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Chemistry 106

Lecture 10: Organic Functional Groups

4/19/18

Our consideration of the behavior of ionizable drugs in buffered environments

gives rise to 2 questions:

Question 1: Since ionizable drugs are pretty much ionized at blood pH, how do they

cross the non-polar portion of biological membranes? That is, if they dissolve well

in water, shouldn’t they have a hard time dissolving in the fatty portion of the cell

membrane?

Answer: The key is “pretty much”. Since an ionizable drug will go back and forth

between ionized and unionized state, it can slip through the cell when unionized (so

long as the unionized form is fairly nonpolar. Recall Sorbitol is never ionized but is

always very polar and cannot cross the cellular barrier).

As an interesting side note, if an ionizable drug can move across a cellular

membrane into a region of different pH, it may become trapped depending on the

pH of that region; e.g. speeding removal of basic drugs by acidifying the urine

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Drug of the Day, Pyrimethamine (Daraprim®)

Used in the treatment of protozoal infections, principally malaria (214 million

cases worldwide, resulting in 438,000 deaths. WHO 2016 malaria factsheet)

Inexpensive and extensively used for eradication programs in South America

and Asia, resistance has become commonplace (the first-line agent,

artemisinin, a traditional Chinese medicine isolated from sweet wormwood, is

also beginning to show resistance)

When used together with sulfadiazine, pyrimethamine may be used to treat the parasitic

infection toxoplasmosis, a rather rare protozoal infection that is seen more commonly in

cat fanciers who have AIDS.

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Question 2: Why do we bother to make the salt form of ionizable drugs in the first

place, if they are going to become ionized in the buffered environment of the

body?

Answer: Speed counts! How fast a drug will dissolve is important and the ionization

status of a drug has a large role to play. If you are injecting morphine IV, you

certainly don’t want the morphine to dissolve slowly as it occludes [blocks] the site

it was injected into. In fact, you want it already dissolved so it can be rushed by

the bloodstream to where it is needed. On the other end of the spectrum, if you

wanted a slow release of drug, an oil-based formulation injected into a large muscle

group may be possible. The classic example is Depot Provera®.

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Organic Functional Groups

There are certain arrangements of C, H, O, N, and X (where X is a halogen – F, Cl,

Br or I) that confer particular chemical and physical reactivities to organic

molecules (and thus drugs). Organic chemists refer to these as functional groups.

And there are 10 common ones. Most drugs contain more than 1 functional group,

as do the examples below – see if you can find all of them!

Alkenes

Contain a C=C double bond. General structure

R2

R3R1

R4 Where R = C or H

Drug example – vitamin A as an antioxidant vitamin. Also, as the molecule that

defines what light is to us (see last 4 pages)

O O

O

OH

O OH

HO.

.

Example: (-)-trans-9-tetrahydrocannabinol

Note that alternating double bonds in a 6-membered ring are not properly

considered alkenes – instead, these are “aromatic” compounds. Aromatic rings are

especially stable and as such are widely found in nature (and drugs which are either

derived from or mimic nature)

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Alkynes

Contain a C to C triple bond. General structure

R2R1 Where R = C or H

Drug example – ethinyl estradiol

Haloalkanes

Carbon based molecules with a halogen (F, Cl, Br, I) attached

Drug examples – volatile anesthetics

FCl

F F

Br H CF3

O

CF3

H

H

FH

Halothane (Fluothane) Sevoflurane (Ultane)

Unnatural in terrestrial systems and difficult for the biological world to deal with

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Ethers

Oxygen with carbon attached to either side. General structure

R1

OR2 Where R = C, cannot be H (or alcohol, water)

Drug examples – codeine, MDMA (Ecstasy)

Codeine MDMA

Example: (-)-trans-9-tetrahydrocannabinol

Notice the ether linkage is missing in cannabidiol (CBD, next page)

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Alcohols

Carbon attached to O which is attached to H. General structure

R1

OH

Where R = C

Drug examples – many! See adrenaline on group exercise 2 and estradiol above,

oxycodone below

The “eth” in ethanol means 2 carbon atoms connected together. The “ol” in

ethanol means it is an alcohol – thus there is no uncertainty about the

structure of ethanol

Question: Is ethanol a drug?

