The first preparative solution phase synthesis of melanotan II

• Main Authors: Vladimir V. Ryakhovsky, Georgy A. Khachiyan, Nina F. Kosovova, Elena F. Isamiddinova, Andrey S. Ivanov
• Format: Article
• Language: English
• Published: Beilstein-Institut 2008-10-01
• Series: Beilstein Journal of Organic Chemistry
• Subjects: melanotan II; solution phase synthesis; peptide synthesis
• Online Access: https://doi.org/10.3762/bjoc.4.39

Melanotan II is a synthetic cyclic heptapeptide used to prevent a sunlight-induced skin cancer by stimulating the skin tanning process. In this paper we report the first solution phase synthesis of the title compound. The hexapeptide sequence has been assembled by [(2+2)+1+1] scheme. After removing the orthogonal protection, a carbodiimide mediated lactamization, involving the ε-amino group of lysine and γ-carboxy group of aspartic acid, led to a cyclic intermediate. Appending N-acetylnorleucine concluded the assembly of melanotan II molecule. Protection of the lateral groups in arginine and tryptophan was omitted for atom and step economy reasons. The total synthesis of melanotan II was accomplished in 12 steps with 2.6% overall yield, affording >90% pure peptide without using preparative chromatography.