4) to 10(-8) M over 48 hours. Amine-carboxyborane derivatives were more effective than calcitonin or simple boron salts. Calcium incorporation into these cells and proline incorporation into collagen was accelerated in the presence of amine carboxyboranes. The amine-carboxyborane derivatives effectively inhibited lysosomal and proteolytic enzymes as well as activities of serine elastase, prostaglandin cyclooxygenase, and 5'-lipoxygenase in mouse macrophages, human PMNs, leukocytes and Be Sal cells. IC50 values were in the range of 10(-6) M. In lactating ovariectomized female rats after administered amine-carboxyboranes for 14 days at 8 mg/kg/day orally, the femur and humerus showed increased volume, weight, density and ash weight. Serum calcium levels were elevated significantly with minimum reductions on serum inorganic phosphate levels. Femur calcium levels were elevated after treatment with amine-carboxyborane derivatives, but not with etidronate. Humerus total lipids after 14 days were slightly elevated probably due to increased levels of triglycerides and phospholipids.

Hypolipidemic, anti-obesity, anti-inflammatory, anti-osteoporotic, and anti-neoplastic properties of amine carboxyboranes.

The amine-carboxyborane derivatives were shown to be effective antineoplastic/cytotoxic agents with selective activity against single-cell and solid tumors derived from murine and human leukemias, lymphomas, sarcomas, and carcinomas. The agents inhibited DNA and RNA synthesis in preference to protein synthesis in L1210 lymphoid leukemia cells. Inosine-monophosphate dehydrogenase apparently is a target site of the compounds; similar effects on phosphoribosyl-pyrophosphate amido transferase, orotidine-monophosphate decarboxylase, and both nucleoside and nucleotide kinases were observed. Deoxyribonucleotide pool levels were reduced in the cells; DNA strand scission was observed with the agents. In rodents, the amine carboxyboranes were potent hypolipidemic agents, lowering both serum cholesterol and triglyceride concentrations, in addition to lowering cholesterol content of very low-density lipoprotein and low-density lipoprotein (LDL) and elevating high-density lipoprotein (HDL) cholesterol concentrations. De novo regulatory enzymes involved in lipid synthesis were also inhibited (e.g., hypocholesterolemic 3-hydroxy-3-methyl-Coenzyme A reductase, acyl-Coenzyme A cholesterol acyltransferase, and sn-glycerol-3-phosphate acyltransferase). Concurrently, the agents modulated LDL and HDL receptor binding, internalization, and degradation, so that less cholesterol was delivered to the plaques and more broken down from esters and conducted to the liver for biliary excretion. Tissue lipids in the aorta wall of the rat were reduced and fewer atherosclerotic morphologic lesions were present in quail aortas after treatment with the agents. Cholesterol resorption from the rat intestine was reduced in the presence of drug. Genetic hyperlipidemic mice demonstrated the same types of reduction after treatment with the agents. The agents would effectively lower lipids in tissue based on the inhibition of regulatory enzymes in pigs. These findings should help improve domestic meat supplies from fowl and pigs. The amine-carboxyboranes were effective anti-inflammatory agents against septic shock, induced edema, pleurisy, and chronic arthritis at 2.5 to 8 mg/kg. Lysosomal and proteolytic enzyme activities were also inhibited. More significantly, the agents were dual inhibitors of prostaglandin cyclooxygenase and 5'-lipoxygenase activities. These compounds also affected cytokine release and white cell migration. Subsequent studies showed that the amine-carboxyboranes were potent anti-osteoporotic agents reducing calcium resorption as well as increasing calcium and proline incorporation into mouse pup calvaria and rat UMR-106 collagen.

Hypolipidemic, Anti-Obesity, Anti-Inflammatory, Anti-Osteoporotic, and Anti-Neoplastic Properties of Amine Carboxyboranes

Hypolipidemic, Anti-Obesity, Anti-Inflammatory, Anti-Osteoporotic, and Anti-Neoplastic Properties of Amine Carboxyboranes

Anti-Inflammatory and Anti-osteoporotic Activities of Base-Boronated Nucleosides and Phosphate-Boronated Nucleotides in Rodents

