chemistry of statins

Question 1

what is cholesterol transported by?

Answer 1

HDL - carry from cells to liver (good)
LDL - carry to cells (bad)

Question 2

3 main phases of cholesterol biosynthesis?

Answer 2

1- formation of mevalonic acid
2 - conversion of mevalonate into farnesyl pyrophosphate
3 - Condensation of two farnesyl pyrophosphates units to yield squalene

Question 3

how do statins work?

Answer 3

competitive inhibitors blocking HMG-CoA reductase which produces mevalonate

Question 4

general structure of type 1 statins? (examples)

Answer 4

polar head and hydrophobic moiety including a decalin ring
- simvastatin, lovastatin

Question 5

way of modifying type 1 statin lovastatin?

Answer 5

making analogues that will have longer interaction with the enzyme
1. Make ether side-chain analogues
2. Homologation of the lactone ring
3. converting lovastatin tomevanolate analogue (changing stereochemistry at the hydroxy-
bearing carbon in the lactone)

Question 6

shortcomings of type 1 statins?

Answer 6

• various side effects
• difficult to synthesise
• large number of asymmetric centres

Question 7

basic structure difference of type 2 statins?

Answer 7

Contain larger hydrophobic moiety with no asymmetric centres

Question 8

why do type 2 statins have lower side effects?

Answer 8

lower hydrophobic character so cant cross membranes easily
targets liver cells

Question 9

purpose of the polar head?

Answer 9

mimics natural substrate of HMG-CoA reductase
binds more strongly but no leaving group

Question 10

binding interaction of atorvastatin?

Answer 10

-polar head binds similarly to natural substrate
- hydrophobic moiety doesn’t
-enzyme flexible and creates Hydrophobic pocket to bind

Question 11

binding interaction of rosuvastatin?

Answer 11

forms additional H-bonding