Synthesis and actions of a melanotropin conjugate, Ac-[Nle4, Glu(gamma-4'-hydroxyanilide)5, D-Phe7]α-MSH4-10-NH2, on melanocytes and melanoma cells in vitro

F. Al-Obeidi, M. Mulcahy, V. S. Pitt, V. Begay, M. E. Hadley, Victor J Hruby

Research output: Contribution to journalArticle

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Abstract

L-Glutamic acid (γ-4'-hydroxyanilide) (GHB) is oxidized by tyrosinase to a quinone which inhibits DNA polymerase, RNA polymerase, and mitochondrial energy production within mushrooms. It was previously shown that GHB can kill B16 melanoma cells in culture, but lacks cytotoxicity for nontyrosinase-containing cells. We have conjugated this drug to a superpotent melanotropic peptide and examined the bioactivity of this conjugate to melanoma cells. 4'-Hydroxyaniline was attached to glutamic acid at position 5 in the superpotent melanotropin fragment analogue, Ac-[Nle4, D-Phe7]α-MSH4-10-NH2. The melanotropin:anilide conjugate, Ac-[Nle4, Glu(γ-4'-hydroxyanilide)5, D-Phe7]α-MSH4-10-NH2, was not cytotoxic to B16 or Cloudman S91 mouse melanoma cells in culture, as determined by cell counts and protein assays. Interestingly, we also found that GHB stimulated melanoma cell tyrosinase above control levels in both melanoma cell lines. In our study, GHB itself also was found not to be cytotoxic to B16 or S91 melanoma cells in culture. In the frog skin bioassay, the melanotropin conjugate was more potent than α-MSH or Ac-[Nle4, D-Phe7]α-MSH4-10 in stimulating melanosome dispersion. These results demonstrate that putative chemotherapeutic ligands can be incorporated into active-site fragment analogues of MSH without loss of biological activity.

Original languageEnglish (US)
Pages (from-to)500-504
Number of pages5
JournalJournal of Pharmaceutical Sciences
Volume79
Issue number6
DOIs
StatePublished - 1990

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Melanocyte-Stimulating Hormones
Melanocytes
Melanoma
Experimental Melanomas
Monophenol Monooxygenase
Cell Culture Techniques
Bioactivity
Glutamic Acid
Anilides
Melanosomes
Bioassay
Agaricales
Level control
DNA-Directed DNA Polymerase
DNA-Directed RNA Polymerases
Cytotoxicity
Cell culture
Biological Assay
Anura
Assays

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science

Cite this

Synthesis and actions of a melanotropin conjugate, Ac-[Nle4, Glu(gamma-4'-hydroxyanilide)5, D-Phe7]α-MSH4-10-NH2, on melanocytes and melanoma cells in vitro. / Al-Obeidi, F.; Mulcahy, M.; Pitt, V. S.; Begay, V.; Hadley, M. E.; Hruby, Victor J.

In: Journal of Pharmaceutical Sciences, Vol. 79, No. 6, 1990, p. 500-504.

Research output: Contribution to journalArticle

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abstract = "L-Glutamic acid (γ-4'-hydroxyanilide) (GHB) is oxidized by tyrosinase to a quinone which inhibits DNA polymerase, RNA polymerase, and mitochondrial energy production within mushrooms. It was previously shown that GHB can kill B16 melanoma cells in culture, but lacks cytotoxicity for nontyrosinase-containing cells. We have conjugated this drug to a superpotent melanotropic peptide and examined the bioactivity of this conjugate to melanoma cells. 4'-Hydroxyaniline was attached to glutamic acid at position 5 in the superpotent melanotropin fragment analogue, Ac-[Nle4, D-Phe7]α-MSH4-10-NH2. The melanotropin:anilide conjugate, Ac-[Nle4, Glu(γ-4'-hydroxyanilide)5, D-Phe7]α-MSH4-10-NH2, was not cytotoxic to B16 or Cloudman S91 mouse melanoma cells in culture, as determined by cell counts and protein assays. Interestingly, we also found that GHB stimulated melanoma cell tyrosinase above control levels in both melanoma cell lines. In our study, GHB itself also was found not to be cytotoxic to B16 or S91 melanoma cells in culture. In the frog skin bioassay, the melanotropin conjugate was more potent than α-MSH or Ac-[Nle4, D-Phe7]α-MSH4-10 in stimulating melanosome dispersion. These results demonstrate that putative chemotherapeutic ligands can be incorporated into active-site fragment analogues of MSH without loss of biological activity.",
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AU - Al-Obeidi, F.

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AU - Hadley, M. E.

AU - Hruby, Victor J

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