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Pharmaceutical Research

, Volume 29, Issue 11, pp 2943–2971 | Cite as

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

  • Yan Lu
  • Jianjun Chen
  • Min Xiao
  • Wei Li
  • Duane D. MillerEmail author
Expert Review

Abstract

Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.

KEY WORDS

antimitotic cancer colchicine multidrug resistance tubulin polymerization inhibitor 

Abbreviations

2-ME

2-methoxyestradiol

ABC

ATP binding cassette

BS

binding site

CA-4

combretastatin A-4

CBSI

colchicine binding site inhibitors

cGMP

cyclic guanosine monophosphate

CNS

central nervous system

CoMFA

comparative molecular field analyses

CoMSIA

comparative molecular similarity indices analyses

DAMA-colchicine

N-deacetyl-N-(2-mercaptoacetyl) colchicine

FDA

Food and Drug Administration

FGF

fibroblast growth factor

HIF

hypoxia-inducible factor

HUVEC

human umbilical vein endothelial cell

LIE

linear interaction energy

MDR

multidrug resistance

MRP

multidrug resistance-associated protein

MTA

microtubule targeting agent

NCI

National Cancer Institute

PDE

phosphodiesterase

Pgp

P-glycoprotein

PK

pharmacokinetic

QSAR

quantitative structure-activity relationships

SAR

structure-activity relationship

SGB

surface-generalized Born

TMP

trimethoxyphenyl

TNF-α

tumor necrosis factor-α

VDA

vascular-disrupting agent

VEGFR

vascular endothelial growth factor receptor

Notes

Acknowledgments & Disclosures

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number R01CA148706. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional supports were provided by the Van Vleet Endowed Professorship.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Yan Lu
    • 1
  • Jianjun Chen
    • 1
  • Min Xiao
    • 1
  • Wei Li
    • 1
  • Duane D. Miller
    • 1
    Email author
  1. 1.Department of Pharmaceutical Sciences, Health Science CenterUniversity of TennesseeMemphisUSA

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