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Role of the Colchicine Ring A and Its Methoxy Groups in the Binding to Tubulin and Microtubule Inhibition

Andreu, Jose M., Perez-Ramirez, Bernardo, Gorbunoff, Marina J., Ayala, David, Timasheff, Serge N.·1998·Biochemistry
DOI 10.1021/bi9728553
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Abstract

The roles of the methoxy substituents on ring A of two ring colchicine (COL) analogues were probed by the synthesis of a number of drugs and the examination of their effect on binding to tubulin, inhibition of microtubule assembly, and induction of GTPase activity. Selective elimination of ring A methoxy groups at positions 2, 3, and 4 weakened all three processes. The effects on binding and inhibition were independent of the nature of ring C (or C'). Specifically, excision of the 2- or 3-methoxy groups weakened binding by ca. 0.4 kcal mol-1, while that of the 4-methoxy group of ring A was weakened by 1.36 +/- 0.15 kcal mol-1. The effect on the inhibition of microtubule assembly, expressed as the equilibrium constant for the binding of the tubulin-drug complex to the end of a microtubule, was more complex and strongly dependent on the nature of ring C (or C'). This was attributed to the abilities of various groups on ring C' to overcome the wobbling in the tubulin-drug complex introduced by the weakening of the anchoring provided by ring A. It is concluded that ring A of COL is not germane to the mechanism of the inhibition of tubulin self-assembly. It serves only as a complex-stabilizing anchor. The control of this process resides in the interactions that key oxygen atoms of ring C of COL or C' of structural analogues establish with the protein. It is proposed that the 4-methoxy group of ring A serves as a key attachment point for immobilization of the drugs on the protein.

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Metadata

Authors
Andreu, J. M., Perez-Ramirez, B., Gorbunoff, M. J., Ayala, D., & Timasheff, S. N.
Affiliations
Department of Biochemistry, Brandeis University, 415 South Street, Waltham, Massachusetts 02254-9110, and Centro de Investigaciones Biológicas, CSIC, Velázquez 144, 28006 Madrid, Spain
Venue
Biochemistry
Publisher
American Chemical Society (ACS)
Published
1998-05-22
Volume
37
Issue
23
Pages
8356-8368
ISSN
  • 0006-2960
  • 1520-4995
DOI
10.1021/bi9728553
Cited by
82
References
0
Language
en

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