Lecture 3 (Intro to MedChem) Flashcards
Most drugs are less than ____ Da
500
conformational freedom
the ability to rotate bonds freely
Rotatable bonds are any single bonds that are: ???
- not part of a ring
- not formed with a terminal atom
- not formed with a hydrogen atom
are amide C-N bonds freely rotatable?
no
bioavailability of ___% is considered the minimum bioavailability for the drug to be used orally
20
with decreasing # of rotatable bonds, the bioavailability ______
increases
we want delta G to be ___?
negative
molecules with lots of freely rotating bonds ____ delta G
increases (unfavourable)
What are Lipinski’s Rule of Fives used to determine?
If a chemical compound can be absorbed orally
*does not dictate pharmacological activity
What are the Lipinski’s Rule of Fives? (5)
1) molecular weight < 500
2) logP < 5
3) < 5 H-bond donors (Sum of NH and OH)
4) < 10 H-bond acceptors (Sum of N and O)
5) < 10 rotatable bonds
Note: #5 was an additional rule added since Lipinski's original article
Often only one isomer will have biological activity. Why?
Because it is the only configuration that will bind to a receptor
In what ways can isomers differ from each other?
- different potency
- metabolized differently
- differing toxicity
What are the 3 types of isomers?
- constitutional (structural/positional)
- configurational
- conformational
Describe constitutional (structural/positional) isomers
- same atomic composition but
- different bonding arrangements between atoms
ex. catechol vs. resorcinol
Describe configurational isomers
-same molecular formula and the same bonds
but
-atoms are arranged differently in space with respect to each other
(think of chiral compounds ex cis/trans)
Two types of configurational isomers?
- optical
- geometric
Describe optical isomers
- mirror images
- non-superimposable
- chiral molecules
- an asymmetric carbon centre that has 4 different groups/atoms bound to it
optical isomers are ____
enantiomers
Define enantiomer
non-superimposable mirror images of each other
optical isomers have ___ physical and chemical properties
identical
Two important differences in properties between enantiomers ?
1) rotation of plane polarized light
2) interaction w chiral environments
Describe the rotation of plane polarized light in enantiomers
each enantiomer rotates plane polarized light to the same degree but different direction
dextrorotary (d) or (+)-enantiomer rotates plane polarized light which way??
to the right (clockwise)
levorotatory (l) or (-)-enantiomer rotates plane polarized light which way?
to the left (counterclockwise)
T or F: you can determine direction of rotation by looking at a compound’s structure
false man
-need a polarimeter to determine direction of plane polarized light experimentally
What type of mixture will not rotate plane polarized light at all?
50:50 mixture (racemic mixture)
For ‘n’ asymmetric centers there are at most __ configurational isomers
2^n
What are diastereomers?
- compounds with more than one asymmetric centre
- not mirror images
- not superimposable
What are meso structures?
- two identical asymmetric centers
- mirror images
- superimposable
(these compounds are not chiral)
in a Fischer projection how do we orientate amino acid?
COO- is up
NH2 is down
(carboxyl group up)
(amino group down)
When we have the amino acid orientated in the correct way as a Fischer projection how do we determine D or L?
If the alpha hydrogen is left = L
If the alpha hydrogen is right = D
proteins are composed of only what type of amino acids?
L-amino acids
When the H’s in a Fischer projection point in the same direction = ?
(for diastereomers)
erythro
When the H’s in a Fischer projection point in opposite directions = ?
(for diastereomers)
threo
Describe geometric isomers
- sp2 hybridized carbon atoms of alkenes and the attached groups lie in the same plane
- rotation around double bond is restricted
When is it possible to have geometric isomers?
If each carbon atom in the double and has different substitutions
how do we differentiate between geometric isomers?
trans/cis
E/Z
How do you determine E or Z?
cut double bond in half
-determine if the higher priority molecules are on the same or opposite sides
Higher priority molecules on the same side
Z (cis)
Higher priority molecules on opposite sites
E (trans)
Describe conformational isomers (conformers)
- isomers characterized by different arrangements of atoms that result from rotation about sigma bonds
- conformers can interconvert between isomeric forms
Newman projections:
what conformation has a higher energy form
eclipsed
Newman projections:
what conformation has a lower energy form
staggered
bulky groups overlapping = ____ energy
highest
we would expect that a drug spends most of it’s time in the ___ form
anti (staggered)
- this is the lowest energy form
6 membered ring takes one or two forms: what are the two forms
boat
chair
normally there is ______ _______ around sigma bonds
free rotation
6 membered rings are all ____ bonds
sigma
chair vs boat:
what is more favoured
chair
boat causes steric interactions between hydrogens or other bulky groups which makes boat conformation unfavourable
Explain boat to chair or chair to boat flipping: what happens
anything that was axial becomes equatorial
anything that was equatorial becomes axial
For bulky substituents the conformation that allows the substituents to be in _____ will predominate
equatorial
