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Mitochondria QSARs Involving Chemical EffectsPowerPoint Presentation

Mitochondria QSARs Involving Chemical Effects

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MitochondriaQSARs Involving Chemical Effects

by Albert Leo

Pomona 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:
- Some antiviral nucleoside analogs display mitochondrial toxicity by inhibiting DNA polymerase-γ.
- The more hydrophobic NSAIDs act as UOP.
- Some mitochondrial toxicity of drugs depends upon free radical production.

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.

Chloroplasts

- The result of Intelligent Design, says Michael Behe (?)Are we intelligent enough to refrain from injuring them?

Mitochondrial Function

Protonophore: weak acid and hydrophobic (log P > 4)

Both ion and neutral forms in innter membrane.

Di-Aryl Amines as Non-Classical Uncouplers

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

- In most cases another (Y) group also present, and so 'buttressing" effect possible.
- McGowan volume and/or CMR may help explain the difference.

2,4-DNP, 6-t-Bu 'buttressing" effect possible.

pKa 4.80; logP 3.55

Pentachlorophenol

pKa 4.69; logP 5.12

Classical Uncouplers(Protonophores)- Set 599: I-50 respiration, rat liver mitochondriaLog 1/C = 1.73 CLOGP – 1.51 bilinCLOGP -0.51;n = 21; r2 = 0.89; OLP =~5.6

- Set 2257: 'buttressing" effect possible.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 = CH 'buttressing" effect possible.3 = BHT

R = P+(Ph)3 = Mito-BHT (ant-obesity lead)

2,4-DNP (1930s)

Uncouplers in Treatment of Obesity- Binds to adenine nucleotide translocase
- Lowers membrane potential (ΔΨm)

Fenfluramine 'buttressing" effect possible.

N-Nitroso analog

metabolism

- Mitochondrial toxicity: membrane swelling and release of Cyt-C.

Kebuzone - anti-rheumatic 'buttressing" effect possible.

Pharmaceuticals with UOP actionAmiodarone - anti-arrhythmic

Protonated logD ~ 5.0; inhibits complexes 1 & II

Complex I-II Inhibitors 'buttressing" effect possible.

Capsaicin Analogs

- Set 6878:log 1/C = 3.44 CLOGP – 0.28 (CLOGP)2 – 4.67n = 6; r2 = 0.98; OLP = 6.08

Complex I-II Inhibitors 'buttressing" effect possible.

Rotenone & Annonacin Analogs

- Set 10754:Log 1/C = 0.14 CLOGP + 7.7; n = 5; r2 = 0.93

Complex I-II Inhibitors 'buttressing" effect possible.

4,7-subs. Acridones

- Set 2373:Log 1/C = 0.74 CLOGP – 1.53 CLOGP2 – 1.36 σ4 + 3.36; n = 22; r2 = 0.90; OLP = 4.5

- Set 3877: 'buttressing" effect possible.Log 1/C = 0.67 CLOGP – 0.93 BiLin CLOGP - 0.35 I-Me + 1.51; n = 13; r2 = 0.86; OLP = 5.6

- Set 3876:log P = 0.73 CLOGP – 1.55 BiLinCLOGP + 1.16 I-3Me + 2.69; n = 12; r2 = 0.96; OLP = 5.65

INHIBITORS OF COMPLEX II (Succinic Dehydrogenase) 'buttressing" effect possible.

- 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 'buttressing" effect possible.

- Set 611: inhibition of succinate dehydrogenase in cinerea botrytis moldLog 1/C = 0.58 CLOGP + 0.043 NVE – 0.219; n = 21; r2 = .88
- Set 699: acting as fungicide on rice sheath blightLog 1/C = -19.9 MgVol + 5.3 MgVol2 + 21.7; n = 24; r2 = 0.88;Opt.vol. = 1.9

Complex II-III Inhibition 'buttressing" effect possible.

- Set 1557: Benzanilides as fungicides inhibiting Complex IILog 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 'buttressing" effect possible.

- Set 1720: Thiazole-anilides as fungicidesLog 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

Complex II-III Inhibition 'buttressing" effect possible.

- Set 2425: Carboxins inhibiting Complex II of yeast pathogen c. laurentiiLog 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 'buttressing" effect possible.

- 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

Complex IV Inhibition 'buttressing" effect possible.

- Set 3882: 4-quinolone analogs inhibiting bacterial cytochrome-CLog 1/C = 0.73 CLOGP – 0.83 bilinCLOGP + 0.53n = 12; r2 = 0.95; OLP = 5.86
- Set 4985: Very similar relationships with cytochrome-C from beef heart mitochondriaLog 1/C = 0.86 CLOGP – 1.29 bilinCLOGP + 2.82n = 21; r2 = 0.90; OLP = 6.35

- Set 7095: 'buttressing" effect possible.C for maximal respiration release in rat liver mitochondrialog 1/C = -1.33 σ - + 9.71; n = 5; r2 = 0.96
- Set 7096: C for inhibition of ATP synthesis in rat liver mitochondrialog 1/C = -1.26 σ -- + 9.56; n = 6; r2 = 0.90

anilino-thiadiazoles

Inhibitors of mammary sarcomas

Mitochondrial Function 'buttressing" effect possible.

Protonophore: weak acid and hydrophobic (log P > 4)

Both ion and neutral forms in innter membrane.

Chloroplast ATP Production 'buttressing" effect possible.

Triazine inhibitors of Plastoquinone 'buttressing" effect possible.

- 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

Ubiquinone CoQ in mitochondria 'buttressing" effect possible.

Plastoquinone (atrazine target) in chloroplastsComplex V Inhibition 'buttressing" effect possible.

- Set 8510: Salicylanilides on exchange of P with ATP in fly mitochondriaLog 1/C = 0.056 NVE + 1.00; n = 15; r2 = 0.95

Complex V Inhibition 'buttressing" effect possible.

- Set 9574: N,N’-diphenyl thiorureas inducing maximal release of state and respiration in rat liver mitochondriaLog 1/C = 1.91 σY = 0.54 L-X + 2.45; n = 12; r2 = 0.95

Anilino-Thiadiazoles 'buttressing" effect possible.

- Set 116: Rat liver mitochondria; 2-X-anilino-1,3,4-thiadiazoles; uncoupling oxidative phosphorylationLog 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-phosphorylationLog 1/C = 1.87 I(CF3) + 0.43 σ - + 3.5; n = 13; r2 = 0.9

Pendimethalin 'buttressing" effect possible.(UOP measured; contradicts 1999 EPA manual)

Trifluralin(UOP measured in plant mitochondria)

Uncouplers in Both Mitochondria & ChloroplastsOryzalin

(probable)

Measurement of Proton Gradient 'buttressing" effect possible.(ΔΨm)

- 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 'buttressing" effect possible.

- 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.

Consequence of Mitochondrial Dysfunction 'buttressing" effect possible.

- 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.

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