Binding to tubulin of the colchicine analog 2-methoxy-5-(2', 3', 4'-trimethoxyphenyl)tropone. Thermodynamic and kinetic aspects.

Bane, Susan; Puett, David; Macdonald, T. L.; Williams, Robley C.

doi:10.1016/s0021-9258(17)42801-8

Cited by 94 publications

(63 citation statements)

References 20 publications

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“…Similar arrangements of colchicine in the binding site of tubulin molecule have also been suggested to explain several properties of colchicine-tubulin interactions (Pyles & Bane Hastie, 1993;Chakrabarti et al, 1996). The reaction of colchicine with tubulin is slow, highly temperature dependent and a poorly reversible process (Wilson, 1970;Bhattacharyya & Wolff, 1974;Cortese et al, 1977;Garland, 1978;Lambeir & Engelborghs, 1981;Bane et al, 1984). These unusual properties are found to be related to its side chain at the C-7 position of the B-ring (Ray et al, 1981;Pyles & Bane Hastie, 1993;Chakrabarti et al, 1996).…”

mentioning

confidence: 64%

Colchicine Binding to Tubulin Monomers: A Mechanistic Study

1997

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The kinetic and thermodynamic parameters for colchicine-tubulin and deacetamidocolchicine-tubulin interaction, under the condition where tubulin is predominantly in its dissociated state (approximately 80% monomer), have been determined. We observe that the kinetic parameters exihibit marked change when colchicine interacts with the monomeric form of tubulin rather than with the dimeric form of tubulin. The reaction of colchicine with tubulin monomers is characterized by an enhanced association rate which is a consequence of the lowering of activation energy. Colchicine-tubulin interaction, which is only poorly reversible, becomes partially reversible under this condition. Differences were also noticed in the thermodynamic parameters: the reaction of colchicine with tubulin monomers is enthalpy driven with small positive entropy, while with tubulin dimers a large positive entropy change was reported. However, no such changes in the binding parameters were observed for the reaction involving deacetamidocolchicine (a colchicine analog devoid of a side chain at the C-7 position of B-ring) with tubulin monomers. We therefore conclude that a single subunit of tubulin is capable of binding colchicine and that the unusual properties of colchicine-tubulin interactions such as the slow association rate, high activation energy, and the poor reversibility are due to the possible contact(s) of the C-7 substituent (in the B-ring) of colchicine with the other subunit of tubulin.

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confidence: 64%

Colchicine Binding to Tubulin Monomers: A Mechanistic Study

1997

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“…Assembly. The interactions of ALLO, TCB, TKB, TMB, TBO, and MTC with tubulin have been characterized in previous studies (Andreu et al, 1984(Andreu et al, , 1991Bane et al, 1984;Medrano et al, 1989Medrano et al, , 1991Hastie, 1989). All inhibit the binding of COL to tubulin, and the binding of each analogue is inhibited by COL and podophyllotoxin (Andreu et al, 1984(Andreu et al, , 1991Medrano et al, 1989Medrano et al, , 1991.…”

Section: Effect Of Colchicine Analogues On the In Vitro Microtubulementioning

confidence: 99%

Stoichiometric and Substoichiometric Inhibition of Tubulin Self-Assembly by Colchicine Analogues