Alcohol reactions: readily oxidized to aldehydes and ketones. Acts as major means

of conjugating (linking together) different molecules - see esters below. Hugely

important to the removal of drugs since the liver possesses a system for adding an

alcohol group, thus polarizing the molecule and hastening its elimination (not to

mention terminating the activity of the drug in the vast majority of cases)

Example: Oxycodone

Examples: (-)-trans-9-tetrahydrocannabinol, and cannabidiol

Question: Why is cannabidiol named cannabidiol?

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Amines

Drug examples – many! See all the stimulant drugs written as bond-line formulas in

lecture 3, and all of the plant alkaloid drugs mentioned to date. General structure

R1N

R2R3 Where R = C or H (but not all 3 R = H or ammonia)

N

N

(S)-nicotine

In addition to promoting a sense of calm, nicotine is a terrific insecticide

Main reaction: weak base - ionizable when treated with acid. Make certain you can

distinguish between an amine and an amide – amides have an adjacent C=O and are

not basic

Aldehydes

C double bonded to O on end of molecule. General structure

R1

O

H Where R = C, H (if H, formaldehyde)

Few examples of aldehyde drugs, as they rapidly oxidize to carboxylic acids.

Example: Vanillin…ok, not really a drug (unless perhaps when mixed with cacao)

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Ketones

C double bonded to O in interior of molecule. General structure

R1

O

R2 Where R = C, not H (if H, aldehyde)

Drug example – hydrocodone

Hydrocodone

Reactions: May be reduced to alcohol, do not oxidize to acids. As such found in

many drugs. Biological example of reduction to alcohol

OH

O

O

NADHOH

O

OH

Good Bad

Carboxylic Acids

General structure RCO2H, or

R1

O

OH Where R = C, H

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Drug examples: Non-steroidal anti-inflammatory drugs

OO

OH

Naproxyn

Reactions: ionizable when treated with base. Condenses with alcohols to form

esters, condenses with amines to form amides

Esters

Condensation between carboxylic acid and alcohol, spitting out water. General

Structure

R1

O

OR2

Where R1 = C, H R2 = C (if H, a carboxylic acid)

Drug examples: Shorter acting local anesthetic agents

Procaine Benzocaine

Cocaine

Reaction: May be hydrolyzed (split with water) to carboxylic acid and alcohol

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Amides

Condensation between carboxylic acid and amine, also spitting out water. General

structure,

R1

O

NR2

R3 Where R = C, H

Drug examples: Longer acting local anesthetic agents. Antibiotics (penicillins and

cephalasporins)

Lidocaine

N

S

OCO

2H

NH H

O

Benzylpenicillin(Penicillin G)

Reaction: May be hydrolyzed (split with water) to carboxylic acid and amine

Proteins are formed from amino acids, where the amine on one amino acid condenses

with the acid portion on another amino acid, which continues over and over

H2O

Serine Cysteine

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On Vision, Vitamin A and the Light Cycle

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11-cis-retinal (bent) binds to the protein opsin giving rise to rhodopsin (visual

purple)

Light strikes the 11-cis-retinal causing it to isomerize to 11-trans-retinal

(straight)

Since the 2 forms of retinal have different shapes, they change the shape

of the protein containing the retinal from rhodopsin to metarhodopsin.

By interacting with a protein [transducin] inside the rod cell, metarhodopsin

II ultimately keeps Na+ from entering the cell, which leads to a nerve

impulse interpreted in the brain as vision

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Taken from the Jülich Institute of Structural Biology and Biophysics

http://www2.fz-juelich.de/isb/isb-1//Photoreception