Aglaroxin C and derivatives as HCV entry inhibitors
A rocaglamide or a rocaglate derivative, particularly aglaroxin C, blocks hepatitis C virus (HCV) entry with improved potency and therapeutic index.
1. A method to inhibit hepatitis C viral infection by administering to a subject a therapeutically effective dosage of a compound having a structure of compound 2:
2. The method of claim 1 , wherein compound 2 comprises compound 3:
3. The method of claim 2 , wherein compound 3 comprises an EC50≥about 200 μM, and a CC50 of about 300 μM when incubated with cells for about 3 hours.
4. The method of claim 1 , wherein:
compound 2 comprises compound 4:
5. The method of claim 4 , wherein compound 4 comprises an EC50 of about 1 μM, a CC50 of about 50 μM, and a TI (CC50/EC50) of about 50, when incubated with cells for about 3 hours.
6. The method of claim 4 , wherein compound 4 comprises an EC50 of about 4 nM, a CC50 of about 300 nM, and a TI of about 75, when incubated with cells for about 48 hours.
7. A method to inhibit hepatitis C viral infection by administering to a subject a therapeutically effective dosage of a compound having a structure of compound 6:
wherein compound 6 is chiral, racemic and comprises both (+) or (−) enantiomers.
8. The method of claim 7 , wherein compound 6 comprises an EC50 of about 100 nM, a CC50 of about 10 μM, and a TI (CC50/EC50) of about 100, when incubated with cells for about 3 hours.
9. The method of claim 7 , wherein compound 6 comprises an EC50 of about 40 pM, a CC50 of about 20 nM, and a TI (CC50/EC50) of about 500, when incubated with cells for about 48 hours.
10. The method of claim 7 , wherein compound 6 comprises compound 7:
wherein compound 7 at C10 is NOT racemic.
11. The method of claim 10 , wherein compound 7 comprises an EC50 of about 200 nM, a CC50 of about 12 μM, and a TI (CC50/EC50) of about 60, when incubated with cells for about 3 hours.
12. The method of claim 7 , wherein compound 6 comprises compound 8:
13. The method of claim 12 , wherein compound 8 comprises an EC50 of about 20 μM, a CC50 of about 100 μM, and a TI (CC50/EC50) of about 5, when incubated with cells for about 3 hours.