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11/14/2008
1
MitochondriaQSARs Involving Chemical
Effects
by Albert LeoPomona College Medicinal Chemistry Project (1969-1993)
BioByte Corp. (1993-present)
The Role of Mitochondria
in Pharmacotoxicology
• “The role of mitochondria in pharmacotoxicology:
a reevaluation of an old, newly emerging topic” (R.
Scatena, et al, Am. J. Physiol. Cell Physiol, 293,
C12-C21, 2007) points out:
1. Some antiviral nucleoside analogs display
mitochondrial toxicity by inhibiting DNA
polymerase-γ.
2. The more hydrophobic NSAIDs act as UOP.
3. Some mitochondrial toxicity of drugs depends
upon free radical production.
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Mitochondria in QSAR• 149 equations dealing with mitochondria
• 1290 unique chemical structures
• Available as a SMILES file on www.biobyte.com
• 26 equations containing 6-X-2,4-dinitro-
phenols
Beginnings of Cellular Life• In Beginnings of Cellular Life, Harold
Morowitz (Yale University Press, 1992)
says: “spontaneous formation of closed
membrane vesicles was the initiating
event in cellular evolution.”
• They maintain separate stable phases in an
aqueous environment.
• They maintain different chemical
compositions between intra- and extra-
cellular compartments.
• They maintain substantial trans-bilayer
electrical voltages, pH differences, and
oxidation potentials.
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Precursors of Chloroplasts &
Mitochondria
• The result of Intelligent Design, says Michael Behe (?)Are we
intelligent enough to refrain from injuring them?
Mitochondria
Chloroplasts
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Mitochondrial
Function
Protonophore: weak acid and hydrophobic (log P > 4)
Both ion and neutral forms in innter membrane.
Fluazinam - anti-fungal
• Set 2447:
log 1/C = 0.18 pKa – 1.57 bilin(pKa) + 0.65 log P’ +
4.67; n = 22; r2 = 0.96; OpKa = 6.96
Di-Aryl Amines as Non-Classical
Uncouplers
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X ‘Normal’ π Special’ π #Expls
2-Cl +0.72 -0.01 3
4-Cl +0.72 -0.02 3
3-CF3 +0.90 +0.01 3
2-F +0.14 -0.07 1
2-Br +0.87 -0.24 2
3-CH3 +0.51 -0.31 1
4-OCF3 +1.00 -0.18 1
• In most cases another (Y) group also present, and so 'buttressing" effect
possible.
• McGowan volume and/or CMR may help explain the difference.
Classical Uncouplers
(Protonophores)
2,4-DNP, 6-t-Bu
pKa 4.80; logP 3.55Pentachlorophenol
pKa 4.69; logP 5.12
• Set 599: I-50 respiration, rat liver mitochondria
Log 1/C = 1.73 CLOGP – 1.51 bilinCLOGP -0.51;
n = 21; r2 = 0.89; OLP =~5.6
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• Set 2257:
1/C = -0.46 pKa + 2.07 P-F + 0.76 P-P + 0.07 NVE +
12.2; n = 39; r2 = 0.96
Malonoben (SF-6847)insecticide
R = CH3 = BHT
R = P+(Ph)3 = Mito-BHT (ant-obesity
lead)
• Binds to adenine nucleotide translocase
• Lowers membrane potential (∆Ψm)
Uncouplers in Treatment of
Obesity
2,4-DNP (1930s)
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• Mitochondrial toxicity: membrane swelling and
release of Cyt-C.
Fenfluramine
N-Nitroso analog
metabolism
Pharmaceuticals with UOP
action
Amiodarone - anti-arrhythmicProtonated logD ~ 5.0; inhibits complexes 1 & II
Kebuzone - anti-rheumatic
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Capsaicin Analogs
Complex I-II
Inhibitors
• Set 6878:
log 1/C = 3.44 CLOGP – 0.28 (CLOGP)2 – 4.67
n = 6; r2 = 0.98; OLP = 6.08
Rotenone & Annonacin Analogs
Complex I-II
Inhibitors
• Set 10754:
Log 1/C = 0.14 CLOGP + 7.7; n = 5; r2 = 0.93
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4,7-subs. Acridones
Complex I-II
Inhibitors
• Set 2373:
Log 1/C = 0.74 CLOGP – 1.53 CLOGP2 – 1.36 σ4 +
3.36; n = 22; r2 = 0.90; OLP = 4.5
2,3-alkyl-Quinolones
• Set 3876:
log P = 0.73 CLOGP – 1.55
BiLinCLOGP + 1.16 I-3Me + 2.69;
n = 12; r2 = 0.96; OLP = 5.65
• Set 3877:
Log 1/C = 0.67 CLOGP – 0.93 BiLin
CLOGP - 0.35 I-Me + 1.51;
n = 13; r2 = 0.86; OLP = 5.6
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INHIBITORS OF COMPLEX
II (Succinic Dehydrogenase)
• Prototype: 3-nitropropionic acid (3-NP):
O2N-CH2-CH2-CO2H
• A natural phytoalexin; present in loco
weed (Astragalus); animal toxin.
