increased drug safety - avoiding reactive metabolites
DESCRIPTION
This is an educational presentation directed towards professionals working with drug design. At the end of the presentaion it is demonstrated how the web application SpotRM provides facilitated learning about mechanisms of reactive metabolite generation from drugs.TRANSCRIPT
Reactive Metabolites -
Hints How to Avoid a Drug Safety Hazard Alf Claesson
© 2012 Awametox Consulting, Stockholm, Sweden. Contact: +4670 553 7131, [email protected]. LinkedIn
Reactive
Metabolite
Reactions
with DNA
Reactions
with proteins
Drug
The liver is usually
the first casualty
Problems…problems…problems…problems..problems…problems…
2
Modified from Gerry Kenna and Roger
Bonnert, AstraZeneca
Reactive
Metabolite (RM)
Reactions
with DNA
Reactions
with proteins
• An important cause of drug-induced illness
and fatality, e.g. DILI= Drug Induced Liver Injury
• A major concern for drug industry and regulators
• Low-dose drugs cause less/no problems
Mutagenicity
Carcinogenicity
Teratogenicity
- Benzidine
- Safrole
Target organ toxicity
(reproducible or
idiosyncratic)
- Paracetamol
- Diclofenac
Immune
hypersensitivity
reactions
(idiosyncratic)
- Antibacterial sulfon-
amides
- Halothane
Drug
The liver is usually the
first casualty
NH2
NH
S
OO
N
N OH
Br
Cl
F
F
F
3
Slightly modified from Steve Swallow (AZ Drug Safety) at the SCI Conference ”Designing Safer
Medicines in Discovery: Current and Emerging Opportunities to Reduce Attrition”, 25th March 2011
Substructural alerts
Genotox/RM
Reactive cpd
Toxic metabolite
(e.g. forms F-acetic
acid)
logP
Light sens.
Solubility
Stability
+ ADME person
Substance related failures of drugs are of great concern
Drug safety is a major cause of drug attrition.
It will take a very long time before we can predict all hazards
This presentation highlights one factor, i.e. metabolism to reactive
species
– Indeed, we can hope to master this cause of attrition! By
experimentation and increased knowledge
Potency in secondary
test model
Potency in primary test model
Practical
synthesis
Pharmacokinetics
Decreased off-target
I potency
Patent issues
Solubility (for
example)
LeadCD
Decreased off-
target II potency
Not efficient
22%
Toxicology
32% Clinical
safety
12%
DMPK
8%
Portfolio
11%
Other reasons
15%
5
The different fates of reactive species formed by enzymatic action
In the scheme below “I” represents a drug which acts as an irreversible inhibitor of a P450 enzyme
– The general term is Mechanism Based Inhibition (MBI) – also known as suicide inactivation/inhibition.
– Indicated by in vitro experiments where enzymes lose activity by time, Time Dependent Inhibition (TDI)
P= RM Covalent binding to
macromolecules
Reaction with water or
glutathion (inactivation)
Extensive MBI of CYPs by a drug is worrysome since it often
leads to interference with metabolism of other drugs (DDI).
There is good correlation between covalent binding of a drug to
proteins and TDI. Nakayama et al. Drug Met Disp 2011, 54, 1247
Reactions that do not occur in most patients at any dose.
But please don’t call them dose independent; drugs given at a dose of
10 mg/day or less are relatively safe!
Characteristics suggest immune mechanism
Also known as hypersensitivity reactions, allergic reactions, type B
reactions, type II reactions
Idiosyncratic Drug Reactions (Jack Uetrecht’s definition)
6
Some toxicity is reproducible and dose-dependent in animals, e.g. that of paracetamol (acetaminophen). This is referred to as Type A toxicity.
For some drugs toxicitiy in man is unpredictable from animal research and is relatively infrequent. This is referred to as Type B toxicity (truly idiosyncratic).
7
In real life
Picture to the right from a
presentation by Jack
Uetrecht. Skin injuries are
a common sign of allergic
drug reactions.
