The interaction between lipid derivatives of colchicine and tubulin: Consequences of the interaction of the alkaloid with lipid membranes (original) (raw)
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Antimitotic activity of colchicine and the structural basis for its interaction with tubulin
Medicinal Research Reviews, 2008
In this review, an attempt has been made to throw light on the mechanism of action of colchicine and its different analogs as anti-cancer agents. Colchicine interacts with tubulin and perturbs the assembly dynamics of microtubules. Though its use has been limited because of its toxicity, colchicine can still be used as a lead compound for the generation of potent anti-cancer drugs. Colchicine binds to tubulin in a poorly reversible manner with high activation energy. The binding interaction is favored entropically. In contrast, binding of its simple analogs AC or DAAC is enthalpically favored and commences with comparatively low activation energy. Colchicine–tubulin interaction, which is normally pH dependent, has been found to be independent of pH in the presence of microtubule-associated proteins, salts or upon cleavage of carboxy termini of tubulin. Biphasic kinetics of colchicines–tubulin interaction has been explained in light of the variation in the residues around the drug-binding site on β-tubulin. Using the crystal structure of the tubulin–DAMAcolchicine complex, a detailed discussion on the pharmacophore concept that explains the variation of affinity for different colchicine site inhibitors (CSI) has been discussed. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 1, 155–183, 2008
Analysis of the near-ultraviolet absorption band of colchicine and the effect of tubulin binding
Journal of the American Chemical Society, 1989
The near-ultraviolet absorption spectrum of colchicine from 290 to 420 nm has been examined in a variety of solvents and bound to tubulin by multiple differentiation of the absorption spectra. The absorption band is shown to be comprised of two transitions, which are T-T* in nature and of different excited-state character. The energies of the transitions do not correlate with solvent properties such as dipole moment, dielectric constant, or refractive index. The lower energy transition was found to shift to shorter wavelength in solvents capable of donating a hydrogen bond, while the higher energy transition was essentially invariant with solvent properties. MNDO calculations on tropone, a model for the C ring of colchicine, and colchicine support the experimental findings and indicate that the benzene moiety of the A ring makes little contribution to the character of these two transitions. Analysis of the absorption and derivative spectra of colchicine bound to tubulin reveals that the absorption spectrum is altered in a manner that is unique to tubulin binding and not mimicked by solvents. It is proposed that the alteration of the electronic transitions in the near-ultraviolet absorption spectrum of colchicine bound to tubulin is the result of the interaction of the colchicine C ring with a ?r-system in the colchicine-binding site. Colchicine, an alkaloid isolated from Colchicum autumnale, exerts its major biological effects by binding specifically and with high affinity to tubulin, the major protein component of the cytoskeletal structure known as the microtubule.l-' The colchicine-tubulin complex substoichiometrically inhibits normal microtubule assembly, resulting in cessation of cellular microtubule-mediated processes. Colchicine has thus received considerable attention due to its utility as a tool for probing microtubule-dependent events in cell biology.
General features of the recognition by tubulin of colchicine and related compounds
European Biophysics Journal, 1998
The kinetic mechanisms of the binding to tubulin of colchicine and eight different analogues have been studied to elucidate details of the recognition mechanism. All of the analogues follow a two step binding mechanism i.e. binding occurs via an initial step with low affinity, followed by an isomerisation of the initial complex leading to the final high affinity state. For several analogues the kinetic and thermodynamic data of both processes are compared here. For all the analogues the ∆G°1 of initial binding at 25°C varies between-13.3 and-28.8 kJ • mol-1. For the second step ∆G°2 varies between-2.4 and-27 kJ • mol-1. These limited ranges of free energy change are, however, obtained by a great variety of enthalpy changes and compensatory entropy changes. Comparison of the data for the first and second steps indicates that structural alterations of the drugs always change the thermodynamic parameters of the two steps, and the changes in the first and the second steps are in opposite directions. The fact that this range of experimental behaviour can be incorporated into a general mechanism encourages the extension of these investigations to other colchicine analogues and related compounds with potential pharmaceutical applications.
