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Natural Product Inspired Scaffolds DesignJetze J. Tepe, Department of Chemistry
N
NR1
R4R3
CO2H
R2Imidazolines
NR1
R4R3
CO2H
R2
1-Dihydropyrrolines
Pyrrolidinones
R3R4
N
HN O
H2N
N
HN O
R1
R4R3
O
NR1
R2
R3
Oxazoles
Dihydroimidazolones
Imidazolones
Triazolines
NN
NH
R1 R2
NN
NR1R2
R3 R3
CO2H
Triazoles
NH
OR5
R3O CO2H
R2
R4
Natual Product Mimics
NH
O
OOH
Salinosporamide A
Cl
O
H
NH
O
NO Me
HO
OH
MeN
HO
Me O
Me
MeMe
HO
N
HN O
N
Me
Me
NH
O
5-(1H-indol-3-yl)-imidazolones
NH
NH
O
N
HN
OH2N
Debromohymenialdisine
N
NH
O
Br
Br
NH
HN
O
O
Agesamide A/B
N
N
HNNH
O
NH
HNH2
H
N
N
O
Br
Br
Cl
N
NH
NH2
HO
Palau'amineX = NH2, DibromophakellinX = OH, Dibromophakellstatin
OO
Oxazolomycin
HN N
X
N
O
NH
Cylindradine A
HNNH
NH
Br
Br
NH O
Br
BrHN
NNH
HNHO O
Nagelamide M
SO3
O
N
HN
HN
NOH
NH2H2N
HN NH
Massadine
HO
NH O
Br
Br
R =
OO
R R
Natural Products New Scaffolds
Marine Sponge Metabolites Screening for Biological activity
NF-kB-luc reporter assay screen (HeLa cells)
NF-kB pathway analysis & target identification
Target confirmation in vitro (purified enzyme assay)
Target validation in vivo(mouse efficacy models)
Chemical optimization
NH
O
OOH
Salinosporamide A
Cl
O
H
NH
O
NO Me
HO
OH
MeN
HO
Me O
Me
MeMe
HO
N
HN O
N
Me
Me
NH
O
5-(1H-indol-3-yl)-imidazolones
NH
NH
O
N
HN
OH2N
Debromohymenialdisine
N
NH
O
Br
Br
NH
HN
O
O
Agesamide A/B
N
N
HNNH
O
NH
HNH2
H
N
N
O
Br
Br
Cl
N
NH
NH2
HO
Palau'amineX = NH2, DibromophakellinX = OH, Dibromophakellstatin
OO
Oxazolomycin
HN N
X
N
O
NH
Cylindradine A
HNNH
NH
Br
Br
NH O
Br
BrHN
NNH
HNHO O
Nagelamide M
SO3
O
N
HN
HN
NOH
NH2H2N
HN NH
Massadine
HO
NH O
Br
Br
R =
OO
R R
Marine Sponge Metabolites Hymenialdisine
NH
O
OOH
Salinosporamide A
Cl
O
H
NH
O
NO Me
HO
OH
MeN
HO
Me O
Me
MeMe
HO
N
HN O
N
Me
Me
NH
O
5-(1H-indol-3-yl)-imidazolones
NH
NH
O
N
HN
OH2N
Hymenialdisine
N
NH
O
Br
Br
NH
HN
O
O
Agesamide A/B
N
N
HNNH
O
NH
HNH2
H
N
N
O
Br
Br
Cl
N
NH
NH2
HO
Palau'amineX = NH2, DibromophakellinX = OH, Dibromophakellstatin
OO
Oxazolomycin
HN N
X
N
O
NH
Cylindradine A
HNNH
NH
Br
Br
NH O
Br
BrHN
NNH
HNHO O
Nagelamide M
SO3
O
N
HN
HN
NOH
NH2H2N
HN NH
Massadine
HO
NH O
Br
Br
R =
OO
R R
Br Axinella verrucosa
NH
NH
Br
O
NHN O
H2N
Hymenialdisine
Pathway: NF-kappaB: Journal of Medicinal Chemistry 2004, 47, 3700
Target: Chk2: Bioorganic & Medicinal Chemistry Letters. 2004, 14, 4319
