SWCNT Growth from Chiral and Achiral Carbon Nanorings: Prediction of Chiralit...
ACS Poster
1. N
N
N
O
CO2Me
CO2Me
SL205 (K4, CMLD005040)
2.0 µM - core dimerization
OMe
N
N
N
O
CO2Me
CO2Me
SL204 (I4, CMLD005019)
IC50 = 3.7 µM
O
N
N
N
O
CO2Me
CO2Me
SL203 (B4/N4, CMLD005037/
CMLD005092)
9.9 µM - core dimerization
CF3
N
N
N
O
CO2Me
CO2Me
SL206 (M4, CMLD005075)
IC50 = 4.7 µM
N
N
N
O
CO2Me
CO2Me
OMe
N
N
N
HN
O
N
N
N
N
O
OMe
CO2Me
CO2Me
N
N
N
N
N
N
N
O
OMe
CO2Me
CO2Me
N
N
Me
MeO
N
N
N
N
O Ph
CO2Me
CO2Me
N
N
N
N
N
N
N
O Ph
CO2Me
CO2Me
N
N
Me
MeO
N
N
N
O
OMe
CO2Me
CO2Me
N
N
N
HO
Synthesis of Small Molecule Inhibitors Against Hepatitis C
May Young, Mark Busch, Kyle Strom, John K. Snyder
Boston University, Chemistry Department
Hepatitis C, the leading cause of liver disease, affects over 170 million people worldwide.1,2 The hepatitis C virus (HCV) encodes 10 viral proteins for infection and propagation and of the 10 HCV proteins, core, the nucleocapsid protein,
presents a unique therapeutic target, as core is responsible for the assembly of new viral particles for viral proliferation through core dimerization and is the most conserved.2,3 The synthesis of small molecule inhibitors against core
dimerization, which initiates viral assembly, is reported. Core dimerization inhibitors synthesized through inverse electron demand Diels-Alder chemistry by the intramolecular cycloaddition of tryptophan derivatives with tethered 1,2,4-
triazines were shown to be active against the HCV proliferation, and, hence, subsequent efforts were focused on tethering a second heterocycle to the parent adduct tetracyclic core structure for preparation of a second generation library.
Diversification of these compounds has been achieved through a copper catalyzed azide-alkyne cycloaddition reaction, which will be screened against hepatitis C for antiviral activity.
• Screen small libraries for core dimerization inhibitors
• Identification of several compounds that exhibit biological
activity against Hepatitis C
N
N
N
MeO2C
MeO
Me
O
CO2Me
CO2Me
SL 201 (N6, CMLD 003452)
IC50 5.7 µM - core dimerization
(validated by resynthesis)
• Preparation of a second-generation
library, using SL 201 as a structural
lead
• Inverse electron demand Diels-Alder
chemistry by the intramolecular
cycloaddition of tryptophan derivatives
with tethered 1,2,4-triazines 2
• Tethering a second heterocycle to the parent adduct tetracyclic
core structure to bind to a secondary pocket on the protein
surface and enhance the inhibition of proton-proton interactions
• Several compounds designed by tethering an azide to the
tetracyclic core for subsequent modification using click
chemistry
Background
Synthesis Scheme
N
H
i) NaH (1.5 eq),
THF, rt, 30 min
ii)
(1.6 eq), 50 °C, 14 h
Br Br N
Br
CO2Me CO2Me