Interactions of long-chain homologues of colchicine with tubulin
European journal of medicinal chemistry, 2016
Several colchicine analogues in which the N-acetyl residue has been replaced by aliphatic, straight-chain acyl moieties, have been synthesized. These compounds show high cytotoxic activity at the nanomolar level against the tumoral cell lines HT-29, MCF-7 and A549. Some of them exhibit activities in the picomolar range against the HT-29 line and are thus two to three orders of magnitude more cytotoxic than colchicine. In this specific cell line, the activities were found to be closely related to the length of the acyl carbon chain, an increase in the latter giving rise to an increase in the cytotoxicity with a maximum in the range of 10-12 carbon atoms, followed by a decrease in activity with still longer chains. Some of the compounds inhibit microtubule assembly and induce the formation of abnormal polymers and present in most cases better apparent affinity constants than colchicine. In addition, at IC50 concentrations the analogues block the cell cycle of A549 cells in the G2/M ph...
Role of B-ring of colchicine in its binding to tubulin
The Journal of biological chemistry, 1981
The chemical specificity of the colchicine-binding site of tubulin is less stringent for the presence of the B-ring than the A- and C-rings of colchicine, Colchicine analogues with modifications in the B-ring bind to tubulin at the same site as colchicine. Analogues with smaller or no substituents in the B-ring bind tubulin remarkably faster than colchicine. Thus, a compound without the B-ring [2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone] binds tubulin even at 4 degrees C and the binding is almost instantaneous at 37 degrees C. Colcemid and 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone bind reversibly to tubulin, whereas colchicine and desacetamidocolchicine bind almost irreversibly, suggesting that the size of the B-ring moiety of colchicine is not related to the reversibility of binding. We conclude that although the presence of the B-ring of colchicine does not appear to be an essential prerequisite for the drug-tubulin interaction, the B-ring substitu...
A fluorescent stopped flow study of colchicine binding to tubulin
Journal of Biological Chemistry
The kinetics of colchicine binding to tubulin has been studied, using a fluorescence stopped flow. The measurements of Garland (Garland, D. L. (1978) Biochemistry 17, 4266-4272) have been extended to high colchicine concentrations and different temperatures. The appearance of fluorescence is biphasic. Both phases depend in a nonlinear way on colchicine concentration. The presence of colchicine dimers at these concentrations has been taken into account. The fast phase is analyzed as a two-step mechanism. The thermodynamic parameters of the fast initial binding, and the activation energy of the slow conformational change, have been determined. The relative magnitude of the slow phase depends on temperature. It is interpreted as a slow preequilibrium between two tubulin conformers. The effect of the microtubule-associated proteins on the different processes is studied. The binding of colchicine to tubulin ring-like oligomers is discussed. Colchicine is a well known microtubule inhibitor. Its mechanism of action has been studied intensively, and, depending
European Journal of Biochemistry, 1997
2-Methoxy-5-(2',3',4'-trimethoxy)-2,4,6-cycloheptatrien-l-one (MTC) is a colchicine analogue that lacks the B ring. 2-Methoxy-5-(2',4'-dimethoxypheny1)-2,4,6-cycIoheptatrien-l-one (MD) is an A-ring analogue of MTC, in which one methoxy group is replaced by a hydrogen atom. This paper describes the kinetic features of MDC binding to tubulin, and compares its behaviour with MTC to analyse the effect of the A-ring modification on the recognition process by tubulin. Binding is accompanied by a strong enhancement of MDC fluorescence and quenching of protein fluorescence. The kinetic and thermodynamic parameters were obtained from fluorescence stopped-flow measurements. The kinetics are described by a single exponential, indicating that this drug does not discriminate between the different tubulin isotypes. The observed pseudo-first-order rate constant of the fluorescence increase upon binding increases in a non-linear way, indicating that this ligand binds with a similar overall mechanism as colchicine and MTC, consisting of a fast initial binding of low affinity followed by a slower isomerisation step leading to full affinity. The K , and k, values for MDC at 25°C were 540% 65 M-' and 7 0 % 6 s-I, respectively. From the temperature dependence, a reaction enthalpy change (AH?) of the initial binding of 4 9 5 11 kJ/mol-' and an activation energy for the second step of 2 8 t 9 kJ/mol ' were calculated.