Lecture 15

Question 1

Natural Systems + Chirality

Answer 1

• Most biological molecules are found in only one specific steroisomer
• Most carbs are D-series
• Most amino acids are L-series
• Usually one enantiomer is active while the other is not

Question 2

Chirality + Drug Targets

Answer 2

• Three-point interactive

- Agonist/substrate with receptor/enzyme site respectively

Question 3

Thalidomide

Answer 3

• S -Safe/effective form
• R, form it was sold in that caused birth defects
• Example of chirality, drug was withdrawn

Question 4

Chirality + Drugs

Answer 4

• Most medicinal agents occur in a single, optically active, isomer form
• Half of drugs available are chiral
• Only one enantiomer has a beneficial effect while the other can be harmful in some cases

Question 5

Chirality _+ Absorption

Answer 5

Methotrexate, the L enantiomer of the drug are actively absorbed while the D- form absorbed in the intestine by passive diffusion.

Question 6

Distribution + Chirality

Answer 6

The S enantiomer of propranolol is selectively bound in heart, whilst the R isomer is selectively incorporated into the adipose tissue.

Question 7

Metabolism + Chirality

Answer 7

R enantiomer of warfarin has longer elimination half life. S-warfarin is metabolized by CYP 2C9, R-warfarin is metabolized by CYP 1A2, 2C19 and 3A4.

Question 8

Excretion + Chirality

Answer 8

Renal clearance of plasma Quinidine is four times greater than quinine, its diastereoisomer

Question 9

Chiral History

Answer 9

• During the “Golden Age” of drug discovery & development, the 1950s to the 1970s, stereochemistry was largely ignored resulting in approximately 25% of pharmaceuticals being marketed as racemates by the 1980s.
• Advances in chemical technology associated with synthesis, analysis and preparative scale separation of chiral molecules resulted in a change in philosophy with respect to drugs.
• Facilitated the pharmacological evaluation of single stereoisomers; increasing concern with respect to safety issues; Regulatory interes

Question 10

Chiral Costs

Answer 10

• 2006, 80% of small-molecule drugs approved by the FDA were chiral
• 75% were single enantiomers
• The field of asymmetric synthesis is expanding rapidly, 50% of chiral drugs use chiral technologies
• Due to FDA policy, decision to create racemic mixture must be justified in quality, safety, and efficacy, may be case-by-case

Question 11

Stereoisomers

Answer 11

-Same constitutional isomer, difference in the way they are arranged in 3D space at one or more atoms.

Question 12

Enantiomer

Answer 12

Compounds that are non-super-imposable mirror images of each other.

Question 13

Achirl

Answer 13

Molecule or object that is superimposable on its mirror image.

Question 14

Stereocenter

Answer 14

• Atom, or group of atoms, that can potentially cause a molecule to be chiral.
• Most common example is carbon
• Quaternary and tertiary nitrogens in junction with bicyclic rings, hypervalent phosphorous (3+ bonds), and hypervalent sulfurs (2+ bonds) can also be chiral, but are unusual

Question 15

Stereogenic Sulfur

Answer 15

Sulfur that is is chiral by its fourth bond being a pair of electrons. EX: Omeprazole

Question 16

Optical Activity

Answer 16

• Enantiomers have optical activity (+ or -)
• Can only tell which one by measuring its rotation in a polarimeter
• Positive is clockwise (dextroratory)
• Negative is counterclockwise (levororatory)
• Optical isomers rotate polarized light

Question 17

Equimolar Mixtures of Enantiomers

Answer 17

• Cancel the effect of each other out
• Only one of the enantiomers being used would result in an overall effect of 100%
• 70% R and 30% S would result in an overall effect of 40% favoring R

Question 18

Relative Configuration

Answer 18

Configuration in terms of D or L

Question 19

Absolute Configuration

Answer 19

Actual configuration around a stereocenter in 3D space. R or S

Question 20

Specific Rotation

Answer 20

Whether a compound is dextrorotatory (+) or leveorotatory (-).

Question 21

IMPORTANT

Answer 21

There is NO implied relationship among relative and absolute configuration and specific rotation. Cannot derive one from knowing another.