Design, synthesis and chemical reactivity of 1,4-naphtoquinone derivatives as cysteine protease irreversible inhibitors

MEDI 70

Claudia Valente, cvalente2@sapo.pt1, Rui Moreira1, Rita C. Guedes1, Jim Iley2, Mohammed Jaffar3, and Kenneth T. Douglas3. (1) CECF, Faculty of Pharmacy, University of Lisbon, Avenida das Forças Armadas, 1600-083 Lisboa, Portugal, (2) Chemistry Department, The Open University, UK, MK7 6AA Milton Keynes, United Kingdom, (3) School of Pharmacy and Pharmaceutical Sciences, University of Manchester, UK, Oxford Road, M13 9PL Manchester, United Kingdom
Quinones are a unique class of compounds that can function (i) as redox cyclers and as (ii) electrophiles via Michael-type addition leading to covalent modification of thiols of vital components. Atovaquone, a hydroxy-1,4-naphtoquinone, used as antiprotoazoal drug is a clear evidence that the potentially high reactivity of this scaffold can be modulated. Papain-like cysteine proteases play crucial roles in diseases such as osteoporosis, rheumathoid arthritis, cancer, and in a wide variety of parasitic infections. In this work, a series of 1,4-naphthoquinone derivatives were found to inhibit papain and bovine spleen cathepsin B in an irreversible manner. The chemical reactivity of the compounds towards cysteine as a model thiol is dependent on the naphthoquinone LUMO energy, whereas papain inactivation is not.

 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, August 20, 2007 BCEC -- Exhibit Hall - B2, Sci-Mix

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007