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At least 217 records · Page 12Linked to original sources
PubMed2001

Structure-activity relationships of phenylcyclohexene and biphenyl antitubulin compounds against plant and mammalian cells.

Phenylcyclohexenes (PCHs) [e.g., trans-4-nitro-5-(2,3,4-trimethoxyphenyl)cyclohexene, 2d] were found to bind weakly to the colchicine site of bovine tubulin, but are the first mimics of colchicine found to have high activity towards plant cells. Structure-activity relationships for PCHs and biphenyl AC-ring analogues of colchicine (e.g., 2,3,4,4'-tetramethoxy-2'-methyl-1,1'-biphenyl, 3e) are discussed.

Animals↗
PubMed2002

New method of synthesis of Vinca alkaloid derivatives.

Vinblastine and vinorelbine analogues have been synthesised by reacting new versatile electrophilic vindoline derivatives with various 3-substituted indoles. The resulting compounds have been evaluated for their antimitotic properties, but exhibited less potent activities in comparison with the standard binary Vinca alkaloids.

Antineoplastic Agents, Phytogenic↗
PubMed2002

Synthesis and mechanism of action of novel pyrimidinyl pyrazole derivatives possessing antiproliferative activity.

Pyrimidinyl pyrazole derivatives 1-4, prepared as a new scaffold of an anti-tumor agent, showed antiproliferative activity against human lung cancer cell lines and inhibited tubulin polymerization. Furthermore, it was found that compound 2 bound at the colchicine site on tubulin, but the tubulin binding pattern was different from that of colchicine. Here, we describe the synthesis of the derivatives and the differences of the action mechanism on tubulin polymerization inhibition between compound 2 and colchicine.

Antineoplastic Agents↗
PubMed1998

Synthesis and antiproliferative activity of a cyclic analog of dolastatin 10.

A cyclic analog of the natural antiproliferative compound dolastatin 10 was synthesized by introducing an ester link between the N- and C-terminal residues which were modified accordingly. The final macrolactonization was performed by using isopropenyl chloroformate and DMAP as reagents. This analog exhibits submicromolar antiproliferative activity against the L1210 and HT29 cell lines and inhibits in vitro tubulin polymerization (IC50, 39 microM).

Animals↗
PubMed1999

A new anti-tubulin agent containing the benzo[b]thiophene ring system.

A new type of inhibitor of tubulin polymerization was discovered based on the 3-aroyl-2-arylbenzo[b]thiophene molecular skeleton. The lead compound in this series, 2-(4'-methoxyphenyl)-3-(3',4',5'-trimethoxybenzoyl)-6-methoxybe nzo[b]thiophene 1, inhibited tubulin polymerization, caused an increase in the mitotic index of CA46 Burkitt lymphoma cells, and inhibited the growth of several human cancer cell lines.

Dose-Response Relationship, Drug↗
PubMed2002

Synthesis and antimicrotubule activity of combretatropone derivatives.

Combretatropone is a hybrid of combretastatin and colchicine in which the o-methoxyphenol of dihydrocombretastatin A-4 is replaced by an alpha-methoxytropone. Derivatives of combretatropone have been synthesized and evaluated for antimicrotubule activity. All combretatropones were less active than the corresponding colchicine derivatives, supporting the idea that loss of ligand conformational entropy upon tubulin binding results in decreased potency for colchicinoid ligands. The structure-activity relationship of the combretatropone series was different than that of the colchicine series. These data indicate that conformationally mobile and conformationally rigid colchicinoids do not interact with the receptor site in the same manner.

Antineoplastic Agents↗
PubMed1997

Synthesis and biological evaluation of 1,1-dichloro-2,3-diarylcyclopropanes as antitubulin and anti-breast cancer agents.

