Flashcards in More Introduction Part II Deck (28):
What are factors affecting drug solubility?
Drug interactions with water
Size of the molecule
Conformation freedom (number of freely rotatable bonds)
What is the molecular weight of the majority of drugs on the market?
The majority are less than 500 Da
How does the number of rotatable bonds affect bioavailability?
The higher the number of rotatable bonds, the lower the bioavailability will be
Why do we care about the number of rotatable bonds?
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
What are Lipinski's rule of fives (overall)?
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?
What are Lipinski's rules of fives (list them)?
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
Where does Lipinski's rules of fives not apply?
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
Why are isomers important in medicinal chemistry?
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)
What are isomers?
Isomers have identical molecular formulas but with different bonding arrangements, or orientations of atoms in space
What are the different types of isomers?
There are three types of isomers (covered in this class): constitutional, configurational, conformational
What is a constitutional isomer?
They have the same atomic composition but different bonding arrangements
What are configurational isomers?
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
What are the two types of configurational stereoisomers?
Optical isomers (chiral)
What are optical isomers?
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
Describe the properties of optical isomers
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
Explain how enantiomers rotate the plane of polarized light
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
How can these rotation values be useful?
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)
What happens if there's more than one asymmetric centre?
For each asymmetric centre in the molecule, there are several configurational isomers (for 'n' asymmetric centres, there are at most 2^n configurational isomers)
What is a diastereomer?
A compound with more than one assymetric centre where the compounds are not mirror images of each other and not superimposable
What are meso structures?
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.
Explain the interaction with chiral environments
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)
What is the difference between D/L and d/l?
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
What is the Cahn-Ingold-Prelog R and S?
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
What is threo and erythro?
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
What are geometric isomers?
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
Explain E/Z designation
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
What are conformational isomers?
Conformational isomers (conformers) are isomers characterized by different arrangements of atoms that result from rotation about sigma bonds
Conformers can interconvert between isomeric forms