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Med Chem Midterm > Lecture 4 Part 2 > Flashcards

Lecture 4 Part 2 Flashcards

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1
Q

name 2 ways in which bioisosteric replacement can be applied to drug development

A
  1. to develop analogues with a similar biological effect
  2. to develop analogues that act as antagonists to normal metabolites (intermediate or end product of metabolism)
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2
Q

as mentioned, bioisosteric can be applied to develop analogues with a similar biological effect.

give a specific example of this

A

antihistamines and cholinergic blocking agents and antihistamines are structurally similar, with only 1 functional group being changed to go from a antihistamine to a cholinergic blocking agent.

thus they have some common side effects like drowsiness.

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3
Q

name the nucleic acid purines/pyrimidines

A

purines = adenine and guanine
pyrimidines = thymine, cytosine, and uracil

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4
Q

as mentioned, bioisosteric replacement can be applied to develop analogues that act as antagonists to normal metabolites.

give a specific example of this

A

when the NH2 group of adenine is replaced by SH (thiol), the molecule becomes 6-mercaptopurine and is an antimetabolite, anti cancer drug

when NH2 group of adenine is replaced with OH, it becomes hypoxanthine – a naturally occurring purine derivative

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5
Q

what is an antimetabolite?

A

interferes with synthesis of DNA constituents (ex: 6-mercaptopurine inhibits the synthesis of purines (adenine?)

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6
Q

in making a bioisosteric replacement, what 8 factors of the group being replaced should be considered?

A

size
shape
electron distribution
lipid solubility
water solubility
pka
hydrogen bonding capacity
chemical reactivity towards cell components and metabolizing enzymes

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7
Q

what do you mean that “shape” of the functional group should be considered when making a bioisosteric replacement?

A

the bond angle and hybridization should be considered

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8
Q

what do you mean when you say that the “electron distribution” of the functional group should be considered when making a bioisosteric replacement?

A

the polarizibility, charge, and dipole should be considered

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9
Q

what does pka mean?

A

the ability of a functional group to dissociate at physiological pH

lower pka = higher acidity (more likely to give up protons)

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10
Q

give a specific example of why chemical reactivity of a functional group towards cell components and metabolizing enzymes should be considered when making a bioisosteric replacement

A

in the case of toluene, the benzylic carbon is HIGHLY SUSCEPTIBLE TO BIOOXIDATED METABOLISM and is cleared from the system very rapidly – has a very short duration of action.

to enhance and prolong the duration of action, the methyl group on toluene can be replaced with something that is STABLE TO METABOLISM – for instance, Chlorine (if the methyl is just there for its small size)

ex of 1 1st generation hypoglycemic

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11
Q

why do we not want to use a functional group that is too chemically reactive?

A

this may lead to a premature, irreversible reaction that can lead to cell death, carcinogenesis, or teratogenesis

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12
Q

true or false

when performing isosteric replacement, there are definitive rules to follow

A

FALSE – there are rough rules, but everything really depends on the situation

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13
Q

what are optical isomers?

A

stereoisomers (same chemical formula, same connectivity) that are NOT interconverted by rotation about single bonds and this is NOT due to restricted rotation, as in the case of geometric isomers

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14
Q

differentiate and compare enantiomers and diastereomers

A

both are optical isomers

enantiomers are non-superimposable mirror images. they have the SAME PHYSICAL AND CHEMICAL PROPERTIES, aside from the fact that:

  • they rotate a plane of polarized light in an equal, but opposite direction (physical property)
  • they react with other chiral compounds at different rates

diastereomers are non-superimposable non mirror images. they have 2 or more asymmetric centers. THEY HAVE DIFFERENT PHYSICAL AND CHEMICAL PROPERTIES

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15
Q

Explain why it is significant that enantiomers react with other chiral compounds at different rates

A

the rates can either be very close to each other (hard to distinguish them apart) OR they can be so different that 1 enantiomer undergoes the reaction while the other enantiomer DOESNT

THIS IS WHY MANY COMPOUNDS ARE BIOLOGICALLY ACTIVE AND THEIR ENANTIOMERS ARE NOT

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16
Q

how can you separate 2 enantiomers?
explain

A

they CANNOT be separated via a TLC plate because they will both move to the same spot (same melting point)

they can only be separated using a stereochemical technique such as by using a chiral column

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17
Q

what can you say about the pharmacokinetic properties of enantiomers

A

they have identical pharmacokinetic properties EXCEPT for when they arrive at the binding site. there, they can differentiate.

when introduced to a chiral environment, they will differentiate

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18
Q

can enantiomers have different transportation/clearance?
where is this most critical?

