Research Topic Seminar 18 June 2005 Studies Toward the Total Synthesis of (±)-Noelaquinone David Amantini WIPF GROUP The Role of Natural Products in Drug Discovery Butler, M. S. J. Nat. Prod. 2004 67 2141. For thousands of years medicine and natural products have been closely linked through the use of traditional medicines and natural poisons. Which is the STATUS of NATURAL PRODUCTS in DRUG DISCOVERY today ? David Amantini @ Wipf Group 1 6/20/2005
Transcript
Research Topic Seminar 18 June 2005
Studies Toward the Total Synthesis of (±)-Noelaquinone
David Amantini
WIPF GROUP
The Role of Natural Products in Drug Discovery
Butler, M. S. J. Nat. Prod. 2004 67 2141.
For thousands of years medicine and natural products have been closely linked through the use of traditional medicines and natural poisons.
Which is the STATUS of NATURAL PRODUCTS in DRUG DISCOVERY today ?
David Amantini @ Wipf Group 1 6/20/2005
Understanding the Cell-Cycle with Natural Products
Schreiber, S. L. et al Chem. Biol. 1996 3 623.
Understanding Protein Function in Cells
Genetic Approach: making mutations in genes that alter the function of the encoded protein
Chemical Approach: to alter the function of the protein directly by using a cell - permeable ligand that binds to the protein in its intracellular environment
Currently the most valuable collection of ligands for use in the study of protein function are NATURAL PRODUCTS or compounds that are closely related to a NATURAL PRODUCT
CELL BIOLOGYNATURAL PRODUCTS CHEMISTRY
Small molecule natural products inhibit progression of the cell cycleby binding to a protein required for cell division, thus helping to
determine the function of the protein
An understanding of cell cycle events helps in understanding the mechanisms of action of many cell - cycle inhibitors
O
Me
O
HO
O N
OO
H
O
MeMe
OH
Me
O
OMe
Me
H
OMe
OH
Me
Me
OMe
H
RAPAMYCIN
Relative Timing of Arrest by Different Cell-Cycle Arrest Agents
TUNICAMYCIN V
Me
Me O
N O
H HOOH
O
NH
O
ON
O
OHOH
OH
O
OH
HOHO
AcHN
APHIDICOLIN
HO
OH
H
Me
HMe
HO
HO
OKADAIC ACID
O
OHO
O
HO
Me
HO
H
Me
H
Me
O
H
O
O
HH
OH
HO
H
Me
O
O
Me
DISCODERMOLIDE
OO
Me
OH
Me
H
HO
Me
OH
Me
Me
Me Me
OH OCONH2
Me
O
O
Me
O O
O
MeOAcO
Me
H
WORTMANNIN
David Amantini @ Wipf Group 2 6/20/2005
The Viridin Family of Steroidal Antibiotic: The Furanosteroids
O
Me
HO O
O
Demethoxyviridiol
HO
O
Me
HO O
O
Viridiol
HO
MeO
O
Me
O O
O
Demethoxyviridin
HO
O
Me
HO O
O
Wortmannolone
O
Me
H
Wipf, P. and Halter, R. J. Org. Biomol. Chem. 2005 3 2053.
O
Me
O O
O
Viridin
HO
MeO
Isolated in 1945 from Gliocadium Virensstructure determined in 1966
Anti - Inflammatory Activity
Antibiotic Activity
Potent and Specific Phosphoinositide 3 - kinase (PI 3K) Inhibitors
O
O
Me
O O
O
Isolated in 1957 from Penicillium Wortmannii and in1972 from Myrothecium Roridium, structure determined in 1972
MeOAcO
Me
H
Wortmannin
Furanosteroids: Proposed Biosynthesis
HO
Me Me
Me
Me
Me
Me
Me
Me
H
Lanosterol
Squalene 2,3-Epoxide
Me
Me Me Me
Me
Me Squalene
Me
OP
OO
P
O
O
O
O
Me
Me
OP
OO
P
O
O
O
O
+
O
O
Me
Me
H
OAcO
O
MeO
O
O
Me
O
O
HO
O
MeO
Viridin Wortmannin
Me
Me
Me
MeMe Me
Me
Me
Me
Me
O
Hanson, J. R. Nat. Prod. Rep. 1995 12 381.
David Amantini @ Wipf Group 3 6/20/2005
Wortmannin Irreversible Inhibition of PI-3 Kinase
O
O
Me
O O
O
MeOAcO
Me
H
IC50 = 4.2 nM
Wortmannin
MeO
Me
OO
OH
OMe
H
IC50 = 4600 nM
HO
Me
OO
OH
OMe
H
IC50 > 32,000 nM
O
O
Me
O O
OH
MeOAcO
Me
H
IC50 = 0.4 nM
O
O
Me
O O
O
MeOAcO
Me
H
IC50 > 500 nM
Me
O
O
Me
O O
O
MeO
Me
H
IC50 = 6.0 nM
O
O
Me
O O
O
MeO
Me
H
IC50 = 16.7 nM
O
O
Me
O O
O
MeOAcO
Me
H
IC50 = 271 nM
O
O
Me
O O
O
MeOAcO
Me
H
(p110 PI-3 kinase)K802
NH2
O
OH
Me
O O
O
MeO AcOMe
H
(p110 PI-3 kinase)K802
NH
Norman, C. S. J. Med. Chem.. 1996 39 1106.
Planar Polycyclics from the Marine Sponge XestospongiaDistribution of Marine Natural Products by Phylum
Biogenetic Origins of Marine Natural Products
David Amantini @ Wipf Group 4 6/20/2005
Planar Polycyclics from the Marine Sponge Xestospongia
O
Me
O
O
OH
OH
Isozonarol
(A Biosynthetic Link ?)
Me
Me
Me
Me
HO
OH
Halenaquinone
Triketide Unit
Sesquiterpene Unit
Are These Compounds Triketides - Sesquiterpenes Hybrids?
O
Me
O
O
O
O
(+)-Halenaquinone
O
Me
O
O
OH
OH
(+)-Halenaquinol
O
Me
O
O
O
(+)-Xestoquinone
Isolated from Xestospongia Sapra in 1960 Isolated from Xestospongia Exigua in 1983
Antibacterial Activity
Cardiotonic Properties
Inhibition of pp60 Kinase
Inhibition of EGF Kinase
Inhibition of the Dual Specificity Phosphatase Cdc25
Protein Tyrosine Kinase (PTK) Inhibition
O
Me
O
O
O
O
(+)-Halenaquinone
O
Me
O
O
OH
OH
(+)-Halenaquinol
O
Me
O
O
O
(+)-Xestoquinone
IC50 = 60 µM
O
Me
O O
O
Viridin
HO
MeOO
O
Me
O O
O
MeOAcO
Me
H
Wortmannin
IC50 = 1.5 µM IC50 = 0.6 µM
IC50 = 30 µMIC50 >> 200 µM
Me
O
O
O
O
IC50 = 27 µM
IC50 values against pp60
Crews, P. et al J. Org. Chem.. 1993 58 4871.
David Amantini @ Wipf Group 5 6/20/2005
Synthetic Efforts Outline
O
O
Me
O O
O
SHIBASAKI (Chiral building block)
MeOAcO
Me
HWortmannin
SHIBASAKI (Diastereoselective Intramolecular Heck Couplings and Diosphenol Claisen)
O
Me
O O
O
Viridin
HO
MeO
SORENSEN (Alkyne Trimerization and p- Claisen Rearr.)
