peptidomimetics and mimicry of -strand / sheets and -sheet sandwiches jian liu merck & co.,...
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Peptidomimetics and Mimicry of -Strand / Sheets and -Sheet Sandwiches
Jian Liu
Merck & Co., Inc.
Rahway, NJ 07065
Research Summary
Pyrrolinone -Strand Peptidomimetic
HIV-1 Protease Inhibitor
1999-presentUPenn
NH
HN
O
NHCH3
OPh
CbzHN
BnO
O
OHN
O
OH
PhO
HN
O
O NH2
OPh
Ph
-Sheet Sandwich
1998-1999UC Irvine
ON
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HNN
O
ON
H
Hi-Pr
O
Me
NH
RAla
RLys
N
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HN
N
O
ON
H
Hi-Pr
O
Me
NH
ROrn
RVal
Cycloaddition of Enol Ethers
1994-1998UCLA
Enantioselective Epoxidation
RR
O
O
R
O R
X
O
O
R
X
O
O R
s-transGround state of enol etherss-cis
s-transs-cis
Transition States
Part I
a. Computational Study on Epoxidation Reactions
b. Conformational Switch for Enol Ethers in Cycloaddition Reactions
Reaction Path Investigation by Computational Methods
R
TS1*
TS2*
Ea1
Ea2
Ea
k1/k2 = e -Ea/RT
P1
P2
Epoxidations of Unfunctionalized Olefins
Liu, J., Houk, K. N. et. al. J. Am. Chem. Soc. 1997, 119, 3385-3386; J. Am. Chem. Soc. 1997, 119, 10147-10152; J. Am. Chem. Soc. 1997, 119, 12982-12983; J. Org. Chem. 1998, 63, 8565-8569
O
OO
H
R'
R O
O
H
R'O
R
R O
R"R' O
R
R N R"
R'O
R
OO
NO
R'R"
R'
R"
R N+ R"
R'O
RN+
O
R'
R"R"'
R"'+
+ +(1)
+
+
+
+
(2)
(3)
+(4)
Part I
a. Computational Study on Epoxidation Reactions
b. Conformational Switch for Enol Ethers in Cycloaddition Reactions
Conformational Switch in Cycloaddition of Enol Ethers
s-cis in ground state s-trans in transition state
Liu, J.; Niwayama, S.; You, Y.; Houk, K. N. J. Org. Chem. 1998, 63, 1064.
O
R
N
O
O R
Stereoselective Cycloaddition Reactions of Chiral Enol Ether
Denmark, S. E. et. al. J. Org. Chem. 1994, 59, 5672; 1995, 60, 3205; 1995, 60, 3574.
Reissig, H. U. et. al. SYNLETT 1990, 514; Angew. Chem. Int. Ed. Engl. 1992, 31, 1033.
