The synthesis of amine-borane adducts of cyclohexylamine, toluidine, and 3'-aminodideoxynucleosides and evaluation of their pharmacological activity.

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

The synthesis of amine-borane adducts of cyclohexylamine, toluidine, and 3'-aminodideoxynucleosides and evaluation of their pharmacological activity.

Diss Abstr Int [B]; 55(6):2173 1994. Unique Identifier : AIDSLINE ICDB/95615356
Burnham BS; Univ. of North Carolina at Chapel Hill

Abstract: A number of the amine-borane adducts of alpha-amino acids and nucleosides, as well as aliphatic, heterocyclic and aromatic amines, have been previously synthesized in this laboratory. Several amine-boranes of diverse structures possess antineoplastic, hypolipidemic, and anti-inflammatory activities in rodents. A series of cyclohexylamine and toluidine carboxy- and cyanoboranes was synthesized to expand the structure-activity relationships (SAR) of the heterocyclic, aliphatic and aromatic amine-boranes. Since boronated nucleosides are likewise antineoplastic, hypolipidemic and anti-inflammatory agents, and 3'- aminodideoxynucleosides (eg, 3'-azidodideoxythymidine and 3'-amino-dideoxythymidine) are antineoplastic and anti-HIV agents, a series of 3'-amine-borane dideoxynucleosides was synthesized and evaluated for pharmacological activity. The toluidine cyanoboranes were synthesized by reacting toluidine hydrochloride with sodium cyanoborohydride in refluxing THF under nitrogen. The cyclohexylamine adducts of carboxyborane and cyanoborane were prepared by amine exchange using trimethylamine-carboxyborane and p-toluidine-cyanoborane, respectively, in excess amine, neat or in THF, at 70 C under nitrogen. 2'-Deoxynucleosides were converted to the 3'-aminodideoxynucleosides by literature methods. The 3'-aminocyano-borane dideoxynucleosides were synthesized by amine exchange using triphenylphosphine-cyanoborane and the 3'-aminodideoxynucleoside in dry DMF at 55 C under nitrogen. 3'-aminocyanoborane dideoxythymidine (B-1) and N-methylcyclohexylamine-cyanoborane (BSB-12) were shown to possess cytotoxic activity in vitro in murine and human tumors and in vivo in Ehrlich ascites carcinoma in mice at 8 mg/kg/day, ip. The cytotoxic mode of action of these compounds in L1210 cells was by inhibition of DNA and RNA syntheses. B-1 inhibited the activities of dihydrofolate reductase, TMP kinase, and mRNA, rRNA, and tRNA polymerases. Similarly, BSB-12 inhibited dihydrofolate reductase activity and mRNA, rRNA, and tRNA polymerases activities in L1210 cells. 3-methylcyclohexylamine-carboxyborane (BSB-7), N-ethylcyclohexylamine-cyanoborane (BSB-11), p-toluidine-cyanoborane (BSB-22), and 3'-aminocyanoborane dideoxythymidine (B-1) decreased serum cholesterol and triglyceride levels in vivo in mice at 8 mg/kg/day, ip, and rats at 8 mg/kg/day, po. These compounds decreased LDL cholesterol and increased HDL cholesterol levels in rats after 14 days at 8 mg/kg/day, po. The agents' cholesterol lowering effects were primarily due to inhibition of neutral cholesterol ester hydrolase activity and increased cholesterol-7alpha-hydroxylase activity. Cyclohexylamine-carboxyborane (BSB-2) and N-methylcyclohexylamine-carboxyborane (BSB-3) and demonstrated weak anti-inflammatory activity in vivo in mice and rats at 8 mg/kg X 2. (Full text available from University Microfilms International, Ann Arbor, MI, as Order No. AAD94-29393)

Keywords: Animal Antineoplastic Agents/*PHARMACOLOGY/THERAPEUTIC USE Antiviral Agents/PHARMACOLOGY/THERAPEUTIC USE Boranes/*PHARMACOLOGY Carcinoma, Ehrlich Tumor/DRUG THERAPY Cholesterol/BLOOD Cyclohexylamines/*PHARMACOLOGY HIV-1/DRUG EFFECTS Leukemia L1210/DRUG THERAPY/GENETICS Mice RNA/METABOLISM Tetrahydrofolate Dehydrogenase/METABOLISM Toluidines/*PHARMACOLOGY Triglycerides/BLOOD THESIS
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M95C3204

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