Etiologies of acute liver failure in
the US (n = 1,321). Data from the
Acute Liver Failure Study Group
registry, 1998–2008 (W. M. Lee).
Abbreviations: AIH = autoimmune
hepatitis; BCS = Budd–Chiari
syndrome; HAV = hepatitis A virus; HBV
= hepatitis B virus; IDR = idiosyncratic
drug reaction.
acetaminophen
Drugs associated with IADRs
Drugs Withdrawn
Aclcofenac (antiinflammatory)
Hepatitis, rash
Alpidem (anxiolytic)
Hepatitis (fatal)
Amodiaquine (antimalarial)
Hepatitis, agranulocytosis
Amineptine (antidepressant)
Hepatitis, cutaneous ADRs
Benoxaprofen (antiinflammatory)
Hepatitis, cutaneous ADRs
Bromfenac (antiinflammatory)
Hepatitis (fatal)
Carbutamide (antidiabetic)
Bone marrow toxicity
Ibufenac (antiinflammatory)
Hepatitis (fatal)
Iproniazid (antidepressant)
Hepatitis (fatal)
Metiamide (antiulcer)
Bone marrow toxicity
Nomifensine (antidepressant)
Hepatitis (fatal), anaemia
Practolol (antiarrhythmic)
Severe cutaneous ADRs
Remoxipride (antipsychotic)
Aplastic anaemia
Sudoxicam (antiinflammatory)
Hepatitis (fatal)
Tienilic Acid (diuretic)
Hepatitis (fatal)
Tolrestat (antidiabetic)
Hepatitis (fatal)
Troglitazone (antidiabetic)
Hepatitis (fatal)
Zomepirac (antiinflammatory)
Hepatitis, cutaneous ADRs
Marketed Drugs
Abacavir (antiretroviral)
Cutaneous ADRs
Acetaminophen (analgesic)
Hepatitis (fatal)
Captopril (antihypertensive)
Cutaneous ADRs, agranulocytosis
Carbamazepine (anticonvulsant)
Hepatitis, agranulocytosis
Clozapine (antipsychotic)
Agranulocytosis
Cyclophosphamide (anticancer)
Agranulocytosis, cutaneous ADRs
Dapsone (antibacterial)
Agranulocytosis, cutaneous ADRs,
aplastic anaemia
Diclofenac (antiinflammatory)
Hepatitis
Felbamate (anticonvulsant)
Hepatitis (fatal), aplastic anaemia
(fatal), severe restriction in use
Furosemide (diurectic)
Agranulocytosis, cutaneous ADRs,
aplastic anaemia
Halothane (anesthetic)
Hepatitis
Imipramine (antidepressant)
Hepatitis
Indomethacin (antiinflammatory)
Hepatitis
Isoniazid (antibacterial)
Hepatitis (can be fatal)
Phenytoin (anticonvulsant)
Agranulocytosis, cutaneous ADRs
Procainamide (antiarrhythmic)
Hepatitis, agranulocytosis
Sulfamethoxazole (antibacterial)
Agranulocytosis, aplastic anaemia
Terbinafine (antifungal)
Hepatitis, cutaneous ADRs
Ticlopidine (antithrombotic)
Agranulocytosis, aplastic anaemia
Tolcapone (antiparkinsons)
Hepatitis (fatal)
Trazodone (antidepressant)
Hepatitis
Trimethoprim (antibacterial)
Agranulocytosis, aplastic anaemia,
cutaneous ADRs
Thalidomide (immunomodulator)
Teratogenicity
Valproic acid (anticonvulsant)
Hepatitis (fatal), teratogenicity
Temp. Withdrawn
or Withdrawn in
other Countries
Aminopyrine (analgesic)
Agranulocytosis
Nefazodone (antidepressant)
Hepatitis (> 200 deaths)
Trovan (antibacterial)
Hepatitis
Zileuton (antiasthma)
Hepatitis
For most of these drugs, bioactivation to reactive metabolites has been demonstrated in vitro or in vivo
Kalgutkar AS and Soglia JR (2005).