The 2′-deoxyribonucleoside cyanoboranes were effective anti-inflammatory agents in rodents at 2–8 mg/kg; they blocked induced edema, septic shock, and pleurisy. Overall compounds 3′, 5′-O-(bis-(triisopropylsilyl)-2′-deoxyinosine (1), 3′,5′-O-bis(triisopropylsilyl)-2′-deoxy-cytidine (10),N3-(cyanoboryl)-2′-deoxycytidine (11), N7-(cyanoboryl)-N2-isobutyryl-3′,5′-O-bis(triisopropylsilyl-2′-deoxyguanosine (20), and N7-(cyanoboryl)-N2-isobutyryl-5′-O-(4,4′-dimethoxytrityl)-3′-O-(triisopropylsilyl)-2′-deoxyguanosine (22) were the most active when all of the anti-inflammatory screens are considered. The agents also blocked both local and central pain caused by inflammation. These nucleosides blocked calcium resorption but were less effective compared to other amine carboxyboranes. The inflammation process appeared blocked by these compounds because of their effectiveness in reducing both hydrolytic lysosomal enzyme and proteolytic enzyme activities. The agents were also dual inhibitors of prostaglandin cyclooxygenase and 5′-lipoxygenase activities in leukocytes and macrophages. These agents at 10−4M demonstrated no specific organ toxicity to ileum mucosa cells grown in tissue culture.

The anti‐inflammatory activity of metal complexes and salts of amine carboxyboranes

AbstractThe metal complexes and salts of amine carboxyboranes were shown to be potent anti‐inflammatory agents in rodents at 8 mg kg−1. They were effective in blocking induced edema, pleurisy and endotoxic shock while blocking both local and central pain processes. The ability of the agents to function as anti‐inflammatory agents is multi‐fold. First, lysosomal enzymes of specific cells, e.g. macrophages, were inhibited with IC50 values in the range of 10−6 M. Collagenase I and II activities were inhibited with IC50 values approximately equal to 10−4 M. The anti‐inflammatory activity of these agents at the molecular levels appears to be due to inhibition of the release of TNFα and Il‐1 from macrophages which indirectly control chemotaxic migration of white blood cells as indicated by the suppression of PMN and macrophage invasion into sponges implanted subcutaneously (SC) in mice. Furthermore, in these invading cells, the agents' blockage of TNFα and Il‐1 or Il‐2 release down‐regulates prostaglandin and leukotriene enzymatic synthetic rates and, consequently, their release, resulting in a reduction of the inflammation process.

Synthesis and Hypolipidemic Activity of Amine‐Carboxyboranes, and Their Amides and Esters in Rodents

A series of amine carboxyboranes including their amides and esters were synthesized and shown to have potent hypolipidemic activity in rodents at 20 mg/kg/day. Ethylamine carboxyborane, di-n-propylamine-carboxyborane, trimethylamine-carbomethoxyborane, n-butylamine carbomethoxyborane, methylamine-N-ethyl carbamoylborane and trimethylamine-N-n-octyl carbamoylborane were the most potent derivatives demonstrating hypocholesterolemic and hypotriglycemic activities in rats orally at 20 mg/kg/day. These derivatives lowered tissue lipids, e.g. cholesterol, in the rat liver, small intestine and aorta. The fecal lipids were elevated. Furthermore, the agents lowered cholesterol and triglycerides in the serum VLDL and LDL fractions but caused elevations in the HDL fraction after 14 days. The agents inhibited hepatic enzymatic activities of rate limiting steps involved in lipid metabolism, e.g. ATP dependent citrate lyase, sn-glycerol-3-phosphate acyltransferase and phosphatidylate phosphohydrolase.

Antineoplastic Activity of a Series of Boron Analogues of α-Amino Acids

A series of amine cyanoboranes, amine carboxyboranes, and boron analogues of α-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 μM. 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.

Anti-Inflammatory Activity of Amine Cyanoboranes, Amine Carboxyboranes, and Related Compounds

Amine cyanoboranes and amine carboxyboranes (boron analogs of α-amino acids) were shown to inhibit inflammation. The analogs effectively blocked general inflammation, induced arthritis, and the writhing reflex associated with inflammation pain, while the inflammation associated with pleurisy was marginally inhibited. The boron analogs were shown in vitro to inhibit the release of lysosomal enzymes from liver and polymorphonuclear neutrophils. Furthermore, prostaglandin synthesis was blocked by these gents at a low concentration, i.e., 10−6M. Liver oxidative phosphorylation processes also were uncoupled by these agents, but the migration of polymorphonuclear neutrophils was unaltered at 10−4M. The elevation of cyclic adenosine monophosphate levels in polymorphonuclear neutrophils correlated positively with in vivo antiarthritic activity. Initial studies in rodents demonstrated that these boron analogs can be used at safe therapeutic doses.