A

yes – if they interact with a chiral compartment.
this is most critical at the drug-receptor binding site

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19
Q

true or false

enantiomers react with chiral compounds at the same rate

A

FALSE

they interact with ACHIRAL compounds at the same rate

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20
Q

give a specific example of how 1 enantiomer can be biologically active while the other is not/is very weak

A

(-) epinephrine is 12-15 times more active than (+) epinephrine as a vasoconstrictor

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21
Q

L-amino acids are either ___ or ____ while D-amino acids are ____

A

L-amino acids are either TASTELESS OR BITTER while D-amino acids are SWEET

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22
Q

true or false

the metabolism for diastereomers may be different

A

true – this is an important consideration

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23
Q

the biological activity of optical isomers is dependent on what?

A

the asymmetry of the drug molecule relative to the asymmetry of the receptor site

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24
Q

in order for optical isomers to be biologically active…..

A

the asymmetry of the drug must be complementary to the asymmetry of the receptor for the drug (ex: (-) epinephrine is more active because the 3 binding sites line up)

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25
Q

name the structural features necessary for maximum vasoconstriction activity of epinephrine

A
  • a (+) charged Nitrogen
    -an aromatic ring
    -a hydroxyl group
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26
Q

what is the sole difference between the 2 enantiomers of epinephrine

A

in the (+) enantiomer, the OH needed for binding is pointing away from the receptor.

in the (-) enantiomer, the OH is positioned correctly, allowing for proper binding at the 3 necessary binding sites

27
Q

besides epinephrine, give another example of how optical isosterism is an important factor in drug-receptor interaction

A

ephedrine and pseudoephedrine are diastereomers.

ephedrine has 2 asymmetric (chiral) carbons. its diastereomer, pseudophedrine, is LESS ACTIVE than ephedrine

28
Q

ephedrine is a ___ agent that causes…..

A

adrenergic agent that causes an increase in blood pressure

29
Q

optical isomers show differences in activity MAINLY because…..

A

they interact with the receptors in a different manner

30
Q

as mentioned, the MAIN reason that optical isomers show differences in activity is because they interact with receptors in a different manner.

what are ADDITIONAL reasons that account for this difference in their biological activity

A

-optically active components of body fluids (like plasma proteins) can form a diastereometric complex with optical isomers, leading to differences in ADME

-there can be preferential metabolism of one isomer over the other by a enzyme that is STEREOSPECIFIC (ie: D-amino oxidase)

-there can be preferential adsorption at a stereospecific site of loss (ex: stereospecific protein binding)

31
Q

diastereomers can result from the presence of….

A

more than 1 chiral center in a molecule, double bonds, or ring systems

32
Q

in enantiomers there is an inversion of ___ chiral centers, while there is an inversion of ___ chiral centers for diastereomers

A

in a pair of enantiomers, both chiral centers are inverted, and for diastereomers only 1 chiral center is inverted

33
Q

can racemic mixtures be used as drugs?

A

the FDA (and other regulatory agencies) have been strict in approving racemic mixtures as drugs.

toxicity data needs to be verified, because sometimes only 1 isomer in the racemic mixture can be metabolized into a toxic substance while the other is totally normal.

sometimes, only 1 enantiomer is active and the other is inactive. this is “okay” as long as the activity of the active enantiomer isn’t affected

34
Q

what makes a molecule chiral?

A

a tetrahedral (sp3) carbon bonded to 4 different groups.

35
Q

what is a chiral center?

A

a carbon with 4 different groups

36
Q

are enantiomers stereoisomers?

A

yes

37
Q

what is geometric isomerism

A

aka cis-trans isomers

stereoisomers that CANNOT be interconverted through rotation about single bonds, due to restricted rotation (either olefins or cyclic compounds)

38
Q

what are olefins?

A

hydrocarbons with one or more double bonds between carbons

39
Q

true or false

cis-trans isomerism arises due to a restricted rotation about a bond

A

true

40
Q

do geometric isomers (cis-trans) show optical isomerism?

A

NO, not unless that happen to be chiral

41
Q

do geometric isomers have the same physical and chemical properties?

