Exploring the Interaction of N/S Compounds with a Dicopper Center: Tyrosinase Inhibition and Model Studies

Tyrosinase (Ty) is a copper-containing
enzyme widely present in plants, bacteria, and humans, where it is
involved in biosynthesis of melanin-type pigments. Development of
Ty inhibitors is an important approach to control the production and
the accumulation of pigments in living systems. In this paper, we
focused our interest in phenylthiourea (PTU) and phenylmethylene thiosemicarbazone
(PTSC) recognized as inhibitors of tyrosinase by combining enzymatic
studies and coordination chemistry methods. Both are efficient inhibitors
of mushroom tyrosinase and they can be considered mainly as competitive
inhibitors. Computational studies verify that PTSC and PTU inhibitors
interact with the metal center of the active site. The KIC value of 0.93 μM confirms that PTSC is a much
more efficient inhibitor than PTU, for which a KIC value of 58 μM was determined. The estimation of the
binding free energies inhibitors/Ty confirms the high inhibitor efficiency
of PTSC. Binding studies of PTSC along with PTU to a dinuclear copper­(II)
complex ([Cu2(μ-BPMP)­(μ-OH)]­(ClO4)2 (1); H-BPMP = 2,6-bis-[bis­(2-pyridylmethyl)­aminomethyl]-4-methylphenol)
known to be a structural and functional model for the tyrosinase catecholase
activity, have been performed. Interactions of the compounds with
the dicopper model complex 1 were followed by spectrophotometry
and electrospray ionization (ESI). The molecular structure of 1-PTSC and 1-PTU adducts were determined by single-crystal
X-ray diffraction analysis showing for both an unusual bridging binding
mode on the dicopper center. These results reflect their adaptable
binding mode in relation to the geometry and chelate size of the dicopper
center.