The Electronic Structure of Distorted Porphyins and Cobalt Schiff Base Derivatives as Novel Enzyme Inhibitors

Citation

Takeuchi, Toshihiko (1996) The Electronic Structure of Distorted Porphyins and Cobalt Schiff Base Derivatives as Novel Enzyme Inhibitors. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/py88-c390. https://resolver.caltech.edu/CaltechTHESIS:11052009-085123252

Abstract

Halogenated porphyrins, which are catalysts for the oxidation of alkanes, were studied by semiempirical AM 1 calculations. The calculations predicted the effects of halogenation of the porphyrin ring on UV-visible absorption spectra and electrochemical data. Predictions regarding the stability of catalysts were made, and have been experimentally verified. INDO/S semiempirical calculations were performed on a series of porphyrins to understand the effects of a highly disfavored distortion that is conserved in cytochromes c. The highest occupied molecular orbitals were destabilized, and the orbital energy of the metal and the lowest unoccupied orbitals change, causing a shift in the redox potential of the heme and a change in the electron transfer properties of cytochromes c. In order to delineate the anti-enzymatic properties of Co(acacen) derivatives, which are potent inhibitors of the herpes virus, carbonic anhydrase (CA), thermolysin (TL), and thrombin (TH) were chosen as targets Inhibition of CA occurs upon incubation with the novel water-soluble Co(II)hydroxypropylacacen (Co(II)hpr) but not with [Co(III)hpr(NH_3)_2 ^+(OAc)^- . The difference in reactivity of the species is a consequence of the steric limitations imposed by the axial ligands bound to the Co(III) complex. [Co(III)acacen(NH_3)_2^+ irreversibly inhibits TL, and this inhibition was prevented by binding a strong reversible inhibitor to the active site of the enzyme before addition of the cobalt species, suggesting that cobalt-acacen derivatives can inhibit enzymes by binding to active site histidines. In an effort to develop more potent and selective enzyme inhibitors, active site-directed peptides were coupled via a peptide bond through a carboxylic acid, which is part of the acacen ligand framework. The peptide coupled derivatives rapidly and irreversibly inhibited TH, and the potency of inhibition was over an order of magnitude better than the uncoupled components.

Thesis Files