O2N
O
O
Ph
Ph
HO
H
N+ O-O
H
O
O
Ph
O
Ph
+Ti(O-i-Pr)2Cl2CH2Cl2
13 : 1
NO
Ph
O
O O
OO
OO
NO
R*
+
Diastereomerically pure
Ground State Conformations of Chiral Enol Ethers
Conformations of Vinyl Methyl Ether in Ground and Transition States
Design of Conformation Fixed Enol Ethers
trans cis trans cis
O O
Designed Diels-Alder Reactions with the Conformation Fixed Enol Ethers
Y NO Y
ON Y NO
Y
ON
Ph
Ph Ph
Ph
ON
Ph
ON
Ph
O
O
1
13.5
b: +33.5
+Y= CH2 : yield = 14%
Y= O : yield = 84%(1)
(2)Y= CH2 : yield = 90%
Y= O : yield = 95%
(3) Competitive Reactions:
a: +
Product Ratio
1
+
Designed 1,3-dipolar Cycloaddition With the Conformation Fixed Enol Ethers
N+
COPh
O-Ph Y ONPh
COPh
Y
N+
COPh
O-PhY O
NPh
COPh
Y
N+
COPh
O-Ph
N+
COPh
O-PhO
O 12.2
Y = CH2: yield= 85%
Y = O, endo : yield= 72%
exo : yield= 23%
(1)
Product Ratio
+
1
(2)
+
(3) Competitive Reactions:
a:
b:
Y = CH2, endo : yield= 46%
exo : yield= 38%
Y = O, endo : yield= 51%
exo : yield= 47%
+
+
1
10.0
Comparison of the Calculated and Experimental Results
k1/k2 = e -Ea/RT
Diels-Alder of Enol Ethers
Calculated Ea (kcal/mol) Experimental Ea (kcal/mol)
Diels-Alder of Alkenes
1,3-Dipolar of Enol Ethers
1,3-Dipolar of Alkenes
2.4 2.1 ( 33.5 : 1)
1.0 1.5 (13.5 : 1)
3.0 1.5 (12.2 : 1)
1.4 1.4 (10.4 : 1)
Rationalization of Conformation Switch
OR
O R
s-transGround state of enol etherss-cis
s-transs-cis
Transition States
XO
OR
XO
O
R
Summary for Ph.D Research at UCLA
RR
O
a. Computation study on epoxidation reaction:
b. Conformation switch of enol ether in cycloaddition reaction:
O
R
NO
O R
s-cis s-trans
O O
O
R
O R
X
O
O
R
X
O
O R
s-transGround state of enol etherss-cis
s-transs-cis
Transition States
Part II
Design, Synthesis and Structure Study of Artificial -Sheet Sandwiches
Previous Study on Artificial -Sheet Structures
Nowick, J. S. et al J. Org. Chem. 1997, 62, 7906-7907.Nowick, J. S. et al Chem. Soc. Rev. 1996, 25, 401-415. Nowick, J. S. Acc. Chem. Res. 1999, 32, 287-296.
-Sheet Mimic
NH
HN
NH
HN
CH3O O
O OCH3 CH3
NH
HN
NH
HN
CH3O
O
O
PhO
N
N
O
Ph
NC
The Importance of the -Sheet Sandwich in Nature
Definition: The -Sheet sandwich is a structure motif in proteins in which two -sheets face each other to form a sandwich. The -sheet sandwich can act as a binding pocket.
Goal of building the artificial -sheet sandwich: To build a chemical model to mimic the three dimensional structures of globular proteins.
Lipid binding protein: 1lif
Design of an Artificial -Sheet Sandwich
Hydrophilic Back
Hydrophobic Face
ON
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HNN
O
ON
H
Hi-Pr
O
Me
NH
RAla
RLys
N
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HNN
O
ON
H
Hi-Pr
O
Me
NH
ROrn
RVal
Artificial -Sheet Sandwich
Xanthene Template
Synthesis of a Model with one Template Holding two -Turn Scaffold Structures
O
N
N
N
NC
N
NC
NH
OPh
NH
PhO
HN
PhO
O
HN
Ph
SO2Cl
NO2
DPPA, Et3N
BnOH, Tolune (80°C)
H2, Pd/C
MeOH
( 78 % )
Collidine, CH2Cl2
( 80 % )
O
CO2H
CO2H
O
NHCbz
NHCbz ( 95 % )
O
NH2
NH2
O
NHSO2Ar
NHSO2Ar
1. PPh3, DEAD, THF HOCH2CH2NHBoc
2. HSCH2CH2OH, LiOH DMF ( 85 %, two steps )
O
NH
NH
NHBoc
NHBoc
Xanthene Diacid
Synthesis of a Model with One Template Holding Two -Turn Scaffold Structures (Cont.)
