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Bioorg Med Chem. 2014 Mar 1;22(5):1558-67. doi: 10.1016/j.bmc.2014.01.037. Epub 2014 Jan 30.

Synthesis of 2,6-disubstituted benzylamine derivatives as reversible selective inhibitors of copper amine oxidases.

Author information

1
Dipartimento di Farmacia, Università di Genova, Via Brigata Salerno, 13, 16147 Genova, Italy.
2
Dipartimento di Farmacia, Università di Genova, Via Brigata Salerno, 13, 16147 Genova, Italy. Electronic address: bertini@difar.unige.it.
3
Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Viale G. Pieraccini, 6, 50139 Firenze, Italy.

Abstract

In order to obtain substrate-like inhibitors of copper amine oxidases (CAOs), a class of enzymes involved in important cellular processes as well as in crosslinking of elastin and collagen and removal of biogenic primary amines, we synthesized a set of benzylamine derivatives properly substituted at positions 2 and 6 and studied their biological activity towards some members of CAOs. With benzylamines 6, 7, 8 containing linear alkoxy groups we obtained reversible inhibitors of benzylamine oxidase (BAO), very active and selective toward diamine oxidase (DAO), lysyl oxidase (LO) and monoamine oxidase B (MAO B) characterized by a certain toxicity consequent to the crossing of the brain barrier. Poorly toxic, up to very active, reversible inhibitors of BAO, very selective toward DAO, LO and MAO B, were obtained with benzylamines 10, 11, 12 containing hydrophilic ω-hydroxyalkoxy groups. With benzylamines 13, 14, 15, containing linear alkyl groups endowed with steric, but not conjugative effects for the absence of properly positioned oxygen atoms, we synthesized moderately active inhibitors of BAO reversible and selective toward DAO, LO and MAO B. The cross examination of the entire biological data brought us to the conclusion that the bioactive synthesized compounds most likely exert their physiological role of reversible inhibitors in consequence of the formation of a plurality of hydrogen bonds or hydrophobic non-covalent interactions with proper sites in the protein. Accordingly, the reported inhibitors may be considered as a set of research tools for general biological studies and the formation of enzyme complexes useful for X-ray structure determinations aimed at the design of more sophisticated inhibitors to always better modulate the protein activity without important side effects.

KEYWORDS:

2,6-Disubstituted benzylamines; Copper amine oxidases; Formylation; Metalation; Reversible inhibitors

PMID:
24529308
DOI:
10.1016/j.bmc.2014.01.037
[Indexed for MEDLINE]

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