Exp. Opin. Drug Metab. & Toxicol. 1:91-141)
Anticancer drugs are visibly absent from the lists.
9
Recent failures of drugs that were on the market
Lumiracoxib (Prexige® from
Novartis) launched 2003-
2004, withdrawn autumn
2007 due to reports of
serious liver adverse
events
NH
O
Cl
F
OH
Sitaxentan (Encysive Pharma) was
withdrawn in 2010 after having been on
the European market for only four years.
This compound has obvious liabilities
regarding hazard for RM formation, yet
no proven link between ADRs and RMs.
C l
ON
N H
S OO
S
O
O
O
S
O
OO
Alkyl
Alkyl halides and sulfonates
[Br,I,Cl]
Electrophilic esters
SNAr electrophiles
N
A
[F,Cl,Br] N
A
OSO2R
Wide variety of structures! (EWG= electronwithdrawing group)
[F,Cl]
EWG
OO
ArO
O
O NH
Oxiranes and aziridines
OSO
2
Michael acceptors
Awareness/avoidance of intrinsic reactivity
[F ,C l]
E W G
Very useful presentation at SCI
Conference, March 25, 2011, on
”Designing Safer Medicines in
Discovery”
Title: ChEMBL & Structural Alerts
By Francis Atkinson
Chemogenomics Group
EMBL – EBI, Hinxton
http://www.soci.org/News/Fine-Safer-Medicines-2011-Papers.aspx
10
11
Shortlived electrophilic intermediates are formed from most drugs during ‘detoxification’
- Imines and iminium ions from alkylamines
- Epoxides from double bonds
- Unsaturated carbonyls
Do not cause a safety problem unless
- Defence mechanisms are overwhelmed
- Key macromolecules are altered - manifested by organ and/or immune toxicity.
RMs can have selective affinity to certain macromolecules
- Genotoxicity vs. other organ tox?
- Structure Reactivity Relationships poorly understood
Reactive metabolites (RMs) from xenobiotics
N+
O
from paracetamol (acetaminophen); not extremely
shortlived. Quinoid species very common as RMs.
Most RM-
forming
reactions are
Phase 1
reactions
Most common RMs
listed at StopRM.org
where references to
reviews are also listed.
12
Phase 1 reactions, i.e. oxidative (cytochromes P-450), reductive (-NO2), and hydrolytic pathways. These are behind most of the RM generation.
Phase 2 reactions, i.e. conjugation reactions like sulfatation and glucuronidation, in general less prone to cause problems by RM generation.
- Important exceptions are formations of nitrene, quinoid and carbenium ion species which are initialized by acetylation, sulfatation, and more
- Formation of acylglucuronides and acyl-CoA thioesters as acylating agents
Metabolic reactions that can generate RMs
All dependent on context - just like organic synthesis…
OOO
O
OH
OH
OH
O
R R= rest of the
drug
R S
O
CoA
Skonberg et al. Exp Op DM Tox 4
(2008) 425
Review
The molecular mechanism of genotoxicity by aromatic amines
Persistent
mutations caused
by intercalated
adducts in hotspots
of DNA lead to
cancer
Repairs
Primary target atom
Nitrenium ion
or nitrene
N H
N N H
N N
O
N H 2
H
N
d R
N N H
N N
O
N H 2
d R
N
+ H + P450
+
+ H +
+
N H 2
N H
N N H
N N
O
N H 2
H
N
d R
N N H
N N
O
N H 2
d R
N
Guanine-rich
DNA motif
CYP1A2 Acetyltransferases
H +
+
• Only 30% of arylamines follow this path
• Rate of HO-N formation and nitrenium ion stability
determine mutagenicity.
