Synthesis and Evaluation of Long-Acting D-Penicillamine Derivatives

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.

Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells

“…Thus, when explaining the different cytotoxic activities of the analyzed compounds, the size, structure, and ring geometry of the attached amine should be taken into account. There have also been reports in the literature that esterification can increase bioavailability and cellular penetration [21][22][23][24]. In addition, other in vitro studies have shown that amidine analogs of melphalan reduce the number of estrogen receptor-positive and estrogen receptor-free breast cancer cells [25,26].…”

Intracellular Delivery of the Reactive Oxygen Species Generating Agent d-Penicillamine upon Conjugation to Poly-l-glutamic Acid

“…We and others have previously shown that D-pen is impermeable to cancer cells. 20,37 The impermeability results from a combination of high hydrophilicity (log P -0.39) 38 and the D-isoform being stereochemically less favored for cellular uptake by the amino acid transporters. 37 Polymer bound drugs have been shown to be taken up by the cells via fluid phase endocytosis.…”

The kinetics and mechanism of the ligand substitution reaction of aquapentacyanoruthenate(II) with d-penicillamine in aqueous medium

“…21 On account of its excellent properties, D-PA has been used for the treatment of Wilson's disease by decreasing excess copper levels through reduction of Cu(II) to Cu(I), in heavy metal poisoning, in cystinuria, in rheumatoid arthritis, and also has several significant applications in biological systems. [22][23][24][25][26][27][28][29] In the past, ruthenium compounds have been widely employed as potential cytostatic agents as well as a possible alternative to drugs containing platinum metal. [30][31][32] Amino and cyano complexes of ruthenium metal, that is, [(NH 3 ) 5 RuL] 2 + and [(CN) 5 RuL] 3 + with pyrazine or pyridine aromatic heterocycles, 33 have been explored previously along with other pentacyano(ligand) complexes of Ru(II) [34][35][36][37] and Fe(II).…”