Z-1,1-Dichloro-2,3-diphenylcyclopropane (1) is an effective anti-breast cancer agent in rodents and in cell culture. We recently determined that 1 inhibits tubulin assembly in vitro and causes microtubule loss in breast cancer cells, leading to accumulation in the G2/M portion of the cell cycle. Aryl ring-halogenated, methoxylated and benzyloxylated derivatives of 1, as well as its E-isomer and the dichlorocyclopropyl derivative of diethylstilbestrol (DES), were synthesized and tested for their ability to inhibit, the assembly of tubulin into microtubules. Including 1, 17 cyclopropyl compounds were tested. One (Z-1,1-dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane (12)) was found to be more active than 1. In addition, E-1,1-dichlorocyclopropylDES (17) was more potent than DES. The E-isomer of 1 (16) was inactive. The cytostatic activities of the compounds against MCF-7 and MDA-MB231 human breast cancer cells, and their abilities to perturb microtubules in MCF-7 cells were also evaluated. Z-Dichloro-2-(4-fluorophenyl)-3-phenylcyclopropane (5), Z-1,1-dichloro-2-(4-fluorophenyl)-3-(4-methoxyphenyl)cyclopropane (11), and Z-1,1-dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane (12) were more potent than 1 against the breast cancer cells.

Animals↗
PubMed1997

Antitumor agents--CLXXV. Anti-tubulin action of (+)-thiocolchicine prepared by partial synthesis.

(+)-Thiocolchicine (2b) was prepared from (+/-)-colchicine (1) in a five-step reaction sequence that included chromatographic separation of appropriate camphanylated diastereomers. Acid hydrolysis of the (+)-diastereomer, followed by acetylation, yielded the desired product 2b. (+)-Thiocolchicine has 15-fold lower inhibitory activity against tubulin polymerization than (-)-thiocolchicine, and is 29-fold less potent for inhibiting growth of human Burkitt lymphoma cells. The enantiomer 2a, prepared from the (-)-camphanylated diastereomer, had potent activity in all assays comparable to that of (-)-thiocolchicine prepared by other methods. These results support the hypothesis that the proper configuration of colchicine-related compounds is an important requirement for their anti-tubulin action.

Antineoplastic Agents↗
PubMed1999

D-ring substituted rhazinilam analogues: semisynthesis and evaluation of antitubulin activity.

Novel (-)- and (+)-rhazinilam derivatives substituted on the D-ring (compounds 3, 4, 5 and 6) have been prepared from (+)-vincadifformine 7 and (-)-tabersonine and evaluated against the disassembly of microtubules into tubulin. Along with this study, a reproducible 'one pot' semisynthesis of (-)-rhazinilam 1 from (+)-1,2-didehydroaspidospermidine 2 was performed allowing the easy preparation of these new compounds.

Alkaloids↗
PubMed2000

Novel allocolchicinoids with an eight membered B-ring: design, synthesis and inhibition of tubulin assembly.

Several B-ring variations of O-methyl androbiphenyline (8), newly accessible from (-)-(M,7S)-colchicine via photooxygenation and subsequent endoperoxide-transformation, were synthesized and evaluated for their inhibitory effects on tubulin assembly in vitro. The amino-allocolchicinoid (9), a key compound in this study, was transformed to the highly potent ketone 10 and by oxidation with H2O2/Na2WO4 to a mixture of syn/anti-oximes, like 11 and 12. These could easily be transformed to hitherto unknown allocolchicinoids 13 and 14 with an eight membered B-ring lactam obtained via a Beckmann rearrangement. Surprisingly both do not notably affect tubulin assembly, despite obvious structural similarities with active analogues of the thiocolchicine- and azasteganacin-series.

Animals↗
PubMed2001

Vinflunine, the latest Vinca alkaloid in clinical development. A review of its preclinical anticancer properties.

Vinflunine is a new Vinca alkaloid uniquely fluorinated, by the use of superacid chemistry, in a little exploited region of the catharanthine moiety. In vitro investigations have confirmed the mitotic-arresting and tubulin-interacting properties of vinflunine shared by other Vinca alkaloids. However, differences in terms of the inhibitory effects of vinflunine on microtubules dynamics and its tubulin binding affinities have been identified which appear to distinguish it from the other Vinca alkaloids. Vinflunine induced smaller spirals with a shorter relaxation time, effects, which might be associated with reduced neurotoxicity. Studies investigating the in vitro cytotoxicity of vinflunine in combination therapy have revealed a high level of synergy when vinflunine was combined with either cisplatin, mitomycin C, doxorubicin or 5-fluorouracil. Furthermore, although vinflunine appears to participate in P-glycoprotein-mediated drug resistance mechanisms, it has proved only a weak substrate for this protein and a far less potent inducer of resistance than vinorelbine. Vinflunine was identified in preclinical studies as having marked antitumour activity in vivo against a large panel of experimental tumour models, with tumour regressions being recorded in human renal and small cell lung cancer tumour xenografts. Overall its level of activity was superior to that of vinorelbine in many of the experimental models used. Interestingly, an in vivo study using a well vascularised adenocarcinoma of the colon has suggested that vinflunine mediates its antitumour activity at least in part via an antivascular mechanism, even at sub-cytotoxic doses. Therefore, these data provide a favourable preclinical profile for vinflunine, supporting its promising candidacy for clinical development. Phase I evaluations of vinflunine have been completed in Europe and phase II clinical trials are now ongoing.

