http://192.168.1.40:8080/xmlui/handle/123456789/1122 Sun, 31 May 2026 13:42:09 GMT 2026-05-31T13:42:09Z http://192.168.1.40:80/xmlui/bitstream/id/71f7e4f8-37c8-4b52-9585-ae03962767bd/bablu.jpg http://192.168.1.40:8080/xmlui/handle/123456789/1122 http://192.168.1.40:8080/xmlui/handle/123456789/2461 Antimicrotubular drugs binding to vinca domain of tubulin Gupta, S.; Bhattacharyya, Bhabatarak Studies on vinca domain binding drugs were done in great details by a number of workers as it is recognized as a potential target for anticancer drug development. Their structures, properties, mode of action, success and failures as potential anticancer drug have been discussed in short details in this review. Among these drugs rhizoxin and maytansine are competitive inhibitors, and bind at the vinblastine binding site of tubulin where as others are non-competitive inhibitors. Besides binding, these drugs also differ in the extent of GTP hydrolysis, GTP exchange and in the stabilization of colchicine binding site. The toxicity level of these drugs towards the host cells and the extent of efflux of drugs by the P-glycoprotein mediated pump are also discussed. DOI: 10.1023/A:1026045100219 Sat, 01 Nov 2003 00:00:00 GMT http://192.168.1.40:8080/xmlui/handle/123456789/2461 2003-11-01T00:00:00Z http://192.168.1.40:8080/xmlui/handle/123456789/2273 The B-ring substituent at C-7 of colchicine and the alpha-C-terminus of tubulin communicate through the "tail-body" interaction Chakraborty, S.; Gupta, S.; Sarkar, T.; Poddar, A.; Pena, J.; Solana, R.; Tarazona, R.; Bhattacharyya, Bhabatarak The carboxy terminals of alphabeta-tubulins are flexible regions rich in acidic amino acid residues that play an inhibitory role in the polymerization of tubulin to microtubules. We have shown that the binding of colchicine and its B-ring analogs (with C-7 substituents) to tubulin are pH sensitive and have high activation energies. Under identical conditions, the binding of analogs without C-7 substituents is pH independent and has lower activation energy. beta-C-terminus-truncated tubulin (alphabeta(s)) shows similar pH sensitivity and activation energy to native tubulin (alphabeta). Removal of the C-termini of both subunits of tubulin (alpha(s)beta(s)) or the binding of a basic peptide P2 to the negatively charged alpha-C-terminus of tubulin causes a colchicine-tubulin interaction independent of pH with a low activation energy. Tubulin dimer structure shows that the C-terminal alpha-tail is too far from the colchicine binding site to interact directly with the bound colchicine. Therefore, it is likely that the interaction of the alpha-C-terminus with the main body of tubulin indirectly affects the colchicine-tubulin interaction via conformational changes in the main body. We therefore conclude that in the presence of tail-body interaction, a B-ring substituent makes contact with the alpha-tubulin and induces significant conformational changes in alpha-tubulin. DOI: 10.1002/prot.20242 Mon, 15 Nov 2004 00:00:00 GMT http://192.168.1.40:8080/xmlui/handle/123456789/2273 2004-11-15T00:00:00Z http://192.168.1.40:8080/xmlui/handle/123456789/2272 Sulfonamide drugs binding to the colchicine site of tubulin: Thermodynamic analysis of the drug-tubulin interactions by isothermal titration calorimetry Banerjee, M.; Poddar, A.; Mitra, G.; Surolia, A.; Owa, T.; Bhattacharyya, Bhabatarak The discovery of several sulfonamide drugs paved the way toward the synthesis of 6 (N-12-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide: E7010) and 7 (N-(3fluoro-4-methoxyphenyl)pentafluorobenzenesulfonamide, T138067), both of which inhibit, tubulin polymerization and are under clinical development. A series of diarylsulforiamides containing an indole scaffold was also found to have antimitotic properties, but, their mode of interactions with tubulin has remained unidentified so far. In this study: we demonstrate that these sulfonamide drugs bind to the colchicine site of tubulin in a reversible manner. They quenched intrinsic tryptophan fluorescence of tubulin presumably due to drug-induced conformational changes in the protein, but were unable to modulate GTPase activity of tubulin in contrast to colchicine that enhances the same enzymatic activity. Further investigation using isothermal titration calorimetry (ITC) revealed that 5 (N-(5-chloro-7-indolyl)-4-methoxybenzenesulfonamide) afforded a large positive value of heat capacity change (DeltaC(p) = +264, cal mol(-1) K-1) on binding to tubulin, suggesting a substantial conformational transition in the protein along with partial enthalpy- entropy compensation. On the other hand. the 2-chloro regioisomer 2 gave a large negative value of DeltaC(p) (-589 cal mol(-1) K-1) along with complete enthalpyentropy compensation. This thermodynamic profile was thought to be attributable to a prominent contribution of van der Waals interaction and hydrogen bonding between Specific groups in the drug-tubulin complex. These results indicate that a mere alteration in the position of a single substituent chlorine on the indole scaffold has a great influence on the drug-tublin binding thermodynamics. DOI: 10.1021/jm0494974 Thu, 27 Jan 2005 00:00:00 GMT http://192.168.1.40:8080/xmlui/handle/123456789/2272 2005-01-27T00:00:00Z http://192.168.1.40:8080/xmlui/handle/123456789/2271 -NH-dansyl isocolchicine exhibits a significantly improved tubulin-binding affinity and microtubule inhibition in comparison to isocolchicine by binding tubulin through its A and B rings Das, L.; Datta, A. B.; Gupta, S.; Poddar, A.; Sengupta, S.; Janik, M. E.; Bhattacharya, Bhabatarak Structure-activity relationship studies have established that the A and C rings of colchicine comprise the minimum structural feature necessary for high affinity drug-tubulin binding. Thus, colchicine acts as a bifunctional ligand by making two points of attachment to the protein. Furthermore, analogues belonging to the iso series of colchicine are virtually inactive in binding to tubulin and inhibiting microtubule assembly. In the present study, we found that the substitution of a hydrophobic dansyl group on the B-ring side chain (C7 position) of isocolchicine reverses the structural alterations at the C ring and the newly synthesized -NH-dansyl isocolchicine restores the lost biological activity of the compound. It inhibits microtubule assembly efficiently with an IC50 value of 10 muM and competes with [H-3]colchicine for binding to tubulin. Moreover, although -NH-dansyl colchicine binding to tubulin involves two steps, the -NH-dansyl isocolchicine-tubulin interaction has been found to occur via a one-step process. Also, the affinity constant of the -NH-dansyl isocolchicine-tubulin interaction is roughly only 3 times lower than that of the -NH-dansyl colchicine-tubulin interaction. These results suggest that the enhanced microtubule inhibitory ability of -NH-dansyl isocolchicine is therefore related to the affinity of the drug-tubulin interaction and not to any conformational changes upon binding tubulin. We also observed that the competition of -NH-dansyl isocolchicine with [3H]colchicine for binding to tubulin was dependent on the tubulin concentration. In conclusion, this paper for the first time indicates that a biologically active bifuntional colchicine analogue can be designed where the drug binds tubulin through its A and B rings, while the C ring remains inactive. DOI: 10.1021/bi048211u Tue, 08 Mar 2005 00:00:00 GMT http://192.168.1.40:8080/xmlui/handle/123456789/2271 2005-03-08T00:00:00Z