Structure-activity studies of novel colchicine analogs.
(1998)- Abstract
- Colchicine, a well-known alkaloid isolated from Colchicum autumnale, interferes with microtubule growth and, therefore affects mitosis and other microtubule dependent functions. We have been interested in the structural requirements of colchicine for tubulin recognition. In particular our interests have been focused on the active colchicine conformation with respect to the pivot bond joining the A- and C- rings. The configuration of the pivot bond is aS and the dihedral angle is close to 54° in colchicine and most of the active analogs. The main objective of the work presented in this thesis was to synthesize and study novel colchicine analogs with systematic variations in the torsional angle between the A- and C-rings. One way to modify... (More)
- Colchicine, a well-known alkaloid isolated from Colchicum autumnale, interferes with microtubule growth and, therefore affects mitosis and other microtubule dependent functions. We have been interested in the structural requirements of colchicine for tubulin recognition. In particular our interests have been focused on the active colchicine conformation with respect to the pivot bond joining the A- and C- rings. The configuration of the pivot bond is aS and the dihedral angle is close to 54° in colchicine and most of the active analogs. The main objective of the work presented in this thesis was to synthesize and study novel colchicine analogs with systematic variations in the torsional angle between the A- and C-rings. One way to modify the dihedral angle of the pivot bond is to change the number of atoms in the B-ring. A number of colchicine analogs have been synthesized and studied by NMR, circular dichroism, X-ray crystallography and by molecular mechanics calculations. The first colchicine derivative with an eight membered B-ring obtained via a Beckmann reaction, is described and only one of the stable atropisomeric enantiomers arrests microtubule assembly. The results demonstrate that highly twisted, conformationally rigid colchicinoids retain tubulin-binding ability provided that they possess the same helicity as colchicine. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/38819
- author
- Bladh, Håkan LU
- supervisor
- opponent
-
- Prof Bane, Susan, USA
- organization
- publishing date
- 1998
- type
- Thesis
- publication status
- published
- subject
- keywords
- Organic chemistry, Organisk kemi
- pages
- 52 pages
- publisher
- Organic Chemistry, Lund University
- defense location
- Department of Chemistry room G
- defense date
- 1998-09-04 10:15:00
- external identifiers
-
- other:ISRN: LUNDL/NKOK-1040-SE
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Organic chemistry (S/LTH) (011001240)
- id
- 26006461-d445-4f6d-9c40-ae8130b8ee6f (old id 38819)
- date added to LUP
- 2016-04-04 11:30:02
- date last changed
- 2018-11-21 21:05:14
@phdthesis{26006461-d445-4f6d-9c40-ae8130b8ee6f,
abstract = {{Colchicine, a well-known alkaloid isolated from Colchicum autumnale, interferes with microtubule growth and, therefore affects mitosis and other microtubule dependent functions. We have been interested in the structural requirements of colchicine for tubulin recognition. In particular our interests have been focused on the active colchicine conformation with respect to the pivot bond joining the A- and C- rings. The configuration of the pivot bond is aS and the dihedral angle is close to 54° in colchicine and most of the active analogs. The main objective of the work presented in this thesis was to synthesize and study novel colchicine analogs with systematic variations in the torsional angle between the A- and C-rings. One way to modify the dihedral angle of the pivot bond is to change the number of atoms in the B-ring. A number of colchicine analogs have been synthesized and studied by NMR, circular dichroism, X-ray crystallography and by molecular mechanics calculations. The first colchicine derivative with an eight membered B-ring obtained via a Beckmann reaction, is described and only one of the stable atropisomeric enantiomers arrests microtubule assembly. The results demonstrate that highly twisted, conformationally rigid colchicinoids retain tubulin-binding ability provided that they possess the same helicity as colchicine.}},
author = {{Bladh, Håkan}},
keywords = {{Organic chemistry; Organisk kemi}},
language = {{eng}},
publisher = {{Organic Chemistry, Lund University}},
school = {{Lund University}},
title = {{Structure-activity studies of novel colchicine analogs.}},
year = {{1998}},
}