Adenocarcinoma↗
PubMed2002

Cytoskeleton, passive tension and the contraction of the rat aorta to phorbol 12,13-dibutyrate.

The influence of passive tension on contractions to phorbol 12,13-dibutyrate (1 microM PBDu) on the thoracic aorta of Wistar and SHR rats, aged 8-12 weeks, and the functional importance of both the actin and the tubulin components of the cytoskeleton, were studied. Contractile responses to PBDu (1 microM) were obtained in aorta rings, at two levels of passive tension: 3 and 0.5g. These responses were expressed as percentage of the maximal response to noradrenaline obtained in the beginning of the experiment at a tension of 2g. Responses to PBDu were significantly larger (P<0.05) at 3g than at 0.5g in both kinds of rats: 226.5+/-34.4%, n=6, versus 143.0+/-28.5%, n=6, respectively, for SHR; 153.0+/-12.9%, n=8, versus 109.0+/-7.3%, n=7, respectively, for Wistar rats. Responses to PBDu were markedly decreased by cytochalasin B (50 microM) (to 61.3+/-14.3%, n=6, at 3g, and 29.6+/-17.8%, n=5, at 0.5g in SHR; to 18.5+/-0.9%, n=6, at 3g, and 6.4+/-1.8%, n=5, at 0.5g in Wistar rats). Colchicine (100 microM) failed to produce a decrease in responses to PBDu in both strains of rats. It is concluded that responses to phorbol ester action depend on passive tension. This difference may depend on filament interaction. Contractions to PBDu in the rat aorta may be highly dependent on actin polymerization.

Actins↗
PubMed1995

Differential effects of ethyl 5-amino-2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate analogs modified at position C2 on tubulin polymerization, binding, and conformational changes.

NSC 613863 (R)-(+) and NSC 613862 (S)-(-) (CI980) are two chiral isomers of ethyl 5-amino 2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate which have potent antitubulin activity. The S-isomer is a more potent antimitotic compound than the R-isomer, and the two isomers differ markedly in binding to tubulin [Leynadier, D., Peyrot, V., Sarrazin, M., Briand, C., Andreu, J. M., Rener, G. A., & Temple, C., Jr. (1993) Biochemistry 32, 10675-10682]. To understand the origin of such differences, we studied the interactions of three R- and S-isomer structural analogs which differ in C2 (the chiral carbon), i.e., C179, NSC 337238, and NSC 330770. C179 is a methylated dehydrogenated achiral compound. It bound to tubulin with an apparent affinity Ka of (2.29 +/- 0.17) x 10(4) M-1, inhibited tubulin polymerization in vitro at a half-inhibitory concentration (IC50) of 100 microM, and presented no GTPase activity. The substitution of -CH3 by -H leads to the NSC 337238 compound. It bound to tubulin with a higher affinity [Ka = (2.62 +/- 0.35) x 10(5) M-1] and inhibited tubulin polymerization at a lower concentration (IC50 = 14 microM). It presented no GTPase activity and induced the formation of abnormal polymers at a protein critical concentration (Cr) of 2 mg mL-1. NSC 330770, a demethylated hydrogenated molecule, interacted strongly with tubulin [Ka = (3.30 +/- 0.56) x 10(6) M-1].(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Vinca alkaloid-induced tubulin spiral formation correlates with cytotoxicity in the leukemic L1210 cell line.

