Towards New Drugs to Fight Cancer and Cancer-Induced Acute- Pain Through a Common Novel Annulation Methodology Krzysztof Kierus , Fernando Cagide- Fagin, Patricia Martínez-Bescos, Ricardo Alonso University of Santiago de Compostela Galicia, Spain
Towards New Drugs to Fight Cancer and Cancer-Induced Acute-Pain Through a Common Novel Annulation Methodology Krzysztof Kierus, Fernando Cagide-Fagin,
Mar 26, 2015
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Towards New Drugs to Fight Cancer and Cancer-Induced Acute-Pain Through a Common Novel Annulation Methodology
Krzysztof Kierus, Fernando Cagide-Fagin, Patricia Martínez-Bescos, Ricardo Alonso
University of Santiago de Compostela
Galicia, Spain
••
o
Towards New Drugs to Fight Cancer and Cancer-Induced Acute-Pain Through a Common Novel Annulation Methodology
Krzysztof Kierus, Fernando Cagide-Fagin, Patricia Martínez-Bescos, Ricardo Alonso
University of Santiago de Compostela
Galicia, Spain
Biological importance of pancratistatin Antineoplastic activity Specific to wide range of
cancer cells Induce apoptosis
Natural sources: Pancratium littorale Hymenocallis pedalis
O
O NH
OH
OH
OH
OH
HO
O
H C
BA
12
3
4
4a
7
10b10
6
www.junglewalk.com
Isolation from natural sources has its drawbacks: Difficult separations and purifications Variability on the content with the species, crop,
recollection time, etc. Expensive: very demanding in terms of time, effort,
facilities, solvents, chromatography – normal and HPLC. It is very difficult to prepare new analogs
Total syntheses of pancratistatinyear group leader steps overall yield (%) ref.
1989 Danishefsky 26 0.13 racemic J. Am. Chem. Soc. 1989; 111, 4829
1995 Hudlicky 14 2 enantiopure J. Am. Chem. Soc. 1995; 117, 3643
1995 Trost 15 11 enantiopure J. Am. Chem. Soc. 1995; 117, 10143
1997 Haseltine >15 1.2 enantiopure Tetrahedron 1997, 53, 11153
1998 Magnus 19 1.2 enantiopure J. Am. Chem. Soc. 1998, 120, 5341
2000 Rigby 22 0.16 enantiopure J. Am. Chem. Soc.
2000, 122, 6624
2001 Pettit 10 3.6 from narciclasine J. Org. Chem. 2001, 66, 2583
2002 Kim 17 5.8 racemic Org. Lett. 2002, 4, 1343
2004 Kim 18 3.8 racemic J. Org. Chem. 2004, 69, 112
Biological importance of tetrodotoxin Voltage-gated, sodium
channel blocker Potential analgesic for
cancer pain
Natural sources: pufferfish (Fugu fish) Bacteria: Pseudoalteromonas
tetraodonis
O
NHNH
OHHO
NH
OH
OH
HOO
O -
1 2
3
4
4a5
6
117 8
8a
910
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Total syntheses of tetrodotoxin
year group leader steps overall yield ref.
