Free Radical

Reactions

Robert Pavletic
 Definition of a Free Radical
-A free radical is a molecule that
contains an unpaired electron

Common notation of a
free radical
 Formation of a Free Radical
-Pairs of electrically neutral free radicals are formed via
homolytic bond breakage
-One common method uses light to cleave a diatomic
molecule into two free radicals
-Another method involves heating in non-polar solvents or
the vapour phase, at high temperatures molecular species
will dissociate into radicals
 Initiation, Propagation and
Termination
• In any given radical reaction there are 3 main steps; Initiation,
propagation and termination
• Initiation is the step in which the free radicals are created
• Once a reactive free radical is formed, it can react with stable
molecules to create new free radicals. This allows new
molecules to be added in a chain reaction. This is the
propagation step
• The final step is to terminate the radicals, often done by
reacting with another radical. This is the termination step.
From paper 1
Paper 1
Free radical oxidation of cholesterol and its
precursors: Implications in cholesterol
biosynthesis disorders
L. Xu ∗ & N. A. Porter
Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University,
Nashville, TN, USA
Introduction
• Cholesterol is abundant in mammalian cells and tissues, and
plays important roles in maintaining plasma membrane
integrity, lipid-raft-mediated cell signaling , activation of the
hedgehog pathway during embryonic development and
myelin formation
• Free radical oxidation of cholesterol and its precursors
contribute significantly to the pathophysiology of a number of
human diseases including Smith–Lemli–Opitz syndrome,
atherosclerosis , Alzheimer ’ s disease, retinal degeneration,
age-related macular degeneration, cataract and Niemann –
Pick C1 disease
Purpose
• The paper Intends to summarize recent
developments and provide a perspective on the
reactivity's of sterols toward free radical oxidation,
the free radical reaction mechanism, and the
biological consequences of oxysterols derived from
the highly oxidizable cholesterol precursor.
Bloch Pathway Kandutsch-Russel
Pathway
Reactivity's of cholesterol and it’s precursors toward
free radical oxidation
• The propagation of the peroxy radical is the rate-determining
step in the free radical oxidation of lipids-2 possible processes
• 1) Hydrogen atom is transferred from a donor to the chain-
carrying peroxyl radical
• 2) A peroxyl radical adds to a double bond
Radical intermediates of cholesterol and it’s
precursors via hydrogen atom transfer
Radical intermediates of cholesterol and it’s
precursors via peroxyl radical addition
1) kH per H-atom is
shown in the
parentheses.
2) Number of
substituents on the
delocalized radical
intermediates.
3) Dihedral angles
between the reactive
C – H and the double
bond plane and the
values in the
parenthesis show the
diff erence from 90 ° .
4) Dihedral angles
between the planes
containing individual
double bond.
5) endo : radical
delocalize within the
same ring; exo :
radical delocalize
across rings.
6) The angle between
the planes C 5,6,7 and
C 7,8,9
7) The angle between
C 5,6,7 and C 7,8,14 .
h value was obtained
by extrapolating the
rate constants of
oleate and linoleate
using their computed
bond dissociation
enthalpy
 Reactivity of Sterols
• The reactivity of the unsaturated sterols is higher than their
acyclic fatty acid analogs and their more flexible cyclic analogs
(such as cyclohexene or cyclohexadienes)
• Better hydrogen donors
• Sterols normally have more alkyl substituents on double
bond(s) than those in fatty acids(lowers activation energy)
• The dihedral angles between the reactive C – H bond and the
adjacent double bond and the planarity the two double
bonds(minimum amount of molecular reorientation is
required to reach the transition state)
• Dienes that adopt cisoid conformations tend to be more
reactive than those adopting trannll soid conformations
 7-dehydrocholesterol (7-DHC)
• 7-DHC is the most reactive cholesterol precursor
• 7-DHC’s normal function is as a precursor to vitamin D3
• This paper examined 7-DHC and it’s derived oxysterols and their
possible role in Smith–Lemli–Opitz syndrome(SLOS)
• SLOS displays a broad spectrum of phenotypes including multiple
congenital malformations, neurological defects, mental
retardation, autism-like behavior, and photosensitivity
Formation of derived oxysterols
Addition of oxygen to free radical intermediates will create
oxysterols

There are three possible positions where oxygen can be added

which determines the stereochemistry of the product
Products of the radical reaction of 7-DHC
Biological consequences of 7-DHC-derived
oxysterols and their role in SLOS
• 7-DHC acted as an excellent hydrogen donor to linoleate peroxyl radicals in
oxidations carried out in liposomes
• 7-DHC has a high reactivity toward oxidation in a biological environment.
• Products generated from photooxidation of 7-DHC induced growth retardation of
cultured rat embryos
• From biological studies of the 7-DHC derived oxysterols the endoperoxide moiety
showed high levels of toxicity(2).
• The 7-DHC oxysterols were also found to affect expression of gene transcripts
related to lipid biosynthesis and cell growth
Conclusions
• More rigid and more substituted sterol structure makes
cholesterol and its precursors more reactive toward free
radical oxidation than the acyclic structures found in fatty acid
• Sterols tend to be more reactive than unstaurated fatty acids
containing the same number of double bonds
• 7-DHC,was closely associated with the pathophysiology of the
human disease Smith–Lemli–Opitz syndrome.
• Continued investigation of the biological activities of the 7-
DHC-derived oxysterols may ultimately lead to new therapies
that may counter the effect of these oxysterol