Synthesis and pharmacological activities of amine-boranes.

A number of amine-boranes and related derivatives possess a wide range of biological activities including antineoplastic, antiviral, hypolipidemic, anti-inflammatory activities, anti-osteoporotic and dopamine receptor antagonist activities. The compounds include borane complexes of alpha-amino acids, aromatic, aliphatic and heterocyclic amines, and nucleosides. The syntheses of amine-borane derivatives are generally carried out by first preparing a tertiary amine- or phosphine-cyano- or carboxyborane to serve as a borane donor for a subsequent Lewis acid exchange reaction. Borane adducts of simple aliphatic amines, heterocyclic amines and nucleic acids demonstrated potent cytotoxic activity in vitro and in vivo against murine and human tumor models. These boron-containing compounds were shown to inhibit DNA synthesis; such inhibition was caused primarily by reducing de novo purine biosynthesis via inhibition of PRPP amidotransferase, IMP dehydrogenase and dihydrofolate reductase activities. Aliphatic, heterocyclic and nucleoside amine-boranes have also been shown to possess hypolipidemic activity in mice and rats. Many boron derivatives from different chemical classes demonstrated both cytotoxic and hypolipidemic activities. They decreased low-density lipoprotein (LDL) cholesterol while increasing high-density lipoprotein (HDL) cholesterol levels. The mode of action of these compounds in the 50-100 microM concentration range appeared to be by increasing lipid excretion from the body and by inhibiting rate-limiting enzyme activities for the de novo synthesis of lipids and cholesterol (e.g., phosphatidylate phosphohydrolase, ATP-dependent citrate lyase, cytoplasmic acetyl coenzyme A [CoA] synthetase, HMG CoA reductase, and acetyl CoA carboxylase). Selected amine-boranes (e.g., trimethylamine-cyanoborane, N-methylmorpholine-cyanoborane, and the base-boronated 2'-deoxynucleosides) have anti-inflammatory, analgesic, anti-arthritic and anti-osteoporotic activities.

Lipid-lowering effects of ethyl 2-phenacyl-3-aryl-1H-pyrrole- 4-carboxylates in rodents.

A series of substituted 2-phenacyl-3-phenyl-1H-pyrrole-4-carboxylates were prepared from substituted acetophenones in 6 steps. The final condensations between a chloroenal and an aminoketone were carried out under neutral conditions in parallel to yield the series listed below. Selected pyrrole derivatives proved to be potent hypolipidemic agents lowering serum triglyceride concentrations in CF-1 male mice after 14 days of I.P. administration. One agent orally lowered serum cholesterol in Sprague-Dawley male rats at 2mg/kg/day after 14 days. The agents demonstrated a lowering of mouse serum LDL- cholesterol levels and selected compounds showed an elevation of serum HDL-cholesterol levels. The cholesterol concentrations in the liver were raised while the cholesterol and triglyceride contents of the aorta were significantly lowered by the selected trisubstituted pyrrole.

Synthesis and cytotoxicity of substituted ethyl 2-phenacyl-3-phenylpyrrole-4-carboxylates.

The substituted ethyl-2-phenacyl-3-phenylpyrrole-4-carboxylates were synthesized by a condensation of a beta-chloroenal and an alpha-aminoketone under neutral conditions. They proved to be potent cytotoxic agents against the growth of murine L1210 and P388 leukemias and human HL-60 promyelocytic leukemia, HuT-78 lymphoma, and HeLa-S(3) uterine carcinoma. Selective compounds were active against the growth of Tmolt(3) and Tmolt(4) leukemias and THP-1 acute monocytic leukemia, liver Hepe-2, ovary 1-A9, ileum HCT-8 adenocarcinoma, and osteosarcoma HSO. A mode of action study in HL-60 cells demonstrated that DNA and protein syntheses were inhibited after 60 min at 100 microM. DNA and RNA polymerases, PRPP-amido transferase, dihydrofolate reductase, thymidylate synthase, and TMP kinase activities were interfered with by the agent with reduction of d[NTP] pools. Nonspecific interaction with the bases of DNA and cross-linking of the DNA may play a role in the mode of action of these carboxylates.

Synthesis and cytotoxicity of cyanoborane adducts of n6-benzoyladenine and 6-triphenylphosphonylpurine.

N6-Benzoyladenine-cyanoborane (2), and 6-triphenylphosphonylpurine-cyanoborane (3) were selected for investigation of cytotoxicity in murine and human tumor cell lines, effects on human HL-60 leukemic metabolism and DNA strand scission to determine the feasibility of these compounds as clinical antineoplastic agents. Compounds 2 and 3 both showed effective cytotoxicity based on ED(50) values less than 4 mug/ml for L1210, P388, HL-60, Tmolt(3), HUT-78, HeLa-S(3) uterine, ileum HCT-8, and liver Hepe-2. Compound 2 had activity against ovary 1-A9, while compound 3 was only active against prostate PL and glioma UM. Neither compound was active against the growth of lung 549, breast MCF-7, osteosarcoma HSO, melanoma SK2, KB nasopharynx, and THP-1 acute monocytic leukemia. In mode of action studies in human leukemia HL-60 cells, both compounds demonstrated inhibition of DNA and protein syntheses after 60 min at 100 muM. These compounds inhibited RNA synthesis to a lesser extent. The utilization of the DNA template was suppressed by the compounds as determined by inhibition of the activities of DNA polymerase alpha, m-RNA polymerase, r-RNA polymerase and t-RNA polymerase, which would cause adequate inhibition of the synthesis of both DNA and RNA. Both compounds markedly inhibited dihydrofolate reductase activity, especially in compound 2. The compounds appeared to have caused cross-linking of the DNA strands after 24 hr at 100 muM in HL-60 cells, which was consistent with the observed increased in ct-DNA viscosity after 24 hr at 100 muM. The compounds had no inhibitory effects on DNA topoisomerase I and II activities or DNA-protein linked breaks. Neither compound interacted with the DNA molecule itself through alkylation of the nucleotide bases nor caused DNA interculation between base pairs. Overall, these antineoplastic agents caused reduction of DNA and protein replication, which would lead to killing of cancer cells.