CN
2) NaHCO3
80°C
3) MeOH,
PhCNO
Template with Two Scaffolds
O
NH
NH
NHBoc
NHBoc
1) TFA/CH2Cl2
( 70 % )
O
NH
NH
HN
NH
CN
CN
( 95 % )
O
N
N
N
NC
N
NC
NH
OPh
NH
PhO
HN
PhO
O
HN
Ph
Crystal Structure of the Model with a Template Holding Two -Turn Scaffolds
Synthesis of the Designed -Sheet Sandwich
O
NH
NH
NH
NH
NC
NC
OCNO
HN
OCH3
NH
O
NH
NH
N
N
NC
NC
O
HN
OCH3
NHN
H
O
O
HN
OCH3
NH
NH
O
OCNO
HN
ROrn(Z)
O
N
NH
N
N
NC
NC
O
HN
OCH3
NH
NH
O
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
O
O
O
N
O
O
N
O
O
RVal
( 94% )
THF, 30 min
( 95 % )
THF, rt, 19 hr
Synthesis of the Designed -Sheet Sandwich (Cont.)
O
N
NH
N
N
NC
NC
O
HN
OCH3
NH
NH
O
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
H2N
HN
O
RAla
O
N
O
O
O
N
N
N
N
NC
NC
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
O
N
O
Cl
O
HN
OO
NH
HN
O
O
CH3
N
O
RLys(Z)
RVal
O
N
N
N
N
NC
NC
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
O
N
O
HN
O
HN
OO
NH
HN
O
O
CH3
NH
N
O
O
RAla
RLys(Z)
RVal
RVal
COCl2, CH2Cl2
NaHCO3 ( sat ), 0 °C, 15 min
•HCl
TEA, THF, rt, 19 hr
-Sheet Sandwich
( 90 %, two steps )
Two Dimensional TLC Test on the Interconvergenceof Different Conformations for -Sheet Sandwich 11
Solvent 10 % MeOH / CHCl3 1D TLC 2D TLC
Possible Conformations for -Sheet Sandwich
Back - Face Face - Face
Back - Back Face - Back
New Design for -Sheet Sandwich with an Additional Linkage between -Sheets
ON
CN
N
O
O
HN
O
O
N
H
NN
O
O
N
H
H
O
Me
NH
RTyr
N
CN
N
O
O
HN
O
O
N
H
NN
O
O
N
H
H
O
Me
NH
ROrn
S
S
Synthesis of -Sheet Sandwich with S-S Linkage
O
N
N
N
N
NC
NC
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
O
N
O
HN
O
HN
OO
NH
HN
O
O
CH3
NH
N
O
O
RCys(Acm)
RTyr(Bn)
RCys(Acm)
2. Dithiothritol
1. NPSCl, AcOH
O
N
N
N
N
NC
NC
O
HN
OCH3
NH
NH
O
NH
HN
O
O
ROrn(Z)
O
N
O
HN
O
HN
OO
NH
HN
O
O
CH3
NH
N
O
O
RCys
RTyr(Bn)
RCys
Synthesis of -Sheet Sandwich with S-S Linkage (Cont.)
O
N
N
N
N
NC
NC
O
HN
OCH3
NHN
H
O
NH
HN
O
O
ROrn(Z)
i-Pr
O
N
O
HN
O
HN
OO
NH
HN i-Pr
O
O
CH3
NH
N
O
O
RCys
RTyr(Bn)
RCys
ON
CN
NO
O
HN
O
O
N
HN
N
O
ON
H
Hi-Pr
O
Me
NH RTyr
N
CN
NO
O
HN
O
O
N
HNN
O
ON
H
Hi-Pr
O
Me
NH
ROrn
S
S50%
(1) O2, MeOH, Cu
(2) HBr/AcOH
Synthesis of -Sheet Sandwich with C-C Linkage
Metathesis Product: ( 3 : 1, trans to cis )
O
N
N
N
N
NC
NC
O
HN
OCH3
NHN
H
O
NH
HN
O
O
ROrn(Z)
O
N
O
HN
O
HN
OO
NH
HN
O
O
CH3
NH
N
O
O
RAllyl
RTyr(Bn)
RAllyl
ON
CN
NO
O
HN
O
O
N
HN
N
O
ON
H
H
O
Me
NH RTyr
N
CN
NO
O
HN
O
O
N
HNN
O
ON
H
H
O
Me
NH
ROrn
1. Grubbs Ru Catalyst CHCl3, 48 hrs, 70%
2. Pd/C, H2, MeOH
NMR Study of the -Sheet Sandwiches with C=C Linkage
No Inter Sheet NOEs Observed Inter Sheet NOEs: H15 - H18; H15 - H20; H18 - H19;
H23 - H27; H26 - H21; H27 - H21.