A

NO - they have differences in both physical and chemical properties

42
Q

true or false

between geometric isomers, pharmacokinetics and pharmacodynamics are likely to be the same

A

FALSE – likely to be different

like diastereomers, they have different physical and chemical properties

43
Q

in the case of geometric isomerism, ___ and ___ in the biological medium is different due to differences in physical and chemical properties

A

absorption and distribution

44
Q

why does trans diethylstilbesterol have higher estradiol activity than cis diethylstilbesterol?

A

the interatomic distances between the 2 hydroxyl groups is similar to estradiol in the trans version of the molecule

45
Q

define conformational isomers

A

they do NOT have identical spatial arrangement of atoms resulting from rotation about single bond(s)

46
Q

at physiological conditions, what do single bonds do?

A

they rotate

47
Q

as mentioned, conformational isomers can rotate their single bonds.
explain this further as it relates to conformational isomers that enter our body

A

there are various conformations of conformational isomers.

HOWEVER, sometimes the energy barrier to change to a certain isomer may not be possible.

therefore, the conformer with the GREATEST DISTANCE BETWEEN THE LARGEST GROUPS (staggered) usually predominates, because it is the least energy demanding

48
Q

name 4 different conformations of conformational isomers and state which is the most stable and least stable.

which is the most/least energy demandiing?

A

staggered
partially eclipsed
fully eclipsed
skew/gauce

requires the most energy to maintain – fully eclipsed. LEAST STABLE

requires the least energy to maintain = staggered. MOST STABLE

49
Q

as mentioned, the conformational isomer with the greatest distance between the largest groups (skewed) usually predominates.

what is the exception to this?
give a specific example

A

when there are stabilizing interactions present that may OVERCOME THE CONFORMATIONAL PREFERENCES

in 2,3-Butanebiol, the skew conformation is favored due to the intramolecular hydrogen bond that stabilizes the molecule

50
Q

which are more rigid — cyclic or noncyclic structures?
why?

A

cyclic structures are more rigid bc there are fewer conformations possible

51
Q

name cyclic compounds from 3 carbons to 6 carbons.
also, name their conformations

A

3 carbons = cyclopropane. PLANAR. can’t conform

4 carbons = cyclobutane. TWIST

5 carbons = cyclopentane ENVELOPE AND HALF CHAIR

6 carbons = cyclohexane CHAIR, HALF CHAIR, BOAT

52
Q

As mentioned, cyclohexane has 3 possible conformations — half chair, chair, and boat.

rank them according to their stability, and state why the most stable is the most stable

A

least stable = boat

middle = half chair

MOST STABLE = chair. this is because all the substituents are away from each other (staggered)

53
Q

true or false

cyclic structures are rarely found in drug molecules

A

FALSE – they are commonly found in drugs, especially 5 or 6 membered heterocyclic ring

54
Q

besides 5 and 6 membered rings, are there any other rings found in drug molecules?

A

3,4,7 membered rings are also found

55
Q

give an example of a 3 membered ring that is occasionally found in drug molecules.

why are 3 membered rings not used a lot in drugs?

A

EPOXIDE – 3 membered ring with oxygen in the middle.

it is highly chemically reactive which is why it’s not commonly used in drugs

56
Q

name some drugs that have 4 membered rings

A

the beta lactam antibiotics – penicillin and cephalosporins

57
Q

name a drug that has a 7 membered ring

A

diazepam (valium)

it is a benzodiazepine antidepressant/hypnotic

58
Q

recap: what drug represents the importance of considering optical isomerism

A

epinephrine and ephedrine

59
Q

recap: what drug represents the importance of considering geometric isomerism

A

estrasiol and diethylstilibesterol (des)

60
Q

is estradiol endogenous?

A

yes

61
Q

explain the difference between “cis” vs “cisoid”/ “trans” vs “transoid”

A

cis and trans are terms used for true geometric isomers

cisoid (skew) and transoid (staggered) are used to describe conformational isomers (NOT GEOMETRIC ISOMERS) that mimic cis and trans

62
Q

Acetylcholine freely rotates in the body around its single bond.
what is the concern with this?

A

acetylcholine has 2 important cholinergic receptors – nicotinic and muscarinic.
to prevent acetylcholine from binding to the wrong receptor, a rigid analogue is made by inserting a 3 membered ring into the structure of acetylcholine. this prevents the free rotation of the molecule so that its isomers are easier to test

63
Q

true or false

it is possible that isomers bind to different receptors in the body

A

true

64
Q
A

Med Chem Midterm (11 decks)

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