Lecture 3 (Intro to MedChem)

Question 1

Most drugs are less than ____ Da

Answer 1

500

Question 2

conformational freedom

Answer 2

the ability to rotate bonds freely

Question 3

Rotatable bonds are any single bonds that are: ???

Answer 3

• not part of a ring
• not formed with a terminal atom
• not formed with a hydrogen atom

Question 4

are amide C-N bonds freely rotatable?

Answer 4

no

Question 5

bioavailability of ___% is considered the minimum bioavailability for the drug to be used orally

Answer 5

20

Question 6

with decreasing # of rotatable bonds, the bioavailability ______

Answer 6

increases

Question 7

we want delta G to be ___?

Answer 7

negative

Question 8

molecules with lots of freely rotating bonds ____ delta G

Answer 8

increases (unfavourable)

Question 9

What are Lipinski’s Rule of Fives used to determine?

Answer 9

If a chemical compound can be absorbed orally

*does not dictate pharmacological activity

Question 10

What are the Lipinski’s Rule of Fives? (5)

Answer 10

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

Question 11

Often only one isomer will have biological activity. Why?

Answer 11

Because it is the only configuration that will bind to a receptor

Question 12

In what ways can isomers differ from each other?

Answer 12

• different potency
• metabolized differently
• differing toxicity

Question 13

What are the 3 types of isomers?

Answer 13

• constitutional (structural/positional)
• configurational
• conformational

Question 14

Describe constitutional (structural/positional) isomers

Answer 14

• same atomic composition but
• different bonding arrangements between atoms

ex. catechol vs. resorcinol

Question 15

Describe configurational isomers

Answer 15

-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)

Question 16

Two types of configurational isomers?

Answer 16

• optical

- geometric

Question 17

Describe optical isomers

Answer 17

• mirror images
• non-superimposable
• chiral molecules
• an asymmetric carbon centre that has 4 different groups/atoms bound to it

Question 18

optical isomers are ____

Answer 18

enantiomers

Question 19

Define enantiomer

Answer 19

non-superimposable mirror images of each other

Question 20

optical isomers have ___ physical and chemical properties

Answer 20

identical

Question 21

Two important differences in properties between enantiomers ?

Answer 21

1) rotation of plane polarized light

2) interaction w chiral environments

Question 22

Describe the rotation of plane polarized light in enantiomers

Answer 22

each enantiomer rotates plane polarized light to the same degree but different direction

Question 23

dextrorotary (d) or (+)-enantiomer rotates plane polarized light which way??

Answer 23

to the right (clockwise)

Question 24

levorotatory (l) or (-)-enantiomer rotates plane polarized light which way?

Answer 24

to the left (counterclockwise)

Question 25

T or F: you can determine direction of rotation by looking at a compound’s structure

Answer 25

false man

-need a polarimeter to determine direction of plane polarized light experimentally

Question 26

What type of mixture will not rotate plane polarized light at all?

Answer 26

50:50 mixture (racemic mixture)

Question 27

For ‘n’ asymmetric centers there are at most __ configurational isomers

Answer 27

2^n

Question 28

What are diastereomers?

Answer 28

• compounds with more than one asymmetric centre
• not mirror images
• not superimposable

Question 29

What are meso structures?

Answer 29

• two identical asymmetric centers
• mirror images
• superimposable

(these compounds are not chiral)

Question 30

in a Fischer projection how do we orientate amino acid?

Answer 30

COO- is up
NH2 is down

(carboxyl group up)
(amino group down)

Question 31

When we have the amino acid orientated in the correct way as a Fischer projection how do we determine D or L?

Answer 31

If the alpha hydrogen is left = L

If the alpha hydrogen is right = D

Question 32

proteins are composed of only what type of amino acids?

Answer 32

L-amino acids

Question 33

When the H’s in a Fischer projection point in the same direction = ?
(for diastereomers)

Answer 33

erythro

Question 34

When the H’s in a Fischer projection point in opposite directions = ?
(for diastereomers)

Answer 34

threo

Question 35

Describe geometric isomers

Answer 35

• sp2 hybridized carbon atoms of alkenes and the attached groups lie in the same plane
• rotation around double bond is restricted

Question 36

When is it possible to have geometric isomers?

Answer 36

If each carbon atom in the double and has different substitutions

Question 37

how do we differentiate between geometric isomers?

Answer 37

trans/cis

E/Z

Question 38

How do you determine E or Z?

Answer 38

cut double bond in half

-determine if the higher priority molecules are on the same or opposite sides

Question 39

Higher priority molecules on the same side

Answer 39

Z (cis)

Question 40

Higher priority molecules on opposite sites

Answer 40

E (trans)

Question 41

Describe conformational isomers (conformers)

Answer 41

• isomers characterized by different arrangements of atoms that result from rotation about sigma bonds
• conformers can interconvert between isomeric forms

Question 42

Newman projections:

what conformation has a higher energy form

Answer 42

eclipsed

Question 43

Newman projections:

what conformation has a lower energy form

Answer 43

staggered

Question 44

bulky groups overlapping = ____ energy

Answer 44

highest

Question 45

we would expect that a drug spends most of it’s time in the ___ form

Answer 45

anti (staggered)

- this is the lowest energy form

Question 46

6 membered ring takes one or two forms: what are the two forms

Answer 46

boat

chair

Question 47

normally there is ______ _______ around sigma bonds

Answer 47

free rotation

Question 48

6 membered rings are all ____ bonds

Answer 48

sigma

Question 49

chair vs boat:

what is more favoured

Answer 49

chair

boat causes steric interactions between hydrogens or other bulky groups which makes boat conformation unfavourable

Question 50

Explain boat to chair or chair to boat flipping: what happens

Answer 50

anything that was axial becomes equatorial

anything that was equatorial becomes axial

Question 51

For bulky substituents the conformation that allows the substituents to be in _____ will predominate

Answer 51

equatorial