More Introduction Part II

Question 1

What are factors affecting drug solubility?

Answer 1

Drug interactions with water
pKa
Log p
Size of the molecule
Conformation freedom (number of freely rotatable bonds)

Question 2

What is the molecular weight of the majority of drugs on the market?

Answer 2

The majority are less than 500 Da

Question 3

How does the number of rotatable bonds affect bioavailability?

Answer 3

The higher the number of rotatable bonds, the lower the bioavailability will be

Question 4

Why do we care about the number of rotatable bonds?

Answer 4

Typically a drug will have to be in a single conformation to cross a membrane and drugs usually adopt one or a few conformations to bind to a receptor or transporter. This means that the more conformational freedom, the less time it will spend in the correct conformation for optimal absorption or binding

Question 5

What are Lipinski’s rule of fives (overall)?

Answer 5

A series of guidelines that determine if a chemical compound with pharmacologic activity can be absorbed orally i.e., does the drug have the chemical properties that will make it have significant absorption and distribution from an oral dosage form to make it a marketable drug?

Question 6

What are Lipinski’s rules of fives (list them)?

Answer 6

Molecular weight of less than 500
LogP of less 5
Less than 5 H-bond donors (sum of NH and OH)
Less than 10 H-bond acceptors (sum of N and O)
Less than 10 rotatable bonds

Question 7

Where does Lipinski’s rules of fives not apply?

Answer 7

The rules were originally intended to be a rule for predicting oral absorption but they have since been used as a guide for the pharmaceutical industry for selection of candidate drugs
They do no dictate pharmacologic activity
They only apply to drugs that are given orally
There are many notable drugs on the market that do no follow these rules, most of which are taken up by transporters or other methods

Question 8

Why are isomers important in medicinal chemistry?

Answer 8

Many drugs exist as isomers, may be synthesized as a mixture of isomers, or have the potential to convert from one isomer to another.
Often only one isomer will have biological activity usually because it is the only configuration that will bind to a receptor (some have different potency, some are metabolized differently, some exhibit differing toxicity)

Question 9

What are isomers?

Answer 9

Isomers have identical molecular formulas but with different bonding arrangements, or orientations of atoms in space

Question 10

What are the different types of isomers?

Answer 10

There are three types of isomers (covered in this class): constitutional, configurational, conformational

Question 11

What is a constitutional isomer?

Answer 11

They have the same atomic composition but different bonding arrangements

Question 12

What are configurational isomers?

Answer 12

Configurational isomers have the same molecular formula and the same bonds but the atoms are arranged differently in space with respect to each other.
These orientations cannot interconvert freely by bond rotation
They only differ in relative spatial orientations of atoms

Question 13

What are the two types of configurational stereoisomers?

Answer 13

Optical isomers (chiral)
Geometric isomers

Question 14

What are optical isomers?

Answer 14

When 4 different groups or atoms are bound to a carbon (sp3 tetrahedral) atom, two distinct tetrahedral molecular forms or optical isomers are possible. They are mirror images of each other and they are not superimposable (chiral). They are also asymmetric. An asymmetric or stereogenic carbon has 4 different groups or atoms bound to it. The two molecular forms are known as enantiomers

Question 15

Describe the properties of optical isomers

Answer 15

Optical isomers that are enantiomers have identical physical and chemical properties (i.e., pKa, melting point,, solubilities, etc.).
Two important differences in properties between enantiomers are: 1) rotation of the plane of polarized light and 2) interaction with chiral environments

Question 16

Explain how enantiomers rotate the plane of polarized light

Answer 16

Each enantiomer rotates the plane of polarized light to the same degree, but in opposite directions
The dextrorotatory (d) or (+)-enantiomer rotates the plane to the right (clockwise)
The levorotatory (l) or (-)-enantiomer rotates the plane to the left (counterclockwise)
The direction of rotation of the plan of polarized light cannot be determined by inspection of the structure. It is a chemical property that must be determined experimentally using a polarimeter

Question 17

How can these rotation values be useful?

Answer 17

They can determine the purity of the enantiomer. If there is a 50/50 mixture of enantiomers, there will be no rotation of polarized light (racemate or racemic mixture)

Question 18

What happens if there’s more than one asymmetric centre?

Answer 18

For each asymmetric centre in the molecule, there are several configurational isomers (for ‘n’ asymmetric centres, there are at most 2^n configurational isomers)

Question 19

What is a diastereomer?

Answer 19

A compound with more than one assymetric centre where the compounds are not mirror images of each other and not superimposable

Question 20

What are meso structures?

Answer 20

Meso structures have two identical asymmetric centres such that the mirror images ARE superimposable (these compounds are not chiral and the compound has a plane of symmetry). They will not rotate light.

Question 21

Explain the interaction with chiral environments

Answer 21

On a basic chemical level, each enantiomer may have different interactions with other chiral molecules.
Many biological molecules are chiral and often only one enantiomer is present in biology. The amino acids that make up proteins are only found in one enantiomer form in biology (L)

Question 22

What is the difference between D/L and d/l?

Answer 22

D and L indicate absolute configuration around an asymmetric carbon and have nothing to do with rotation of plane of polarized light.
D and L are determined with respect to a reference compound i.e., all amino acids are D or L depending on if the alpha H points in the right or left direction when the COOH group is up and the NH2 is down

Question 23

What is the Cahn-Ingold-Prelog R and S?

Answer 23

The structure of an enantiomer is designated as R or S
Atom directly attached to the asymmetric carbon are given priority based on their atomic number
Where two directly attached atoms have the same priority, you move to the next atom directly attached to assign priority (when you find that the same priority is assigned at this point you can look at other atoms attached to the same carbon. If a double bond is present, the attached double bond atom is counted twice). Once all attach atoms are assigned priority, the lowest priority group is turned into the page and the remaining face out. An ark is drawn connected the groups facing out from highest to lowest priority.
Clockwise: rectus (R)
Counterclockwise: sinister (S)`1

Question 24

What is threo and erythro?

Answer 24

When the hydrogen’s in Fischer’s projections point in the same direction, it is erythro
When the hydrogen’s in Fischer’s projections point in opposite directions, it is threo
Based on carbohydrate chemistry threose and erythrose

Question 25

What are geometric isomers?

Answer 25

The spy hybridized carbon atoms of alkenes and the attached groups lie in the same plane, and rotation around the double bond is restricted.
If each carbon atom in the double bond has a different substitution, it is possible to have geometric isomers
Sometimes geometric isomers have very different chemical properties

Question 26

Explain E/Z designation

Answer 26

E is trans; Z is cis
Priority is assigned to substituents on either carbon of the double bond
If the higher priority groups are on the same side, it is Z
If the higher priority groups are on opposite sides, it is E

Question 27

What are conformational isomers?

Answer 27

Conformational isomers (conformers) are isomers characterized by different arrangements of atoms that result from rotation about sigma bonds
Conformers can interconvert between isomeric forms

Question 28

Describe the cyclohexane ring system

Answer 28

6 membered rings all sigma bonds
Normally there is free rotation around sigma bonds however, cyclohexane exists in two major forms: chair confirmer and boat confirmer