PAPER www.rsc.org/pps | Photochemical & Photobiological Sciences
Photophysical characterization of atorvastatin (Lipitor
R
) ortho-hydroxy
metabolite: role of hydroxyl group on the drug photochemistry†
Emilio Alarc´ on,
a
Mar´ ıa Gonz ´ alez-B´ ejar,
a
Serge Gorelsky,
a
Roberto Ebensperger,
b
Camilo Lopez-Alarc´ on,
b
Jos´ e Carlos Netto-Ferreira*
a,c
and Juan C. Scaiano
a
Received 28th April 2010, Accepted 9th August 2010
DOI: 10.1039/c0pp00102c
The influence of the phenolic hydroxyl group of ortho-hydroxy atorvastatin metabolite (Ato-OH) on the
photochemistry of atorvastatin (Ato) has been evaluated by steady and time-resolved experiments.
Direct excitation of Ato and Ato-OH led to phenanthrene-like intermediate formation, being ~30% for
Ato-OH less efficient than that for its parent compound in methanol. Both, Ato and Ato-OH are able
to quench benzophenone (E
T
~69 kcal mol
-1
) and xanthone (E
T
~74 kcal mol
-1
) triplet excited state
with rate constants close to diffusion limit control which suggest energy transfer mechanism is taking
place. In fact, lower triplet energies ~63 kcal mol
-1
and p,p* character, were confirmed by DFT
calculations for both compounds. Interestinlgy, only Ato-OH can act as a hydrogen donor towards
triplet benzil excited state (E
T
~ 54 kcal mol
-1
)due to the presence of the phenolic hydroxyl group.
Nevertheless, the presence of this group in Ato-OH does not modify to a significant degree the
compound reactivity toward singlet oxygen. The importance of triplet energy transfer in biological
systems to form Ato and Ato-OH triplet excited state as well as the hydrogen donor capacity of
Ato-OH toward triplet excited state are discussed in the present communication.
Introduction
Nowadays there are several well-known pathways of chemiex-
citation at the cellular level, which are dependent on enzymes
with oxygenase type activity. These lead to the formation of
excited triplet states without previous light absorption. In fact,
in a series of pioneering contributions, Cilento et al.
1–4
showed
the production of the triplet excited state of several molecules in
reactions such as enzymatic activity, radical recombination or dis-
proportionation, dioxetane decomposition or lipoperoxidation.
4
In biological systems, almost all triplet excited states are effi-
ciently trapped by dissolved oxygen giving rise to singlet oxygen
5
and/or superoxide anion.
6
Nevertheless, the interaction with other
molecules such as drugs, proteins and nucleic acids and their
constituents can be an alternative pathway to deactivate the
triplet excited state. These processes can take place by different
mechanisms:
7
(i) triplet–triplet energy transfer to other molecules
in the ground state, (ii) hydrogen abstraction by a triplet carbonyl
from a phenolic compound, (iii) cycloaddition, leading to oxetane
formation through a reaction between n,p* triplet carbonyls and
thymine or thymidine, (iv) electron transfer such as in the oxidation
a
Department of Chemistry and Centre for Catalysis Research and Innovation,
University of Ottawa, Ottawa, Ontario, Canada K1N 6N5
b
Departamento de Farmacia, Facultad de Qu´ ımica, Pontificia Universidad
Cat´ olica de Chile. C.P., 782 0436, Santiago, Chile
c
Departamento de Qu´ ımica, Universidade Federal Rural do Rio de Janeiro,
Antiga Rio-S˜ ao Paulo km 47, Serop´ edica, 23851-970, Rio de Janeiro, Brazil
†Electronic Supplementary Information (ESI) available: Transient ab-
sorption spectra for Ato-OH and Ato after laser excitation at 266 nm in
methanol, normalized singlet oxygen emission time profiles (at 1270 nm)
in the absence or in the presence of Ato and benzophenone triplet–triplet
transient absorption spectra after 2.0 ms laser excitation at 355 nm: in
the absence or in the presence of 56 mM of Ato or Ato-OH. See DOI:
10.1039/c0pp00102c/
of guanine and finally (v) physical triplet deactivation (collisional
processes).
7,8
The efficiency for (i) and (ii) will be dependent on
the triplet energy of the acceptor, the nature of the triplet excited
state, and on the phenolic bond strength, respectively. It is obvious
that the presence of a phenolic group in a molecule can favour
hydrogen abstraction leading to production of phenoxyl radical,
which only occurs when the triplet energy of the species containing
the phenolic group is higher than that for the triplet carbonyl.
A representative example of a compound containing a phenolic
group in its molecular structure without major differences
in its biological function relative to the parent compound
is the ortho-hydroxy metabolite of atorvastatin ([3R,5R]-2-
fluoro-phenyl-b-d-dihydroxy-5-(1-isopropyl)-3-phenyl-4-[(2-
hydroxyphenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, see
Scheme 1). Atorvastatin (Ato) is a drug commonly prescribed
under the name of Lipitor
R
from Pfizer. It is able to inhibit
the enzymatic activity of 3-hydroxy-3-methylglutaryl coenzyme-
A (HMGCoA) reductase, which is a fundamental enzyme
for cholesterol synthesis.
9,10
Ato has also been employed in
lipid disorders therapy related to atherosclerotic processes
9
and
Alzheimer’s treatment.
11
Oxidative processes, among other factors,
have been suggested to be responsible for these degenerative
illnesses
12
and several studies have been performed in order to
Scheme 1 Chemical structure of Ato (left) and its ortho-hydroxy metabo-
lite (right).
1378 | Photochem. Photobiol. Sci., 2010, 9, 1378–1384 This journal is © The Royal Society of Chemistry and Owner Societies 2010