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N ε Functionalization of Metal and Organic Protected L ‐Histidine for a Highly Efficient, Direct Labeling of Biomolecules with [Tc(OH 2 ) 3 (CO) 3 ] +
Author(s) -
Pak Jae Kyoung,
Benny Paul,
Spingler Bernhard,
Ortner Kirstin,
Alberto Roger
Publication year - 2003
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200204445
Subject(s) - histidine , chemistry , moiety , bioconjugation , stereochemistry , amine gas treating , derivatization , phenylalanine , protecting group , yield (engineering) , urea , derivative (finance) , medicinal chemistry , combinatorial chemistry , amino acid , organic chemistry , materials science , biochemistry , alkyl , high performance liquid chromatography , economics , financial economics , metallurgy
Abstract Two different pathways for the introduction of an acetyl group at N ε in a N α , N δ , and ‐COO protected histidine to afford N ε ‐(CH 2 COOH)‐histidine derivative 7 b are presented. The purpose of this study is the coupling of 7 b to amino groups in bioactive molecules such as peptides. After full deprotection of such a bioconjugate, histidine provides three coordination sites which efficiently coordinate to [ 99m Tc(OH 2 ) 3 (CO) 3 ] + or [Re(OH 2 ) 3 (CO) 3 ] + in a facial geometry. This allows the development of novel radiopharmaceuticals. Selective derivatization at the N ε position has conveniently been achieved by concomitant protection of N α and N δ with a carbonyl group forming a six‐membered urea. Cyclic urea ring opening with Fm‐OH, coupling of phenylalanine as a model to 7 b through its primary amine and removing of all protecting groups in one step gave a histidine derivative of phenylalanine which could be labeled at 10 −5 M with 99m Tc in very high yield and even in about 50 % yield at 10 −6 M . The Xray structure of a complex with [Re(CO) 3 ] + in which anilin is coupled to 7 b confirms the facial arrangement of histidine. A second pathway applies directly the [Re(CO) 3 ] + moiety as a protecting group. This is one of the rare examples in which a metal fragment is used as a protecting group for organic functionalities. The coordination to histidine protects the N α , N δ and COO group in one single step, subsequent alkylation with BrCH 2 COOH(R) at N ε , coupling to phenylalanine and oxidative deprotection of [Re(CO) 3 ] + to [ReO 4 ] − gave the corresponding bioconjugate in which histidine is coupled to phenylalanine through an acetylamide at N ε . Both methods offer convenient pathways to introduce histidine in a biomolecule under retention of its three coordination sites. The procedures are adaptable to any biomolecule with pendant amines and allow the development of novel radiopharmaceuticals or inversed peptides.