1972 Kishi 30 0.65 racemic J. Am. Chem. Soc. 1972, 94, 9217
2003 Isobe 69 0.17 enantiopure J. Am. Chem. Soc. 2003, 125, 8798
2003 Du Bois 33 1.09 enantiopure J. Am. Chem. Soc. 2003, 125, 11510
2004 Isobe 39 0.13 enantiopure Angew. Chem. Int. Ed. 2004, 43, 4782
2005 Sato 32 0.1 racemic J. Org. Chem. 2005, 70, 7496
2006 Isobe 22 0.22 enantiopure Chem. Asian. J. 2006, 1-2, 125
Formation of main carbon ring
O
O NH
OH
OH
OHOH
HO
O
H C
BA
12
34
4a
7
10b10
6
Pancratistatin (1)
O
NHNH
OHHO
NH2
OH
OH
HOO
O
Tetrodotoxin (TTX, 2)
-
1 2
3
4
4a5
6
117 8 8a
910
H
O
NO2
Ar
+R
O
R
R R
OH
NO2
O
Ar
β-aryl-α-nitro-α,β-enals
Synthesis by: nitration of 3-(2-furyl)-propenal and 3-(5-methyl-2-furyl)-
propenal condensation of guaiazulene with nitromalondi-aldehyde
O
FF
F
NO2
O
NO2O
R
R = H, CH3, NO2NO2
O
a) Sitkin, A. I.; Klimenko, V. I.; Fridman, A. L. Zh. Org. Khim. 1975, 11, 2452. b) Klimenko, V. I.; Sitkin, A. I.; Fridman, A. L. Vses. Nauchn. Konf. Khim. Tekhnol. Furanovykh Soedin., [Tezisy Dokl.], 3rd, Riga, USSR, 1978; Stradyn, Y. P., Ed. pp 116-17. c) Kirby, E. C.; Reid, D. H. J. Chem. Soc. 1961, 3579-93. d) S. Goldmann, M. Bechem, Ger. Offen. (1994), DE 4222770 A1
New strategy
ArNO2 +
O
HH
Ar O O2NOH+
ArNO2
OH
ArNO2
O
H
O
NO2
Ar
+
O
O O
RO OR
OH
NO2
O
Ar
R = C(CH3)
H
O
NO2
O
O
NHNH
OHHO
NH2
OH
OH
HOO
O
Tetrodotoxin (TTX, 2)
-
H
O
NO2
O
OO
O NH
OAc
OAc
OAc
AcO
O
H
12
3
4
4a
7
10b10
6
H
O
NO2
O
O O
O NH
OAc
OAc
OAc
AcO
O
H
12
3
4
4a
7
10b10
6
OO
O
O
O
O
O
O
O
O
O
3
4
5
Annulation reactions
Tetrodotoxin, the synthetic challenge
O
NHN
OHHO
NH2
OH
OH
HOO
O -
O
NO2
HOO
OO
H
O
NO2
O
O
O O+
Path to pancratistatin analog
H
O
NO2+
O
O
O
O O
OH
NO2
O
O
O
O O
NiCl2, NaBH4
O O
OH
NH2
OH
O
O
MeOH
pyrrolidine
30%
3 6
7
O O
OH
NH2
OH
O
OO
NH2
O
O
O
OO
O
HN
O
O
O
OO
OMe
O
2,2-DMP, p-TsOH
acetone
ClCO2Me, DMAP
CH2Cl2
Yield 49% for 3 steps
78
9
O
HN
O
O
O
OO
OMe
O
OH
HN
O
O
OH
OMe
O
HO
OH
p-TsOH, MeOH
CH2Cl2
OAc
HN
O
O
OAc
OMe
O
AcO
OAc
Ac2O
pyridine
Yield 74% for 2 steps
910
11
OAc
HN
O
O
OAc
OMe
O
AcO
OAc
OAc
NH
O
O
OAcAcO
OAc
O
Tf2O, DMAP
CH2Cl2
96%
O
O NH
OH
OH
OH
OH
HO
O
H C
BA
12
34
4a
7
10b10
6
Pancratistatin (1)
11 12
Enantioselective annulation reaction
+
O
O O
H
O
NO2
O
H
O
NO2
O
O
O
OO
NO2OH
O
+
O
O O
O
OO
NO2OH
OO
93% e.e.
>99% e.e. (after crystallization)
80% e.e.
Summary
We have successfully elaborated a new route to nitroenals
We have developed a new annulation methodology to aminocyclohexitols
We proved the utility of the annulation methodology in a 0.8g scale synthesis of a pancratistatin analog
Enantiopure synthesis is possible by use of chiral inducer combined with crystallization.
Prof. Ricardo Alonso Alonso Dr Umadevi Bhoga M.Sc. Patricia Martínez Bescos M.Sc. Fernando Cagide Fagin Olaia Nieto García Hugo Lago Santomé
Dr Juan Carlos Ortiz Dr Lidia Ozores Dr Luis Fernando Roa de la
Fuente M.Sc. Marta Fernández González
Project suported by:Xunta de Galicia through Project PGIDIT05BTF20901PR
Spanish Ministries of Science and Technology BQU2002-01176
Fellowship awarded to L.O.
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