Chemical optimization: Bioorganic & Medicinal Chemistry 2012, 20, 1475
Application: Protection of normal cells from ionizing radiation ACS Chemical Biology 2012, 7, 172
Scaffold 1IC50 8 nM
In collaboration with: Sandra O’Reilly, Justin McCormick
Marine Sponge Metabolites Palau’amine
NH
O
OOH
Salinosporamide A
Cl
O
H
NH
O
NO Me
HO
OH
MeN
HO
Me O
Me
MeMe
HO
N
HN O
N
Me
Me
NH
O
5-(1H-indol-3-yl)-imidazolones
NH
NH
O
N
HN
OH2N
Hymenialdisine
N
NH
O
Br
Br
NH
HN
O
O
Agesamide A/B
N
N
HNNH
O
NH
HNH2
H
N
N
O
Br
Br
Cl
N
NH
NH2
HO
Palau'amineX = NH2, DibromophakellinX = OH, Dibromophakellstatin
OO
Oxazolomycin
HN N
X
N
O
NH
Cylindradine A
HNNH
NH
Br
Br
NH O
Br
BrHN
NNH
HNHO O
Nagelamide M
SO3
O
N
HN
HN
NOH
NH2H2N
HN NH
Massadine
HO
NH O
Br
Br
R =
OO
R R
Br
Pathway: NF-kappaB: Journal of Natural Products 2012, 75, 980-985
Target: Proteasome: Journal of Natural Products 2012, 75, 980-985
Chemical optimization: Organic Letters 2011, 13, 4550-4553
Application: NEW MECHANISM: Multiple myeloma
N
N
HNNH
O
NH
HNH2
H
Cl
N
NH
NH2
HO
Palau'amine
Angewandte Chemie Int. Ed. 2015 54, 2830-2833.
S3 pocket with dibromophakellin
S1 pocket with bortezomib
Common Ala49Thr mutation
Covalent 1N Thr- boronicester bond
Our scaffold in S3 binding
All other MM drugs in S1
binding pocket
NN
HNN
OBr
NH2
Natural Product Mimics
Pathway: NF-kappaB: Journal of the American Chemical Society 2006, 128, 9137
Target: Proteasome: ACS Chemical Biology, 2013, 8, 578
Chemical optimization: Journal of Medicinal Chemistry, 2013, 56, 5974
Application: Multiple Myeloma ACS Chemical Biology, 2013, 8, 578
N
NR1
R4R3
CO2H
R2
In collaboration with:
Bill Henry, Justin McCormick & Katherine Weilbaecher
End of treatment
N
NR1
R4R3
CO2H
R2Imidazolines
NR1
R4R3
CO2H
R2
1-Dihydropyrrolines
Pyrrolidinones
R3R4
N
HN O
H2N
N
HN O
R1
R4R3
O
NR1
R2
R3
Oxazoles
Dihydroimidazolones
Imidazolones
Triazolines
NN
NH
R1 R2
NN
NR1R2
R3 R3
CO2H
Triazoles
NH
OR5
R3O CO2H
R2
R4
Natual Product Mimics
Natural Product Mimics
Chemical Modification
N
NR1
R4R3
CO2H
R2
Mechanism: NEW MECHANISM: Proteasome Assembly
Mycobacterium Tuberculosis
With Robert Abramovitch
N
NR1
R4R3
CO2H
R2Imidazolines
NR1
R4R3
CO2H
R2
1-Dihydropyrrolines
Pyrrolidinones
R3R4
N
HN O
H2N
N
HN O
R1
R4R3
O
NR1
R2
R3
Oxazoles
Dihydroimidazolones
Imidazolones
Triazolines
NN
NH
R1 R2
NN
NR1R2
R3 R3
CO2H
Triazoles
NH
OR5
R3O CO2H
R2
R4
Natual Product Mimics
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