O
Me5
Me6N
CN
NO
O
H28N
O
O
NMe
H11
NN
O
O
N
H26
H27
O
Me22
NH12
RTyr
N
CN
NO
O
H25N
O
O
NMe
H9
NN
O
O
N
H23
H24
O
Me21
NH10
Bu7
Bu8
H4
H1
H2
H3
H13H14
H15
H16H17
H18
ROrn
H31
H32
H19
H20
H30
H29 Me
Me
Me
MeH
MeMe
H
O
Me5
Me6N
CN
NO
O
H28N
O
O
NMe
H11
NN
O
O
N
H26
H27
O
Me22
NH12
RTyr
N
CN
NO
O
H25N
O
O
NMe
H9
NN
O
O
N
H23
H24
O
Me21
NH10
Bu7
Bu8
H4
H1
H2
H3
H13H14
H15
H16H17
H18
ROrnH19
H20
H30
H29 Me
Me
Me
MeH33
MeMe
H34
H31
H32
Summary of Postdoc Research at UC Irvine
a. Designed and synthesized the artificial -sheet sandwich:
b. Designed and synthesized the -sheet sandwich with homogenous conformation:
ON
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HNN
O
ON
H
Hi-Pr
O
Me
NH
RAla
RLys
N
CN
NO
O
(CH2)2
HN
O
O
NH
CH3
HNN
O
ON
H
Hi-Pr
O
Me
NH
ROrn
RVal
Artificial -Sheet Sandwich
ON
CN
NO
O
HN
O
O
N
HNN
O
ON
H
Hi-Pr
O
Me
NH RTyr
N
CN
NO
O
HN
O
O
N
HNN
O
ON
H
Hi-Pr
O
Me
NH
ROrn
S
S
Artificial -Sheet Sandwichwith a Second Linkage
Part III
Design, Synthesis and Structure Study of -Strand Peptidomimetic Based on Pyrrolinone Backbone
Concept for the Design of -Strand Peptidomimetic Based on Pyrrolinone Backbone
NH
HN
NH
O
O
O
O
HN
R H
R H
R H
R H O
O
O
OR
R
R
R H
NH
O
R
HN
O
R
NH
O
R O
R H
NH
O
R
HN
O
R
NH
O
R O
R H
Nitrogen-Displaced Pyrrolinones
NH
NH
HN
Peptide -Strand ConformationDisplaceNitrogens
CyclizePyrrolinone
Rings
IncorporateEnaminone
Functionality
NH
OR
NH
ORH
N
OR
HN
RH O
NH
HN
NH
O
O
O
O
HN
H R
H R
H R
H R
NH
HN
NH
O
HN
NH
OR
NH
ORH
N
OR
HN
RH O
R
R
R
RH
O O
ODisplace
Carbonyls
CyclizePyrrolinone
Rings
IncorporateEnaminone
Functionality
Carbonyl-Displaced Pyrrolinones
Peptide -Strand Conformation
Precigoux, G et. al. J. Am. Chem. Soc. 1987, 109, 7463.Smith, A. B. III; Hirschmann, R. et. al. J. Am. Chem. Soc. 1994, 116, 9947.
