Synthesis and biological activities of fatty acid conjugates of a cyclic lactam alpha-melanotropin.
Four fatty acid conjugates of a cyclic lactam-bridged alpha-MSH fragment analogue were synthesized and their potencies and biological activities compared in several melanotropin bioassays. Palmitoyl, myristoyl, decanoyl, and hexanoyl conjugates of H-Asp-His-D-Phe-Arg-Trp-Lys-NH2 were prepared. In the in vitro mouse melanoma cell assay, each of the conjugates was 10-100 times more potent than alpha-MSH or the substrate peptide in elevating tyrosinase activity. The shorter conjugates of hexanoic and decanoic acid were as potent as alpha-MSH in the lizard skin bioassay, whereas the longer myristoyl and palmitoyl analogues were about 100 times less potent. The potency of the myristoyl and palmitoyl conjugates increased with time in contact with the skins. These observations may be related to the more lipid-like nature of these peptide-fatty acid conjugates. Each of the conjugates exhibited prolonged melanotropic activity in the lizard skin bioassays and in the mouse S91 melanoma tyrosinase bioassay, since the biological response continued following removal of the conjugates from the incubation media. The prolonged residual melanotropic activity resulted from conjugation of the fatty acids to the MSH fragment analogue since the analogue itself did not exhibit prolonged activity.
al-Obeidi
F
F
Department of Chemistry, University of Arizona, Tucson 85721.
Hruby
V J
VJ
Yaghoubi
N
N
Marwan
M M
MM
Hadley
M E
ME
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000627:therapeutic use; D008116:Lizards; D009074:Melanocyte-Stimulating Hormones / Q000031:analogs & derivatives* / Q000737:chemistry; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008969:Molecular Sequence Data; D014442:Monophenol Monooxygenase / Q000378:metabolism; D010456:Peptides, Cyclic / Q000138:chemical synthesis*
D000970:Antineoplastic Agents; D005227:Fatty Acids; D010456:Peptides, Cyclic; D009074:Melanocyte-Stimulating Hormones; D014442:Monophenol Monooxygenase