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15 Cards in this Set
- Front
- Back
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3 major interactions with small molecules.
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- External electrostatics (polyamines)
- Groove binders (Netropsin) - Intercalators (Daunomycin) |
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Characteristics of Groove Binders
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- Pyrrol plus donor and acceptor groups that interact with A-N3 and T-O2 in the minor groove. Mainly hydrogen bond interactions. Increase overall entropy by substitution of water, no entropy change.
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Characteristics of Intercalators
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- Main stabilizing interaction in DNA is stacking. Sugar of Daunomycin interacts with PO3- of DNA, and rings intercalate.
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How does footprinting work?
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- Drug binds to DNA, and you can use DNase I to randomly cut DNA. Run a gel and see bases that you have. If you don't see some is because the drug is there.
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NMR
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- A ligand changes the way a proton is affected by a magnetic field. In upfield protons are shielded; in downfield protons are deshielded. The J coupling tell you how a proton influence the other, if it is 0 is because they are perpendicular to each other.
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2D-NMR
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- Besides decay there is also exchange spin that can be induced in protons that are close by.
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Nucleophile
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- Negatively charged, nucleus seeker.
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SN1 substitution
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- Formation of 1 carbocation, this is the slow step.
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SN2 substitution
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- Concerted step, two species involved in slow step, transition state. Reaction coordinate, energy of activation can be lowered by enzyme.
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Detoxification of epoxyde
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- This is an SN2 type reaction with inversion of configuration.
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Phase I
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- Activation or detoxification of Xenobiotic through P450. Oxidation of alcohol to carbonyl, of SH to S-S, of alkene to epoxide, oxydation of N-H to N-OH and the esterification. Reduction of NO2 to N-OH and then esterification. Hydrolysis (alkene to alcohol).
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Phase II
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- Conjugation of electrophiles of Phase I. Need a nucleophile. Instead of this DNA adduct formation.
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G adducts
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- Aflatoxin B1 or nitrogen mustard attack N7 or O6.
- Mytomicin C attacks N2 - Aromatic amines or nitroaromatics attack C8 |
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Triangle of Dipple
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- O6 (SN1) localized charge (hard atom) binds 1-naphthyl hydroxyl amine.
- N7 (SN2) MMS - N2 delocalized charge polycyclic hydrocarbons. - C8 - Aromatic amines or nitroaromatics |
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Reactivity-Selectivity Principle
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- More reactive alkylating agents are less discriminating. Oxygen more reactive. Depends on rate constants.
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