Bioinspired Cu(II) complexes with tunable axial donors: unravelling structure-function correlations in phenoxazinone...

Area of Science:

• Bioinorganic Chemistry
• Catalysis
• Medicinal Chemistry

Background:

• Phenoxazinone synthase (PHS) is a multi-copper oxidase essential for Actinomycin D biosynthesis.
• PHS catalyzes the oxidative coupling of o-aminophenol (OAP) to form phenoxazinone chromophores.
• Actinomycin D is a crucial anticancer agent.

Purpose of the Study:

• To design and synthesize mononuclear copper(II) complexes emulating PHS copper sites.
• To investigate the effect of tunable axial donor atoms (N, O, S) on complex geometry, redox potential, and catalytic activity.
• To elucidate the mechanistic basis of PHS activity through experimental and computational studies.

Main Methods:

• Synthesis and full characterization of three copper(II) complexes (1, 2, 3) with varying axial donors.
• Spectroscopic techniques (e.g., UV-Vis, EPR) for structural and electronic analysis.
• Density Functional Theory (DFT) and time-dependent DFT (TDDFT) for computational modeling.

Main Results:

• Complexes 1 (N4), 2 (N3O), and 3 (N3S) were synthesized and characterized.
• Axial donor substitution systematically altered geometry, redox potential, and OAP oxidation catalytic efficiency.
• Complex 2 (N3O) showed superior substrate binding and catalytic activity (2 > 3 > 1) for OAP to APX conversion.
• DFT studies confirmed experimental findings on geometry and electronic structure, highlighting increased Cu-ligand covalency in complex 2.

Conclusions:

• Subtle modifications in the coordination sphere significantly impact copper complex electronic structure, redox behavior, and catalytic performance.
• The N3O complex demonstrates enhanced catalytic efficiency, providing insights into PHS mechanism.
• This study offers a mechanistic rationale for phenoxazinone synthase activity and guides the design of novel bio-inspired catalysts.