Sulfotransferases
N ..N
+ H
N
Reactive nitroso
compounds can also be
formed from anilines
and nitro compounds
DNA products, CRT 2003
See Shamowsky et al. JACS 2011, 133, 16168, and McCarren et al. J
Cheminfo 2011, 3:51
14
Precursors of RMs
Phenyls/benzene – Can form arene oxides and quinoid species
– Problem substituents: nitro, amino (anilines and masked anilines)
– Halo substituents – influence fate of arene oxides
– Alkoxy groups (facilitate hydoxylation and also undergo dealkylation)
– Alkyl groups on aromatics HO-alkyl eliminations to reactive quinomethanes (benzoquinone methides)
Heteroaryls – Thiophenes
– Thiazoles
– Furans, and more…
Other groups – Many, e.g. alkenes ( allylic alcohols), alkynes, alkyl
halides. Also carboxylic acids (form acylglucuronides and thioesters), and more…
Aromatics
Heteroaromatics
Aliphatics
Oxidations by cytochromes P-
450, FMNs, peroxidases
Reduction
15
Epoxides, especially on aromatic rings (‘arene oxides’)
Benzene very frequent group in drug candidates
– Lots of varied substituents and fusions
– Indispensible to medicinal chemists?
RMs formed by epoxidation of the ring
– Labile arene oxides are formed
– As an example, 1,2-naphtalene oxide
was isolated in 1968 by famous NIH
scientists (Daly, Jerina, Witkop et
al. JACS 50 6525)
– Enzymatic inactivation/detoxification
by epoxide hydrolases and/or
GSH S-transferases (also
by direct reaction
with GSH)
GSH is used in vitro to trap RMs and thus indicate/measure their presence
‘NIH shift’ O
More easily formed than
benzene oxide, E =
70.1 and 59.8 kcal/mol,
respectively (Mats
Svensson, AZ).
Glutathione (GSH)
mM conc. in hepato-
cytes
CYP O
R
OH
SG
R
OH
OH
R
OH
R
GSH
H2O
Enzyme
Rearr.
16
Characteristics of dangerous epoxides
Not inactivated fast enough (in relation to
amounts formed)
Toxic quantities able to reach and modify
macromolecules
Learning from experience is possible:
– Polyaromatic oxides are known carcinogens, being
stabilized arene oxides, e.g from benzopyrene
– Other epoxides also have insidious behaviour -
balanced and targeted reactivity towards sensitive
proteins/DNA
O
O
O
‘Stable’ epoxide
from toxic -
naphtoflavone.
Aflatoxins easily form
epoxides on their fused
dihydrofurans (lead to
1,4-dioxo compounds)
O
O
O
O
O O
H
H
NO
NH2
O
‘Stable’ epoxide from
carbamazepine
Lamotrigine is known to form epoxide(s)
NH2
N
NH2
N
N
Cl
Cl
NH2
N
NH2
N
N
Cl
Cl
OCl
N
N
NH2
N
NH2
Cl
GS
NH2
N
NH2
N
N
Cl
Cl
OH
GS
Human
P450 2A6.Rat P4502C11
GSH - H2O
M-I M-II
Maggs et al. (2000) and Chen et al. (2009). Both research groups conclude that
a reactive, but somewhat stabilized, epoxide is formed. Formed in minor
amounts in vivo (reaction products isolated from bile only). Notably, it is also
formed in keratinocytes.
The isomeric analogue irsogladine, a PDE4 inhibitor, is metabolized to an
epoxide via a major pathway. This isomerizes to phenols (Sugiyama et al.
Arzneimittelforschung 1986, 36, 1229)
N
N N
Cl
Cl
NH2
NH2
N
N N
Cl
Cl
NH2
NH2
O
N
N N
Cl
Cl
NH2
NH2
OH
Quinoids comprise a major category of RMs
O
[C,N,O]
R
OH
[C,N,O]
R
OH
[C,N,O]
Nu
RNuP450 or
otherenzyme
In this large group the electrophilic system consists of a quinone, a quinone-
imine, a quinone-diimine, or the corresponding methides, the quinone
methides (quinomethanes) and quinone-imine methides. Only the para isomers
are depicted below.