MeOH, H2SO4
reflux, 3 hN
H
COOH
i) LiOH (5 eq), THF/H2O, rt, 4 h
ii) (COCl)2 (2.6 eq), DMF (cat.),
CH2Cl2, rt, 1 h
iii) Triazine (1.6 eq), TEA (2.4 eq),
DMAP (cat.), CH2Cl2, rt, 3 h
N
Br
N
N
N
CO2Me
CO2Me
HN
OMe
Triazine
O
N
N
N
N
OMe
MeO2C
CO2Me
N
Br
O
N
N
N
N
OMe
MeO2C
CO2Me
PhCl,
reflux, 12 h
N
Br
N
N
O
OMe
CO2Me
CO2Me
N
N3
N
N
O
OMe
CO2Me
CO2Me
NaN3 (1.2 eq), DMF,
50 °C, 10 h
Click Chemistry
N
N3
N
N
O
OMe
CO2Me
CO2Me
N
N
N
O
OMe
CO2Me
CO2Me
R
N
N
NR
(+)-Sodium L-ascorbate,
CuSO4
1:1:1
tBuOH:H2O:CH2Cl2
80 °C, 30 min
NHAc
OH
N
OMe
• Click reactions – reactions that can be accomplished very simply
• Used to build second heterocycle onto the parent core
• Performed an azide-alkyne cycloaddition with a copper catalyst
using a variety of substituents to build a small library wherein the
structure of second heterocyclic ring varies
Future Work
Works Cited
1. Wei, W.; Cai, C.; Kota, S.; Takahashi, V.; Ni, F.; Strosberg, A.D.;
Snyder, J.K. New Small Molecule Inhibitors of Hepatitis C
Virus. Bioorganic & Medicinal Chemistry Letters. 2009, 19,
6926 – 6930.
2. Ni, F.; Kota, S.; Takahashi, V.; Strosberg, A.D.; Snyder, J.K.
Potent Inhibitors of Hepatitis C Core Dimerization as New Leads
for Anti-Hepatitis C Agents. Bioorganic & Medicinal Chemistry
Lett. 2011, 2198 – 2202.
3. Kota, S.; Takahashi, V.; Ni, F.; Snyder, J.K.; Strosberg, A. D.
Direct Binding of a Hepatitis C Virus Inhibitor to the Viral
Capsid Protein. PLoS ONE. 2012, 7, e32207.
4. Benson, S.C.; Gross, J.L.; Snyder, J.K. Indole as a Dienophile in
Inverse Electron Demand Diels-Alder Reactions: Reactions with
1,2,4-Triazines and 1,2-Diazines. J. Org. Chem.1990, 55,
3257-3269.
Acknowledgements
Dr. John K. Snyder
Kyle Strom
Mark Busch
Boston University CIC
Boston University CMLD
• Reduce original 6 membered D-ring to a 5 membered ring
• Yield lower molecular weight with high molecular weight being
a major drawback for previous molecules
N
N
N
O
CO2Me
CO2Me
SL209 (A5, CMLD005699)
IC50: 1.4 µM - core dimerization
EC50: 3.2 µM - viral replication inhibiton
(validated by resynthesis)
N
N
N
O
CO2Me
CO2Me
SL210 (N3, CMLD005084)
2.0 µM - core dimerization
OMe
OMe
OMe
N
N
CH3
N
O
CO2Me
CO2Me
SL207 (F5, CMLD005012)
11.5 µM - core dimerization
OCH3
N
N
CH3
N
O
CO2Me
CO2Me
SL208 (F5, CMLD005006)
4.0 µM - core dimerization
O
O
Second Generation Library Attachment of a Second Heterocycle
N
N
N
O
CO2Me
CO2Me
O
N
N
N
O
CO2Me
CO2Me
N
N
N
O
CO2Me
CO2Me
N
N
N
O
CO2Me
CO2Me
( )n SL235: n =1, IC50 1.9 µM, CC50 <36 µM
MW = 930; cLogP = 10.5
SL236: n = 2, IC50 1.0 µM, CC50 <36 µM
MW = 958; cLogP = 10.1
SL231
IC50 = 98 nM
CC50 <100 µM
MW = 960
cLogP = 10.2
N
N
N
O
COOMe
COOMe
N
N
N
OMe
SL250
IC50 92 nM
MW = 653
cLogP = 4.4
N
N
N
O
COOMe
COOMe
N
N
N
NH
O
SL251
IC50 341 nM
MW = 702
cLogP = 7.9
Diversification