Synthesis and Antitumour Effect of the Melanogenesis-based Antimelanoma Agent N-Propionyl-4- S-cysteaminylphenol

• Published in: Biochemical pharmacology 1998-06, Vol.55 (12), p.2023-2029
• Main Authors: Tandon, Manju, Thomas, Panakkezhum D, Shokravi, Mohammed, Singh, Shradha, Samra, Satinder, Chang, Daniel, Jimbow, Kowichi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - adverse effects; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Cystamine - adverse effects; Cystamine - analogs & derivatives; Cystamine - chemical synthesis; Cystamine - therapeutic use; Cysteamine - adverse effects; Cysteamine - analogs & derivatives; Cysteamine - chemical synthesis; Cysteamine - therapeutic use; cysteaminylphenol; depigmenting potency; General aspects; Humans; Hypopigmentation - chemically induced; Medical sciences; Melanins - metabolism; melanocytotoxicity; melanoma chemotherapy; Melanoma, Experimental - drug therapy; Melanoma, Experimental - metabolism; Mice; Mice, Inbred C57BL; Pharmacology. Drug treatments; Phenols - adverse effects; Phenols - chemical synthesis; Phenols - therapeutic use; Skin Neoplasms - drug therapy; Skin Neoplasms - metabolism; Tumor Cells, Cultured - metabolism; tyrosinase
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(98)00090-2

Chemotherapy of malignant melanoma is still a great challenge, as no effective drugs are available. The development of melanogenesis-based drugs is a promising area of research because melanogenesis is a unique biochemical pathway operating only in melanoma cells (and their normal counterparts) so that the tumour can be targeted. We have been using cysteinylphenol, a sulphur-containing analogue of tyrosine, and derivatives for that purpose. N-Acetyl-4- S-cysteaminylphenol was found to have the best antimelanoma effect in cell culture systems and in mice bearing B16 melanoma tumours. It also caused depigmentation of the skin, suggesting the possibility of use as a hypopigmenting agent. To improve the efficiency of the drug, we thought of replacing the acetyl group in N-acetyl-4- S-cysteaminylphenol with a propionyl group in the hope that increased hydrophobicity would increase the cellular uptake of the drug. N-Propionyl-4- S-cysteaminylphenol was synthesized by condensing 4-hydroxythiophenol with 2-ethyl-2-oxazoline. The drug showed both cytostatic and cytocidal effects in a human melanotic melanoma cell line. The drug was found to be a good depigmenting agent for the black hair follicles of C57 black mice when given s.c. for 14 days. A 10-day treatment with N-propionyl-4- S-cysteaminylphenol at 300 mg/kg body weight reduced the growth rate of B16 melanoma s.c. tumours in mice by 36%. The propionyl derivative was found to increase the life span of mice bearing melanoma more effectively than did the acetyl derivative.