Testa et al. (Drug Disc Today 2012, 17, 549) have analysed the literature and
conclude: “A markedly greater source of worry and potential toxicity is seen
with redox reactions, most significantly with the formation of quinones,
quinonimines, quinonimides and quinone-diimines, which accounted for 40%
of all toxic and/or reactive metabolites identified in this work.”
In addition, from the abstract of a review (Monks et al. Current Drug Metab
2002): Quinones are ubiquitous in nature and constitute an important class of naturally occurring
compounds found in plants, fungi and bacteria… For example, the quinones of polycyclic aromatic
hydrocarbons are prevalent as environmental contaminants and provide a major source of current
human exposure to quinones. ... . Quinones are oxidants and electrophiles, and the relative
contribution of these properties to quinone toxicity is influenced by chemical structure,
in particular substituent effects.
All roads lead to Rome…or to quinoids (1)
From phenols diphenols quinones
When R= X-H the formation of a phenol or aminophenol is facilitated.
Even more facilitation….
Real drug examples exist NH
F
RO
NH
F
RN
O
R
- HF
O
XH
OH
X
O
X
OH
XH
X = O,N
1,4-elimi-nation
Oxid.Rearr.
O
R OH
ROALK
R
OH
OH
R
O
O
R
OH
OH
Nu R
O
OH
MeR
NuOxid. Oxid.
COMT
19
All roads lead to Rome…or to quinoids (2)
Quinone methides (quinomethanes) and quinone-imine methides.
Thompson et al. studied the phenol below (Toxicology 2001, 160, 197).
OH
OS
O
O
O
[O,N]
H
H
[N,O][O,N]
OH
H
- H2OOxid.
OH OOH
OH
When the benzylic alcohol forms
a sulfate (via SULT enzymes)
the elimination is even faster
The sulfates of the
corresponding 4-
alkoxy-benzylic
alcohols would also
be quite reactive.
O
OS
O
O
O
R
20
All roads lead to Rome…or to quinoids (3)
Spontaneous loss of HF gives rise to a reactive, toxic species (Thompson et al. 2000)
Merck cpd published in 2005.
Decomposes to a carboxylic acid
on standing in a water solution
Order of events can be different (Kalgutkar et al. DMD 2007)
The example also shows that the leaving group can be a ”phenol”
Lefluonomide is a licensed
rheumatoid arthritis drug.
Instability due to isoxazole
ring opening dominates. No
reports of imine-methide
formation.
OH
F
FF
O
FF
- HF
NH
O NO
OH
F
F F
F
N
NH
FO
O
F
NH
N N
N
OCl
N
N
OCl
OH
R
Cl
O
Cyp
N
N
OR
21
22
Paracetamol can be directly oxidised to a reactive acetylated quinoneimine
Massive amounts of NAPQI will
exhaust GSH reserves
N
O
O
N
O
O
S
R
NH
O
OH
S
R
NH
O
OH
R-SHOx. Proton
shifts
NAPQ
Well-known quinoid-forming motifs of real drugs
Kassahun, K. Studies on the Metabolism of Troglitazone to Reactive Intermediates in Vitro and in Vivo. Chem Res Toxicol
2001, 14, 62
O
OH
O
S
NH
O
O
O
O
O
S
NH
O
O
O
OH
GS
R
The thiazolidine ring might also
entail RM problems. But these are
not significant in low-dose
rosiglitazone (Avandia®, GSK) and
pioglitazone (Actos®, Lilly).
Troglitazone - withdrawn from the market.
23
Oxidation of heteroaromatics
Acyl glucuronides (AGs) and acyl-CoA as
RMs
Special case – the antiepileptic felbamate
Formation of acyl halides (halothane)
A few other mechanisms of RM formation are shown on the following four slides
24
Heteroaromatics can also cause problems
Thiophenes form epoxide and/or S-oxides (tienilic acid, a
diuretic drug, is a classic example; withdrawn 1982)
– The epoxide can also hydrolyse and ring-open
– Simple thiophenes largely abandoned within AZ
Thiazoles can also cause problems
S
O
O COOH
Cl
Cl
S+
R
O
S R
Nu
S R
O
S R
Nu
S R
Nu(p450
)
OH
NuH
Add.-Elim.
