Alkylating angiotensin II analogs: Synthesis, analysis, and biological activity of angiotensin II analogs containing the nitrogen mustard melphalan in position 8

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Abstract
Melphalan derivatives suitable for peptide synthesis, i.e., Boc-Mel and Mel-OBzl.cntdot.HCl, were prepared, and the integrity of their nitrogen mustard alkylating groups were examined by NMR, Volhard chlorine analysis and colorimetric assay with 4-(p-nitrobenzyl)pyridine. By using the sensitive colorimetric assay, the stability of melphalan toward conditions commonly used for peptide synthesis, purification and bioassay was evaluated. Further qualitative and quantitative assessment of the integrity of nitrogen mustard groups in angiotensin II was attempted to evaluate the significance of the observed biological results. [Ac-Asn1,Mel8]angiotensin II was a potent competitive antagonist of angiotensin II in vitro (rat uterus) but a transient and reversible inhibitor in vivo.