Peptides and Peptidomimetics Which Forms -Strand/Sheets
CO2Me
NH2
Ph
N
N
N
O
O
O
CO2Me
NHBocPh
N
N
N
O
O
O
NH
HN
O
NH
CH3
OPh
CbzHN
BnO
O
H2NNH
HN
NH
OHO
O
O
O
OH
Parallel-Sheet in Solid State
Anti-parallel -Sheet in Solid State
Parallel-Sheet in Solid State
What Kind of Conformation?
H
H
H
H
HH
Retrosynthesis of Tris Carbonyl Displaced Pyrrolinone
NH
O
HN
O
NH
CH3
OPh
CbzHN
BnO
HN
O
NH
CH3
OPhCbzHN
BnO
O O
TeocHN
HN
O
NH
CH3
OPh
H
O
TeocHN
CH3
OCbzHN
BnO
TeocHN CHO
BnO CH3
OBocHN
BnOH
O
NHCbz
CH3
Ph
A B C D
+
NH
O
CH3Ph
BocHN
O
+
A
B
Synthesis of Fragment A and B
HO2C
NH2 NO
O
AllocN
O
O
AllocOBn
NHO
O
O
OBn NH2OBn
HO
CbzNHOBn
HO
TeocNHOBn
HO
CbzNHOBn
H3C
O
TeocNHOBn
H
O
( 88 %, three steps )
CbzCl, TEA, CH2Cl2
( 61 % )
3. Alloc-Cl, CH2Cl2
( 60 %, three steps )
1. NaOH, EtOH, H2O
2. t-BuCHO, pentane reflux, 3d
L-Leu 0 °C, 14d
KHMDS, BnOCH2Cl
THF, -78°C
1. 1N NaOH, MeOH
2. (COCl)2, PhH, reflux
NaBH4, MeOH 0 °C
( 65 % )
1. TPAP, NMO MS 4Å, CH2Cl2
3. TPAP, NMO MS 4Å, CH2Cl2
2. MeMgBr, THF - 78 °C
A
TPAP, NMOMS 4Å, CH2Cl2
B
Teoc-succimide, TEA, CH2Cl2
( 85 % )
( 94 % )
( 72 %, three steps )
over 20 : 1 cis : trans
Synthesis of Fragment D
S. Knight
HO2C
NH2
Ph NO
O
Alloc
PhN
O
O
Alloc
PhCH3
NHO
O
O
CH3
Ph HOCbzHN CH3
Ph
CbzHN CH3
O
H Ph
D
KHMDS, CH3I
D-Phe
2. t-BuCHO, pentane reflux, 3d
3. Alloc-Cl, CH2Cl2THF, -78 °C
1. NaOH, EtOH, H2O
1. 1N NaOH, MeOH
2. NaBH4, MeOH MS 4Å, CH2Cl2
Et3N, THF, 0 °C
( 44 %, five steps )
TPAP, NMO
2. (COCl)2, PhH, reflux
1. Cbz-Cl, DMAP
( 81 % )
( 74 %, three steps )
0 °C, 15d
Synthesis of Fragment C
S. Knight
HO2C
NH2
ON
O
Alloc
ON
O
Alloc
OBn
ONH
O
OBn
O
HO
NHBocOBn
H
NHBocOBn
O
H3C
NHBocOBn
OH
H3C
NHBocOBn
OO
BocHN
BnO
C
L-Val
1. NaOH, EtOH, H2O
2. t-BuCHO, petane, reflux, 3d
3. Alloc-Cl, CH2Cl2 0 °C, 14d