NuH
Tienilic acid
+
OS
NH
Duloxetine (Cymbalta®)
does not appear to
show RM tox problems.
Daily dose is 60 mg.
Thiabendazole (an
anthelmintic), given
1-3 g/day shortterm
NH
N
S
N
NH
N
O
O S
NH2
H+P450
Invoked mechanisms: – Direct acylation (of amino groups)
– In theory, the acyl glycoside can isomerize by acyl migration to expose a free aldehyde (semiacetal) which can react with amines and rearrange further.
Rare proven cases. Benzoic acids don’t have AG problems whereas aryl acetic acids (many NSAIDs) might have
– Many NSAIDs withdrawn from the market because of hepatotoxicity. Mechanism? Most stuctures have other potential liabilities stemming from aromatic substructures, e.g. zomepirac
25
Reviews: Skonberg et al. Exp Op DM Tox 4
(2008) 425.
Bailey & Dickinson. Chemico-Biological
Interactions 145 (2003) 117/137
Acyl glucuronides (AGs) and acyl-CoA as RMs
From AZ workshop 2007: “The poorly defined link
between acyl glucuronides and toxicity was considered not to reflect evidence of
absence (of such a link), but rather absence of evidence (of such a link).”
Zomepirac,
withdrawn 1984
or O
O H
O H
OH
OO
O
O
R R
O
NH
R 1R 1-N H 2R S
O
CoA
O
R
O
O
NH
OH
OHO
O
Prot
O
N
OH
OCl
O
O
N H2
O
NH2
O
O H
O
NH2
O
O
O
NH2
O
H O H
O
N H
O
O
H
NH
N
Alb
O
N
NAlb
H
E s te ra s e s
A lc o h o ld e h yd ro -g e n a s e
F o rm e d v ia s p o n -ta n e o u s lo s s o f c a rb a m ic a c id
26
Special case – the antiepileptic felbamate
Mechanism
Reaction of the isolated hemiaminal 1 with albumin
(Alb) was studied by Roller et al. in Chem Res Tox
2005, 15, 815. They concluded that conjugate
addition mainly goes via a histidine residue.
1
Within a year of its release in 1993
• 34 cases of aplastic anemia resulting in 13 deaths (Incidence rate 1:4800 – 1:37000)
• 23 cases of hepatotoxicity resulting in 5 deaths (Incidence rate 1:18000 – 1:25000
Black box warning (severe restriction in use)
• thousands of patients estimated to be on drug
Note
No glutathione
conjugates in liver
microsomes and human
hepatocytes.
No covalent binding to
liver microsomes and
human hepatocytes.
27
Volatile anaesthetics and hepatotoxicity
Halothane – introduced1956,
“Delayed” liver injury in ~1: 3000 patients who receive multiple exposures,
and liver failure in ~1: 30,000
Enflurane - introduced in UK in 1981
“Delayed” liver injury in ~1: 100,000 patients who receive multiple exposures
Isoflurane - introduced in UK in 1984
Very rare case reports of “Delayed” liver injury, ~ <1: 100,000 patients who
receive multiple exposures
Sevoflurane - introduced in 1990, initially in Japan
Currently one of the most widely prescribed volatile anaesthetics in developed
nations. Rare case reports of “delayed” liver injury, from Japanese literature;
Desflurane - introduced 1956
Currently one of the most widely prescribed volatile anaesthetics in
developed nations. A few isolated case reports of “delayed” liver injury
F C C
F
F
Br
H
Cl
F C C
F
F
O
Cl
F C C
F
F
O
Protein
CYP 2E1
Halothane TFA-Cl TFA-protein
Mechanism of
halothane
activation
28
Resources on reactive metabolites
Literature reviews (see comprehensive list on stoprm.org), e.g.
