Synthesis and Biological Assessment of Furoquinolines, Pyrroloquinolines and Analogues towards Cholinesterases and Monoamine Oxidases

A broad spectrum of possible functions of Cu-AOs, ranging from cell adhesion, cell growth regulation, to clinical applications are described. Their action may be related to the control of H 2 O 2 levels as they are reported to be inactivated by the same H 2 O 2 they produce, upon prolonged exposure to amine in excess over oxygen. This was demonstrated in pea seedling and pig kidney amine oxidase, and in bovine serum amine oxidase (BSAO). For the latter enzyme, inactivation by aldehydes, assisted by H 2 O 2 , was also reported. H 2 O 2 , which was formerly considered as an undesirable toxic product of oxygen reduction, is now believed to be involved in the regulation of cellular functions as intracellular messenger [1]. A condition for inactivation was the TPQ cofactor of BSAO to be in reduced form. Then, the TPQ reduced form was stabilized by inactivation, since a band appeared at 310 nm in the uv-vis difference spectrum with respect to native BSAO, while the reactivity with carbonyl reagents decreased. The Cu 2+ EPR signal was not affected by inactivation, but, as reported above, a radical of low intensity formed at g = 2.001. The radical might derive from a conserved residue in proximity of the active site, such as the tyrosine at hydrogen-bonding distance of TPQ ionized hydroxyl, which becomes ionized upon TPQ reduction. The proposed mechanism of inactivation was confirmed in Lathyrus cicera (red vetchling) amine oxidase (LCAO) [2], which, at difference from BSAO, forms the Cu +-semiquinolamine radical, with a characteristic uv-vis spectrum, when oxygen is exhausted by an excess of amine in a closed cuvette. The inactivation, lasting about 90 min, is simultaneous with the radical decay and with the formation of a broad band (shoulder) at 350 nm. No inactivation occurs, when a thousand-fold excess of amine is rapidly oxidized in a LCAO solution stirred in open air. Thus, the inactivation is a slow reaction of the reduced enzyme with H 2 O 2 , following the turnover phase. Catalase protects LCAO from inactivation. This effect is substrate-dependent, varying from full protection (benzylamine) to no protection (putrescine). In absence of H 2 O 2 , a specific inactivating reaction, without formation of the 350 nm band, is induced by some aldehydes, notably putrescine. The inactivation by H 2 O 2 may be part of an auto-regulatory process in vivo, possibly …