( 84 %, three steps )
KHMDS, BnOCH2Cl
THF, -78 °C
( 84 % )
1. 1N NaOH, MeOH
2. (COCl)2, PhH, reflux1. Boc2O, DMAP Et3N, THF
2. NaBH4, MeOH 0°C,
( 61 %, four steps )
TPAP, NMOCH2Cl2, MS 4Å
MeMgBrTHF, -78 °C
( 60 % )
TPAP, NMOCH2Cl2, MS 4Å
( 99 % )
( 96 % )
Synthesis of Mono Pyrrolinone
S. Knight
MeOH, rt
CH2Cl2
Dess-Martinperiodinane
H2, Pd/C
( 86% )
1. HCO2H, Pd black MeOH
1. MeMgBr, THF
( 81% )
2. Dess-Martin
( 60 %, for two steps )
+
( 98% )
LiHMDS
THF, -78 °C
2. TPAP, NMO
( 70 %, two steps )
C D
BocHNO
BnOH
O
NHCbz
CH3
PhBocHN
O
BnO
OH
NHCbz
CH3
Ph
BocHNO
BnO
O
NHCbz
CH3
Ph
NH
CH3
OPh
BocHN
BnO
NH
CH3
OPh
BocHN
H
O
NH
CH3
OPh
BocHN
O
Synthesis of Bis Pyrrolinone
N CH3
OPh
BocHN
OBoc
THF, -78 °C - 0 °C
KHMDS (1.1 eq),Boc2O ( 2.5 eq )
( 85 % )
NH
CH3
OPh
BocHN
O TeocHN CHO
BnO
N CH3
OPh
BocHN
OBoc
OHTeocHN
BnO
LiHMDS ( 5 eq ), THF, -78 °C
B ( 2 eq )
( 60 - 85 % )
NH
CH3
OPh
BocHN
OTeocHN
BnO
O2. Dess- Martin, Pyr, CH2Cl2, rt
( 76 % )
1. NaHSO4 ( sat ), THF, rt, 24 hr
HN
O
NH
CH3
OPh
TeocHN
BnO
TsOH ( 4 eq ), EtOH 85 °C, 25 min
( 82 % )
HN
O
NH
CH3
OPh
H2N
BnO
( 0 - 5 % )
+
Synthesis of Tris Pyrrolinone
HN
O
NH
CH3
OPh
TeocHN
BnO HN
O
NH
CH3
OPh
TeocHN
HOHCOOH, Pd Black
MeOH
( 91 % )
HN
O
NH
CH3
OPh
TeocHN
TMSO
TMSCl ( 2 eq ), TEA (4 eq)
( 89 % )
HN
O
N CH3
OPh
TeocHN
TMSO
Boc
KHMDS(1.1 eq),Boc2O (3.0 eq)
THF, -78 °C - 0 °C
( 85 % )
HN
O
N CH3
OPh
TeocHN
HO
Boc
4 % AcOH / MeOH
( 95 % )
HN
O
N CH3
OPh
TeocHN
H
Boc
ODMSO, DCC
Pyridine, TFA, PhH
Synthesis of Tris Pyrrolinone (Cont.)
HN
O
N CH3
OPh
TeocHN
H
Boc
O
CH3
OCbzHN
BnO
TeocHN
HN
O
N CH3
OPh
Boc
CbzHN
BnO
O OHLiHMDS, THF, -78 °C
( 23 %, two steps )
A
TeocHN
HN
O
N CH3
OPh
Boc
CbzHN
BnO
O OH
Retro Aldol Reaction:
CbzHN
BnO
O O
HTeocHN
HN
O
N CH3
OPh
Boc+
H
Synthesis of Tris Pyrrolinone (Cont.)
