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Tesi definitiva

Tesi definitiva

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Published by: Cristiano Hamdiansyah Sempadian on Oct 31, 2012
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CONTENTS1.
 
General introduction ........................................................................................................... 2
1.1.
 
Tumor: what it is? ........................................................................................................ 11.2.
 
Defects of the mechanisms of cell replication and death. ............................................ 31.3.
 
Cancer chemotherapy ................................................................................................... 41.4.
 
Microtubules ................................................................................................................ 51.4.1.
 
How microtubules work throughout the cell division cycle ........................... 71.4.2.
 
Tubulin binding site ......................................................................................... 91.4.2.1 Colchicine binding site ..................................................................... 101.4.2.2 The vinca domain ............................................................................. 111.4.2.3. Taxol
 
binding site ............................................................................. 121.4.3. Multi drug resistance ...................................................................................... 13
2.
 
Microtubules depolymerization inducing agents .......................................................... 17
2.1.
 
Hemiasterlins ............................................................................................................. 172.2.
 
From Hemiasterlin to HTI-286 .................................................................................. 202.2.1
 
SAR study on natural hemiasterlin ................................................................. 21
3.
 
Scopes and aims ................................................................................................................. 26
3.1 Development of synthetic routes for the synthesis of A-fragment ............................ 263.1.1 Vedej’s synthetic approach to fragment A. .................................................... 283.1.2. Durst’s synthetic approach ............................................................................. 293.2. Toward the synthesis new analogues of HTI-286 ...................................................... 30
4. Results and discussion ....................................................................................................... 34
4.1 Potentiality of silver oxidein nucleophile substitution reaction ................................. 344.2 Synthesis of the fragment BC .................................................................................... 364.3 Synthesis of racemic mixture of bromoderivatives .................................................... 374.4 Nucleophilic substitution reaction catalyzed by silver oxide ..................................... 394.4.1 Synthesis of 
tert 
-Leucine derivatives ............................................................. 404.4.2 Synthesis of Valine derivatives ...................................................................... 414.4.3 Synthesis of Phenylalanine derivatives at N-terminus ................................... 43
5. Biological evaluation ......................................................................................................... 466. Conclusions and perspectives ........................................................................................... 52
6.1 Toward the pro-drug with stilbene 5c ........................................................................ 546.1.1 Synergistic effect between
(R,S)(S)(S)
-76a,
(R,S)(S)(S)
-81a
 
and stilbene 5c. ............................................................................................... 546.1.2 Project for a reciprocal prodrug between stilbene 5c and
(S)(S)(S)
76a ........ 55
7.
 
Experimental section ......................................................................................................... 58
7.1.
 
General methods ........................................................................................................ 587.2.
 
Experimental procedures and analytical data. ............................................................ 597.2.1.
 
Synthesis of fragment BC .............................................................................. 59
8.
 
Hemiasterlin: references ................................................................................................... 979.
 
Microtubules depolymerization inducing agents .......................................................... 100
9.1. Epothilones ............................................................................................................... 1009.2.
 
Structure and SAR of epothilones ............................................................................ 1029.2.1.
 
C12-C13 modifications ................................................................................ 1039.2.2.
 
Side chain modifications .............................................................................. 1049.2.3 C1-C5 and C6-C11 fragment modifications ................................................ 1059.2.4. Epothilones in clinical trials ......................................................................... 106
10.
 
Scopes and aims .............................................................................................................. 108
10.1. Project aims .............................................................................................................. 10810.2.
 
Retrosynthetic analysis ............................................................................................ 110
11.
 
Results and discussion .................................................................................................... 115
11.1. Synthesis of heterocyclic core .................................................................................. 11511.1.1
 
First synthetic approach ............................................................................... 11511.1.2 Second synthetic approach ........................................................................... 11611.1.3 Third synthetic approach .............................................................................. 11711.1.4 Fourth synthetic approach ............................................................................ 11811.1.5 Fifth synthetic approach ............................................................................... 11911.1.6 Choice of the best protecting group ............................................................. 12011.1.6.1. Benzyl side chain protection ........................................................ 12011.2. Synthesis of the homoallylic alcohol. ...................................................................... 12211.2.1 Diastereoselective aldol reaction .................................................................. 12411.2.1.1. Evans aldol reaction ..................................................................... 12511.3. Toward the synthesis of the cyclopropane key intermediate 15 .............................. 12711.4 Conclusions .............................................................................................................. 129
12.
 
Experimental procedures .............................................................................................. 131
12.1. General Informations ............................................................................................... 131
13. References ...................................................................................................................... 156
 

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