Synthesis and evaluation of long-acting D-penicillamine derivatives.
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.
Department of Surgery, University of Arizona Medical Sciences Center, Tucson, Arizona 85718, USA. mchvapil@hotmail.com
Milos
M
Chvapil
Filip
F
Kielar
Frantisek
F
Liska
Alexandra
A
Silhankova
Klaus
K
Brendel
D000230:Adenocarcinoma / Q000188:drug therapy; D000438:Alcohols / Q000737:chemistry; D000629:Aminopropionitrile / Q000032:analysis* / Q000138:chemical synthesis* / Q000627:therapeutic use; D000818:Animals; D017439:Cicatrix, Hypertrophic / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D003240:Connective Tissue Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003251:Constriction, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004951:Esterification; D005260:Female; D000441:Hexanols / Q000737:chemistry; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D000267:Tissue Adhesions / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome; D014525:Urethral Stricture / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
D000438:Alcohols; D000441:Hexanols; D000629:Aminopropionitrile; D003094:Collagen; D010396:Penicillamine