TeocHN
HN
O
N CH3
OPh
Boc
CbzHN
BnO
O OH
NH
HN
O
NH
CH3
OPh
CbzHN
BnO
O
1. Dess-Martin, Pyr, CH2Cl2
2. TFA, rt, 15 min( 18 %, two steps )
H2, Pd/C
NH
HN
O
NH
CH3
OPh
H2N
BnO
O
74 %
+
N
HN
O
NH
CH3
OPh
CbzHN
BnO
X - Ray Crystallography and NMR Study
Part IV
Design and Synthesis of Pyrrolinone Based HIV-1 Protease Inhibitor
Previous Peptidomimetic HIV-1 Protease Inhibitors
OHN NH2
OPh
OH N
N O
PhPh
O O
O
IC50 1.3 nM, CIC95 800 nM
OHN
OPh
OH NPh
O O
OH
IC50 2 nM, CIC95 100 nM
OHN
O
OH
Ph
HN
O
Ph
NH
O
CH3
Ph
10 % inhibition at 3 M
OHN
O
OH
PhO
HN
O
O NH2
OPh
Ph
HH
H
Smith, A. B., III, Pasternak, A., Hirschmann, R. et. al. J. Med. Chem. 1997, 40, 2440-2444
Retrosynthesis of Second Generation Carbonyl Displaced Pyrrolinone HIV-1 Protease Inhibitor
OHN
O
OH
PhO
HN
O
O NH2
OPh
Ph
BocNO
H
OPh
Ph
O
NHCbz
OBn
Ph
+
BocHNO
O
Ph
BocHNOH
O
Ph
ON
O
Alloc
Ph
BocHNOH
O
Ph
L-Phe
D-Phe
Available from PreviousCarbonyl-Displaced PyrrolinoneHIV-1 Inhibitor Project
Synthesis of Carbonyl Displaced Pyrrolinone HIV-1 Protease Inhibitor
1. Dess-Martin Periodinane Pyr, CH2CL2
2. H2, Pd(OH)2, MeOH, Overnight
( 72 %, two steps )
BocNO
Ph
PhHN
O Ph
OHa. Cl3CCON=C=O, CH2Cl2
b. K2CO3, MeOH / H2OBocN
O
Ph
PhHN
O Ph
O NH2
O
1. 1N HCl / MeOH
2. O
O OO
N
O
O Et3N, CH2Cl2
OHN
O
OH
PhO
HN
O
O NH2
OPh
Ph
( 54 % )
( 62 %, two steps )
O
NHCbz
OBn
Ph
a. LiHMDS, THF, -78 °C
b.BocN
OH
OPh
Ph
( 35 - 43 % )
BocNO
OH O
NHCbz
Ph OBnPh
Ph
X-Ray Crystal Structure of HIV-1 Protease Complexed with Inhibitor
H2O
Asp29
Asp25
Asp225
H2O
Ile250 Ile50
Gly27
A. Pasternak
OHN
OPh
OH N
Ph
O O
OHH
IC50 2 nM, CIC95 100 nM
X-Ray Crystal Structure of HIV-1 Protease Complexed with Inhibitor
Asp29
Asp25
Asp225
H2OIle250
Ile50
Asp230
Gly227
L. Zawaki
OHN
O
Ph
OH N
Ph
O O
O NH2
OH
IC50 2.1 nM, CIC95 250 nM
Design of New Carbonyl Displaced Pyrrolinone HIV-1 Protease Inhibitor
Asp230
Gly227
Asp225
Asp25
Asp29
Ile250Ile50
OH
Ph
PhHN
OPh
NH2OH
HNO
OO
Summary of Postdoc Research at UPenn
a. The tris carbonyl-displaced pyrrolinone was synthesized and the structure is being studied:
b. A carbonyl-displaced pyrrolinone HIV-1 protease inhibitor was designed and synthesized. A new design was made based on modeling:
NH
HN
O
NH
CH3
OPh
CbzHN
BnO
O
NH
HN
O
NH
CH3
OPh
H2N
BnO
OOH
Ph
PhHN
OPh
NH2OH
HNO
OO
OHN
O
OH
PhO
HN
O
O NH2
OPh
Ph
Acknowledgements
Professor Ken N. Houk (UCLA)
Professor James S. Nowick (UC Irvine)
Professor Amos B. Smith, III (UPenn)
Professor Ralph Hirschmann (UPenn)
Thank You