• Human toxin in fungal-contaminated
sugar cane (China)
• Used as neurotoxin model for
Huntington's disease
Complex II-III
Inhibition
• Set 611: inhibition of succinate dehydrogenase in cinerea
botrytismold
Log 1/C = 0.58 CLOGP + 0.043 NVE – 0.219; n = 21; r2 = .88
• Set 699: acting as fungicide on rice sheath blight
Log 1/C = -19.9 MgVol + 5.3 MgVol2 + 21.7; n = 24; r2 = 0.88;
Opt.vol. = 1.9
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Complex II-III
Inhibition
• Set 1557: Benzanilides as fungicides inhibiting Complex II
Log 1/C = 1.04 CLOGP – 1.7 Bilin CLOGP -1.48 Es-X2 – B1-R2 -
1.17 σR + 1.33; n = 32; r2 = 0.89; OLP = 5.28
Complex II-III
Inhibition
• Set 1720: Thiazole-anilides as fungicides
Log 1/C = 0.64 CLOGP + 0.95 σ + 1.2 I 2,6 + 3.89; n = 42; r2 =
0.85
• I2,6 shows that di-ortho substitution is especially strong
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Complex II-III
Inhibition
• Set 2425: Carboxins inhibiting Complex II of yeast pathogen c.
laurentii
Log 1/C = -1.95 B1-4 – 0.72 σ – 1.32 I2,6 + 7.9; n = 14; r2 = 087
• In this set, 2,6-disubstitution weakens inhibitory action.
Complex IV Inhibition
• Set 1006: Inhibition of cytochrome-C from horse
heart mitochondria by alkanols (including -diols)
Log 1/C = 0.35 log P – 0.70; n = 7; r2 = 0.91
• Set 1643: Inhibition of cytochrome-C by catechols
(from same source)
Log 1/C = -5.83 σ + 2.80; n = 9; r2 = 0.97
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Complex IV Inhibition
• Set 3882: 4-quinolone analogs inhibiting bacterial
cytochrome-C
Log 1/C = 0.73 CLOGP – 0.83 bilinCLOGP + 0.53
n = 12; r2 = 0.95; OLP = 5.86
• Set 4985: Very similar relationships with cytochrome-C
from beef heart mitochondria
Log 1/C = 0.86 CLOGP – 1.29 bilinCLOGP + 2.82
n = 21; r2 = 0.90; OLP = 6.35
• Set 7095: C for maximal respiration release in rat
liver mitochondria
log 1/C = -1.33 σ - + 9.71; n = 5; r2 = 0.96
• Set 7096: C for inhibition of ATP synthesis in rat
liver mitochondria
log 1/C = -1.26 σ -- + 9.56; n = 6; r2 = 0.90
anilino-thiadiazolesInhibitors of mammary sarcomas
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Mitochondrial
Function
Protonophore: weak acid and hydrophobic (log P > 4)
Both ion and neutral forms in innter membrane.
Chloroplast ATP
Production
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Triazine inhibitors of
Plastoquinone
• Set 2252:
Log 1/C = 0.61 log P -0.96 bilinLogP -0.24 WRB-X -0.2
D-Y -0.51 T1-Y -2.8 I-Me + 8.46;
n = 47; r2 = 0.89; OLP = 4.5
Plastoquinone (atrazine target) in
chloroplasts
Ubiquinone CoQ in mitochondria
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Complex V Inhibition
• Set 8510: Salicylanilides on exchange of P with ATP in fly
mitochondria
Log 1/C = 0.056 NVE + 1.00; n = 15; r2 = 0.95
Complex V Inhibition
• Set 9574: N,N’-diphenyl thiorureas inducing maximal release of
state and respiration in rat liver mitochondria
Log 1/C = 1.91 σY = 0.54 L-X + 2.45; n = 12; r2 = 0.95
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Anilino-
Thiadiazoles
• Set 116: Rat liver mitochondria; 2-X-anilino-1,3,4-
thiadiazoles; uncoupling oxidative phosphorylation
Log 1/C = 1.01 I(CF3) -2.13 σ + 8.83; n = 11; r2 =
0.89
• Set 117: Spinach chloroplasts; 2-X-anilino-1,3,4-
thiadiazoles; uncoupling photo-phosphorylation
Log 1/C = 1.87 I(CF3) + 0.43 σ - + 3.5; n = 13; r2 =
0.9
Uncouplers in Both Mitochondria &
Chloroplasts
Pendimethalin(UOP measured; contradicts 1999 EPA manual)
Oryzalin(probable)
Trifluralin(UOP measured in plant mitochondria)
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Measurement of
Proton Gradient
(∆Ψm)
• Now available as a simple kit; e.g.
Molecular Probes B-34,950, Mitotracker
• Why not used during drug and pesticide
development? Basis for QSARs?
• MTT Assay for mitochondrial reductase:
could it be basis for QSAR?
Acknowledgements
• Dr. Gilman Veith: for his support, both moral
and financial.
• Prof. Corwin Hansch: for his skill and
persistence in accumulating and organizing
the data for so many QSARs.
• Prof. Toshio Fujita: for his insight in creating
and applying QSARs.
• Mr. Michael Medlin: for preparing the slides
for this presentation.
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Consequence of
Mitochondrial Dysfunction
• Production of ROS (e.g. H2O2) from non-phosphorylating
respiration results in oxidative stress.
• Disability of aging most commonly ascribed to this oxidative
stress
• mDNA not as well protected nor as easily repaired as nDNA
• Mit.-dysfunction signaled to nucleus via RR (retrograde
response) but this fails thru extensive use.
• In simpler life forms (yeast, C.elegans) a deficiency in
complex IV (cytochrome-c) lengthens life span, but "quality of
life" not a concern.
• Could be a major factor in degenerative
diseases: Parkinson's, Alzheimer's, neuropathy, myopathy,
Type II Diabetes. etc.