Kalyani J. Patil Research Topic Seminar June 3 rd 2006 O O O OH MeO A B C D E O Progress Toward the Synthesis of Progress Toward the Synthesis of the the Tetracyclic Tetracyclic Core of the Core of the Viridin Viridin Family Family Kalyani Patil @ Wipf Group
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Progress Toward the Synthesis of the Tetracyclic Core of the
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Kalyani J. PatilResearch Topic Seminar
June 3 rd 2006
O
O
O
OHMeO
A B
C D
EO
Progress Toward the Synthesis ofProgress Toward the Synthesis ofthe the Tetracyclic Tetracyclic Core of the Core of the ViridinViridin
FamilyFamily
Kalyani Patil @ Wipf Group
OutlineOutline
• Isolation and Structure
• Biological Activity
• Synthetic Approaches Toward Furanosteroids
• Tetracyclic Core of Viridin - Wipf Group
• Future Work
Kalyani Patil @ Wipf Group
• Isolated from fungi• Possess antifungal, antibiotic, and anti-inflammatory activity• Potent inhibitors of phosphatidylinositol 3-kinase (PI3-K)
Structure of Structure of FuranosteroidsFuranosteroids
O
O
O
OHMeO
HO
ViridiolO
O
O
OHMeO
Viridin (2 nM)
A B
C D
EO
O
O
O
OH
Demethoxyviridin (0.1 nM)
OO
O
O
OH
HO
Demethoxyviridiol
O
O
O
O
Wortmannin (4.2 nM)
OAc
O
MeO
O
H
HH
12
3
20
4 510
19
67
8911
12
13
18
1415
16
17
Kalyani Patil @ Wipf Group
Isolation of Isolation of FuranosteroidsFuranosteroids
O
O
O
OHMeO
HO
ViridiolO
O
O
OHMeO
Viridin
O
O
O
O
O
Wortmannin
OAc
O
MeO
Isolated in 1945 from Gliocladium virens
Structure Determined in 1966 by X-Ray Crystallography
Originally Isolated as Antifungal Agent
Isolated from Gliocladium deliquescens and G. virens
Antifungal and Phytotoxic Metabolite
Isolated in 1957 from Penicillium wortmannii and in 1972 from Myrothecium roridium
Structure Determined in 1972 Kalyani Patil @ Wipf Group
Planar Planar Polycyclics Polycyclics from Marine Spongefrom Marine SpongeXestospongiaXestospongia
O
O
O O
(+)-Halenaquinone
O
OH
OH O
O
O
O
O O
O
(+)-Halenaquinol(+)-XestoquinoneIsolated from Xestospongia Sapre in 1960
Isolated from Xestospongia Exigue in 1983
• Antibacterial Activity• Cardiotonic Properties• Inhibition of pp60 Kinase• Inhibition of EGF Kinase• Inhibition of the Dual Specificity Phosphatase Cdc25
• Nucleophilic Attack at the Electrophilic C-20 Position of the Furan Ring by Lys802 of p110 PI-3-Kinase
Kalyani Patil @ Wipf Group
PKB Regulation Through Inhibition of thePKB Regulation Through Inhibition of thePhophorylation Phophorylation at the 3-Position of at the 3-Position of Inositol Inositol LipidsLipids
Wipf, P.; Halter, R. J. Org. Biomol. Chem. 2005, 3, 2053.
Structural Analogs and ICStructural Analogs and IC5050 Values for inValues for invitro PI-3 vitro PI-3 Kinase Kinase InhibitionInhibition
O
O
O
OO
AcO
H
MeO
WortmanninIC50 = 4.2 nM
O
O
OHOH
IC50 = 4600 nM
MeO
O
O
OHOHHO
IC50 = > 32,000 nM
O
O
OH
OO
AcO
H
MeO
IC50 = 0.4 nM
O
O
O
OO
AcO
H
MeO
IC50 = >500 nM
O
O
O
OOH
MeO
IC50 = 6 nM
O
O
O
OOH
MeO
IC50 = 16.7 nM
O
O
OOH
MeO
IC50 = 271 nM
AcO
OKalyani Patil @ Wipf Group
Synthesis of Synthesis of FuranosteroidsFuranosteroids