Left: 1,3,4-Thiadiazole

Right: 1,2,5-Thiadiazole

Name these molecules

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Left: s-Triazole

Right: 1-H-1,2,4-Triazole

Name these molecules

[image]

Left: Oxazolidin-2-one

Right: Oxazolidin-2,4-dione

Name these molecules

[image]

Left: 3H-1,4-benzodiazepine

Right: 1H-1,4-benzodiazepine

If DG is negative, then we have a spontaneous reaction.

DG = DH - TDS

Enantiomers are stereoisomers that are mirror images of each other.

Diastereoisomers are stereoisomers, however they are not mirror images.

When you have a proton (H) on N, you need at least 3 resonance forms.

Amide is not acidic because it only has 2 resonance forms.

p > 0.5 is lipophilic

p < 0.5 is hydrophilic

p = Sp

1. Determine functional groups
2. Look on chart to determine solubility
3. Add up number of carbons it will dissolve
4. Compare to number of carbons in molecule

1. Determine functional groups
2. Determine if each functional group is acidic, basic or neutral
3. Determine the pKa of each functional group (look at the chart)
4. Use the 2-unit rule to determine the pH that will form a salt at that particular location.

Acids are soluble in buffers 2 units above their pKa

Bases are soluble in buffers 2 units below their pKa

Quats are quaternary ammonium ions

ALWAYS soluble in water and at ALL pH buffers

Primarily in the liver.

However, enzymes for xenobiotic-metabolism are found in nervous tissue, kidney, lung, plasma, GI tract

Loss of Electrons is Oxidation (LEO)

Gain of Electrons is Reduction (GER)

LEO goes GER

σ < 0

More prone to oxidation

Examples are amino and hydroxy functional groups on a conjugated system

σ > 0

less prone to oxidation

Examples are a nitro or sulfonamide on a conjugated system

1. Determine functional groups
2. Determine if functional groups are acidic, basic or neutral
3. Determine form of that functional group at specified pH
4. Determine if system is pi-excessive or pi-deficient

Esters

Amides

Carbamates

Ester hydrolysis will always give you a carboxylic acid and alcohol as products.

The bond is broken between the two oxygens in the ester.

Carboxylic acid and primary amine (NH₃ if terminal)

Esters

Amides

Carbamates

Nitriles

Hydrolysis

O-dealkylation

N-dealkylation

Azo Reduction

Nitro Reduction

Products are generally phenolic and the position of hydroyl group can be influenced by the type of substituents on the ring

Electron-donating substituents enhances para- and ortho-hydroxylation

Electron-withdrawing substituents reduce or prevent meta-hydroxylation

Example:  for monosubstituted benze compounds, para-hydroxylation usually predominates with some o-products

Dealkylation of secondary and tertiary amines to yield primary and secondary amines, respectively

Typical N-substituents removes include methyl, ethyl, n-proply, n-butyl, and benzyl

The breaking of an ether into alcohols

Increased chain length or branching reduces the rate of dealkylation

Example:  codeine metabolized into morphine

Part of Phase I Metabolism

Reducing an azo group (-NN-) into two primary amines

Part of Phase I Metabolism

Reducing nitro group (-NO₂) to primary amine

A glucose is attached to xenobiotic substrates, catalyzed by UDP-glucoronyltransferases.

Phenols and alcoholic hydroxyls are the most common functional groups to undergo this reaction.

Hard drugs are compounds designed to contain the structural characteristics necessary for pharmacological activity, but in a form that is not susceptible to metabolic or chemical transformation.  Toxic metabolites are avoided, efficiency of action is increased, and less readily elimination is reduced.

Soft drugs are active compounds that after exerting their desired pharmacological effect are designed to undergo metabolic inactivation to give a nontoxic product.  These are considered to be the opposite of prodrugs.

Carrier-linked prodrugs are drugs which have been attached through a metabolically labile linkage to another molecule.

Bioprecursor prodrugs are drugs that contain no promoiety, but rather rely on metabolism to introduce the function necessary to create an active species.

Polymer-drug (conjugates)

Dendrimers

Micelles

Advantages

1. Slow degredation time
2. water soluble
3. avoid liver and spleen
4. control where and when drug is released

Disadvantages

1. Low drug-carrying capacity (PEG carries only 2 drug molecules)
2. Formation of structures due to folding

Advantages

1. Higher carrying capacity (up to 25% of wt.)
2. small size
3. snythesis is much easier and consistent

Disadvantge

Move in and out of tumor tissue very rapidly

Advantage

May be viewed as "natural biomolecule

Disadvantage

Low carrying capacity