title: Structure-toxicity relationship of phenolic analogs as anti-melanoma agents: an enzyme directed prodrug approach.
abstract: The aim of this study was to identify a phenolic prodrug compound that is minimally metabolized by rat liver microsomes, but yet could form quinone reactive intermediates in melanoma cells as a result of its bioactivation by tyrosinase. In current work, we investigated 24 phenolic compounds for their metabolism by tyrosinase, rat liver microsomes and their toxicity towards murine B16-F0 and human SK-MEL-28 melanoma cells. A linear correlation was found between toxicities of phenolic analogs towards SK-MEL-28 and B16-F0 melanoma cells, suggesting similar mechanisms of toxicity in both cell lines. 4-HEB was identified as the lead compound. 4-HEB (IC(50) 48h, 75muM) showed selective toxicity towards five melanocytic melanoma cell lines SK-MEL-28, SK-MEL-5, MeWo, B16-F0 and B16-F10, which express functional tyrosinase, compared to four non-melanoma cells lines SW-620, Saos-2, PC3 and BJ cells and two amelanotic SK-MEL-24, C32 cells, which do not express functional tyrosinase. 4-HEB caused significant intracellular GSH depletion, ROS formation, and showed significantly less toxicity to tyrosinase specific shRNA transfected SK-MEL-28 cells. Our findings suggest that presence of a phenolic group in 4-HEB is critical for its selective toxicity towards melanoma cells.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1406 Coulter Drive, Amarillo, TX 79106, USA.
authors: Nikhil M
authors: NM
authors: Vad
authors: Prabodh K
authors: PK
authors: Kandala
authors: Sanjay K
authors: SK
authors: Srivastava
authors: Majid Y
authors: MY
authors: Moridani
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000201:enzymology* / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000235:genetics / Q000378:metabolism; D010636:Phenols / Q000737:chemistry / Q000633:toxicity*; D011355:Prodrugs / Q000737:chemistry / Q000633:toxicity*; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D010636:Phenols; D011355:Prodrugs; D017382:Reactive Oxygen Species; D014442:Monophenol Monooxygenase; D005978:Glutathione