Selective coupling of methotrexate to peptide hormone carriers through a γ-carboxamide linkage of its glutamic acid moiety: Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate activation in salt coupling

A. Nagy, B. Szoke, A. V. Schally

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

A convenient synthetic method is described for the preparation of peptide-methotrexate (MTX) conjugates in which MTX is coupled selectively through the γ-carboxyl group of its glutamic acid moiety to a free amino group in peptide analogs. The syntheses of a somatostatin analog-MTX conjugate (MTX-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2) (AN-51) and two conjugates of analogs of luteinizing hormone-releasing hormone (LH-RH) with MTX [Glp-His-Trp-Ser-Tyr-D-Lys(MTX)-Leu-Arg-Pro-Gly-NH2] (AJ-04) and [Ac-Ser-Tyr-D-Lys(MTX)-Leu-Arg-Pro-NH-Et] AJ-51 are presented as examples. Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) was used in the synthesis for activation of 4-amino-4-deoxy-N10-methylpteroic acid, which reacted with the potassium salt of glutamic acid α-tert-butyl ester in dimethyl sulfoxide to form the suitably protected MTX derivative. This synthesis provides an example of the high suitability of BOP reagent for the salt-coupling method. The selectively protected MTX derivative was then coupled to the different peptide carriers and deprotected under relatively mild conditions by trifluoroacetic acid. The conjugates of MTX with hormonal analogs are suitable for targeting to various tumors that possess receptors for the peptide moieties.

Original languageEnglish (US)
Pages (from-to)6373-6376
Number of pages4
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number13
DOIs
StatePublished - Jul 1 1993
Externally publishedYes

Keywords

  • Chemotherapy agents
  • Cytotoxic peptides
  • Drug targeting
  • Site-selective conjugation

ASJC Scopus subject areas

  • General
  • Genetics

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