Pérez-Ramírez¹,

Andreu²,

Gorbunoff³

et al. 1996

Biochemistry

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The mechanism of the stoichiometric and substoichiometric inhibitions of tubulin self-assembly by several structural analogues of colchicine (COL) was investigated. The inhibition data were analyzed in terms of a simple model that takes into consideration Kg, the normal microtubule growth constant, equal to Cr-1 (Cr is the critical concentration for microtubule formation), and Kb, the binding constant of the drug to tubulin. In this manner, the value of the microtubule inhibition constant (Ki), which is the binding constant of the tubulin-drug complex to the end of a growing microtubule (which stops the microtubule growth), was determined. The results of the analysis of microtubule inhibition by the various colchicine analogues show that all the inhibitions can be expressed reasonably by this model. The strongest inhibitors found were colchicine (COL), allocolchicine (ALLO), and the biphenyl keto analogue 2,3,4-trimethoxy-4'-acetyl-1,1'-biphenyl (TKB), which had essentially identical values of Ki = (2.1 +/- 0.3) x 10(6) M(-1). MTC, the two-ring analogue of colchicine, was weaker (Ki = 5.6 x 10(5) M(-1). A most striking result was that tropolone methyl ether (TME), which is ring C of COL, and which binds very weakly to tubulin (Kb = 3.5 x 10(2) M(-1)), is a substoichiometric inhibitor. Its Ki value of 8.7 x 10(5) M(-1) makes it identical in strength to MTC, suggesting that ring A makes little or no contribution to the induction of assembly inhibition. The three biphenyls, which bind to tubulin with similar affinity, spanned the spectrum from strong substoichiometric inhibition (TKB) to stoichiometric inhibition for 2,3,4-trimethoxy-4'-carbomethoxy-1,1'-biphenyl (TCB) and an intermediate mode for the methoxy derivative 2,3,4,4'-tetramethoxy-1,1'-biphenyl (TMB). The extent of tubulin bound to drugs at 50% inhibition (r) was ca. 2% for TKB, ALLO, and COL, i.e. one liganded tubulin for every 40-50 molecules of free protein (substoichiometric). This ratio was 1:1.5 for TCB (stoichiometric) and 1:6 for TMB (intermediate). For TME, which is a single ring compound, it was 1:25. The progression of the stoichiometries varied directly with Ki and was totally unrelated to the values of Kb, which indicated the control of the stoichiometry by Ki and the close thermodynamic linkage between r and Ki. Comparison of the inhibitory capabilities of the various drugs identified the need for strong substoichiometric inhibition of a carbonyl group on ring C or C'. Furthermore, this group must be properly oriented by interaction with the protein or by the structural rigidity imparted by ring B, as in ALLO. The simple linked equilibrium model developed in this paper permits the alignment of drugs along a continuum that ranges from stoichiometric to strong substoichiometric modes of microtubule inhibition. Furthermore, it shows that the previously identified two classes are the two ends of a monotonously progressing spectrum described by a single mechanism of action.

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“…Competition experiments were performed with the polymerization inhibiter MTC, which binds rapidly to tubulin but with moderate affinity. 16, 17 The results suggest that 2 and 3 bind slightly more strongly to tubulin than MTC. No binding results are available for 4.…”

Section: Enantiomeric Resolution and Circular Dichroism Spectrum Ofmentioning

confidence: 95%

Stereochemical variations on the colchicine motif. Peracid oxidation of thiocolchicone. Synthesis, conformation and inhibition of microtubule assembly

2004

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When 7-oxodesacetamidothiocolchicine (1) was treated with various peroxides in order to afford a Baeyer-Villiger rearrangement, a complex mixture of products was formed, which included the sulfoxide, (2) and sulfone, (3). When peracetic acid was used two additional products were formed; a C-ring lactone (4) and a ring-contracted allocolchicine derivative (5). The sulfoxide (2) was semi-preparatively resolved into enantiomers by chromatography on microcrystalline triacetylcellulose. Rotational barriers around the A-C pivot bond of, and were determined by dynamic 1H NMR analysis. The compounds, and exhibit moderate inhibition of tubulin polymerization, according to in vitro turbidity studies, whereas was inactive.

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Binding to tubulin of the colchicine analog 2-methoxy-5-(2', 3', 4'-trimethoxyphenyl)tropone. Thermodynamic and kinetic aspects.

Cited by 94 publications

References 20 publications

Colchicine Binding to Tubulin Monomers: A Mechanistic Study

Colchicine Binding to Tubulin Monomers: A Mechanistic Study

Stoichiometric and Substoichiometric Inhibition of Tubulin Self-Assembly by Colchicine Analogues

Stereochemical variations on the colchicine motif. Peracid oxidation of thiocolchicone. Synthesis, conformation and inhibition of microtubule assembly

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