ABSTRACT
This study extends the use of two lathyrogens, ss-aminopropionitrile (BAPN) and D-penicillamine (DPA) from daily systemic or local-topical administration to long-time acting agents. This was achieved by converting the hydrophilic drugs into lipophilic derivatives. The synthesis of functional derivatives of DPA consisted in esterification with methyl-, hexyl-, or benzyl alcohols in the presence of thionylchloride. The esters formed were hydrochlorides, acidic and soluble in water. During neutralization in vitro or in vivo by tissue fluid, an oily substance is formed that elutes from a hydrogel polymer at a much slower rate than hydroplilic DPA itself. The degree of lipophilicity, measured as a partition coefficient between octanol/water, was highest for hexyl ester and lowest for methyl ester DPA. A single injection of either DPA hexyl ester HCl or 3-hexyl(amino) propionitrile into the full thickness skin incision wound in rats significantly lowered the breaking strength of the wound 12 days after injection, indicating the interference with collagen cross-linking. Both agents injected into the breast adenocarcinoma in Fisher rats significantly inhibited tumor growth without any signs of local or systemic toxicity. We conclude that these lipophilic lathyrogens with prolonged effectiveness are suitable in the treatment of pathologies, consisting of excessively cross-linked or deposited collagen (fibrotic adhesions, strictures, stenosis, and scar contractures) and in the treatment of single, solitary tumors, malignant and benign.
Subject(s)
Aminopropionitrile/analysis , Aminopropionitrile/chemical synthesis , Cicatrix, Hypertrophic/drug therapy , Connective Tissue Diseases/drug therapy , Neoplasms/drug therapy , Penicillamine/analogs & derivatives , Penicillamine/chemical synthesis , Adenocarcinoma/drug therapy , Alcohols/chemistry , Aminopropionitrile/therapeutic use , Animals , Cicatrix, Hypertrophic/metabolism , Cicatrix, Hypertrophic/physiopathology , Collagen/drug effects , Collagen/metabolism , Connective Tissue Diseases/metabolism , Connective Tissue Diseases/physiopathology , Constriction, Pathologic/drug therapy , Constriction, Pathologic/metabolism , Constriction, Pathologic/physiopathology , Esterification , Female , Hexanols/chemistry , Mammary Neoplasms, Experimental/drug therapy , Molecular Structure , Neoplasms/metabolism , Neoplasms/physiopathology , Penicillamine/therapeutic use , Rats , Rats, Inbred F344 , Tissue Adhesions/drug therapy , Tissue Adhesions/metabolism , Tissue Adhesions/physiopathology , Treatment Outcome , Urethral Stricture/drug therapy , Urethral Stricture/metabolism , Urethral Stricture/physiopathologyABSTRACT
The basic fraction of a 2-aminopropionitrile polymer was subjected to acid hydrolysis and was analyzed by means of GC-MS, after trimethylsilylation. The fundamental polymer structural units were alanine, 2,2'-iminodipropionic acid, N-(1-cyanoethyl)alanine, N-ethylalanine, glycine, cyanoglycine, and 5-amino-4-carboxyimidazole residues. The last three units may be derived from hydrogen cyanide. Oligomeric combinations of these units were also detected in the hydrolyzate, due to partial hydrolysis of the polymer.