– Kalgutkar et al. (Pfizer), have written many reviews; large one from 2005*
– Uetrecht – perspectives
– Baillie – 20 years experience…
Presentations – Some available on the Internet. Also search for presentations at
http://www.slideshare.net.
– A Claesson has collated several presentations at stoprm.org
Databases etc. – SpotRM is a new web application available at spotrm.com
• Structures and text can be searched. Mechanisms of RM formation detailed.
– ’MDL METAB’, now from Accelrys, available to many industrial chemists and
ADMET persons
• Excellent source of metabolite structures
– Mechanism Based Toxicity Database (MBT), from GVK Biosciences
– Lhasa Limited is a resource center that provides info on software and knowledge
– ChEMBLdb (recently added: new drug approvals), Chemspider, and ChemPub
Other resources – Directory of computer-aided Drug Design tools (ADME Toxicity)
* A Comprehensive Listing of Bioactivation Pathways of Organic Functional Groups. 65 pages
Highlighted on next slides
SpotRM is a freely accessible web application that
facilitates learning about how to avoid introducing
RM liabilities into new test compounds
Hits Name and
type of
drug
Market
status
Link to
mechanism
and more info
Link to
mechanistic
context
Clozapine Withdrawn
(largely)
Clozapine M6523
Quetiapin
e
On the
market
(2011)
Clozapine
Mechanism in Context
C l
N
N
N
NH
N
S
N
N
OH
O
These electrophiles (here BQI) are acceptors of nucleophiles in proteins such as amines and
thiols which might lead to antigen formation and to loss of, or impaired, function. They are
also electron acceptors which, in the context of toxicology, could lead to interference with
biochemical processes where electron transport is occurring. For example, quinones are
highly redox active molecules which can redox cycle with their semiquinone radicals, leading
to formation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and
ultimately the hydroxyl radical. Production of ROS can cause severe oxidative stress within
cells through the formation of oxidized cellular macromolecules, including lipids, proteins,
and DNA (review by Bolton et al. 2000).
Fig 2. Unsubstituted o- and p-quinoneimines.
O
O
Nu
H
H
H
R
OH
OH
Nu
RO
O
R
NuH
redox cycling oxidative stress
O
NH NH
O
Fig 1. Addition of a nucleophile to a
substituted p-benzoquinone followed
by rearomatization. This can be
followed by a new round of oxidation-
addition. Also, quinones can accept
electrons and generate radicals.
Draw a structure to make a
substructure search
Or type a textword: generic
name or other word (brand
names are not searchable).
Hits are presented in a table con-
taining links to details of current
hypotheses of how a drug forms
reactive metabolites.
The mechanism is also placed in
context of similar reactions .
Hypothesis of
Mechanism
Avoiding reactive metabolites
© 2012 Awametox Consulting, Sweden. Contact: [email protected]
Schematics
Avoiding reactive metabolites
© 2012 Awametox Consulting, Sweden. Contact: [email protected]
The search results lead to expert reports and to original literature data
Hypothesis of Mechanism
Mechanism in Context (text
document on 3-7 pages)
These electrophiles (here BQI) are acceptors of nucleophiles in proteins such as amines and
thiols which might lead to antigen formation and to loss of, or impaired, function. They are
also electron acceptors which, in the context of toxicology, could lead to interference with
biochemical processes where electron transport is occurring. For example, quinones are
highly redox active molecules which can redox cycle with their semiquinone radicals, leading
to formation of reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and
ultimately the hydroxyl radical. Production of ROS can cause severe oxidative stress within
cells through the formation of oxidized cellular macromolecules, including lipids, proteins,
and DNA (review by Bolton et al. 2000).
Fig 2. Unsubstituted o- and p-quinoneimines.
O
O
Nu
H
H
H
R
OH
OH
Nu
RO
O
R
NuH
redox cycling oxidative stress
O
NH NH
O
Fig 1. Addition of a nucleophile to a
substituted p-benzoquinone followed
by rearomatization. This can be
followed by a new round of oxidation-
addition. Also, quinones can accept
electrons and generate radicals.
Original
literature
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