The ability of a class of C-20' modified vinca alkaloid congeners to induce tubulin spiral formation was investigated relative to their ability to inhibit microtubule assembly, their cytotoxicity against a leukemic cell line, L1210, and their measured and calculated partition coefficients. These studies were prompted by the observation that the energetics of vinca alkaloid-induced tubulin spiral polymers, or spiraling potential, is inversely related to their clinical dosage and are aimed at the long-term goal of developing the ability to predict the cytotoxic and antineoplastic properties of antimitotic drugs. We demonstrate here that vinca-induced tubulin-spiraling potential is significantly correlated with cytotoxicity against L1210 cells. This is consistent with the size of spirals formed being proportional to the relaxation time for polymer redistribution, the lifetime of cell retention, and effects on microtubule ends and dynamics. Spiraling potential also correlates with calculated but not measured partition coefficients. Surprisingly, spiraling potential does not correlate with the ability to inhibit microtubule formation with purified tubulin or microtubule protein. For the set of C-20' modified compounds studied, the largest inhibitory effects on spiraling potential and cytotoxicity are caused by multiple sites of halogen (-F, -Cl) substitution with the introduction of increased rigidity in the ring. This suggests the C-20' position interacts with a hydrogen bond acceptor or an electrophilic region on the protein that electrostatically disfavors halogen substitutions. These studies are discussed in terms of the cellular mode of action of antimitotic drugs, particularly the importance of microtubule dynamics during mitosis and the factors that regulate those dynamics.

Animals↗
PubMed1987

Inhibition of tubulin self-assembly and tubulin-colchicine GTPase activity by guanosine 5'-(gamma-fluorotriphosphate).

The inhibitory effects of guanosine 5'-(gamma-fluorotriphosphate) [GTP(gamma F)] on both the polymerization and the colchicine-dependent GTPase activity of calf brain tubulin have been studied. The results demonstrate that this analogue of GTP, with a fluorine atom on the gamma-phosphate, is a reversible competitive dead-end inhibitor of the colchicine-induced GTPase activity with a K1 value of (1.8 +/- 0.6) X 10(-4) M. GTP(gamma F) did not promote assembly of tubulin from which the E-site guanine nucleotide had been removed. It binds to the exchangeable nucleotide site competitively with respect to GTP, diminishing both the rate and extent of tubulin polymerization. Treatment in terms of the Oosawa-Kasai model of the inhibitory effect of GTP(gamma F) on the assembly led to a value of Kdis = 1.1 X 10(-6) M for the complex GTP(gamma F)-tubulin. This analogue does not bind to the postulated third site. The growing of tubulin polymers at 37 degrees C was arrested by GTP(gamma F), and only limited depolymerization was induced by the addition of this analogue after assembly in the presence of GTP. This result confirms that the E-site is blocked in the polymer and that this analogue can bind only to the ends of the polymers. Sedimentation velocity and circular dichroism studies showed that the conformation of the tubulin-GTP(gamma F) complex is not identical with that of tubulin-GTP. This is caused by the replacement of the hydroxyl group in the gamma-phosphate by the fluorine group, which have 2.20- and 1.35-A van der Waals radii, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Carbamate formation on tubulin: CO2/bicarbonate buffers protect tubulin from inactivation by reductive methylation and carbamoylation and promote microtubule assembly at alkaline pH.

Carbamoylation and reductive methylation of tubulin have been shown previously to inhibit microtubule assembly, probably by attack on essential internal lysine residues [Mellado, W., Slebe, J., & Maccioni, R.B. (1982) Biochem. J. 203, 675-681; Szasz, J., Burns, R., & Sternlicht, H. (1982) J. Biol. Chem. 257, 3697-3704]. We show first that this inhibition is blocked by the presence of HCO3-/CO2 buffer at physiological concentrations during the carbamoylation or reductive methylation. Under conditions that block assembly, the amount of radiolabeled cyanate or formaldehyde incorporated by these reactions in the absence of HCO3-/CO2 was approximately four carbamoyl or five methyl groups in a ratio of approximately 1.7 alpha chain/beta chain. In the presence of HCO3-/CO2, the formaldehyde incorporation is decreased roughly 0.5 mol in each of the alpha and beta chains, and cyanate incorporation, roughly 1.0 mol/mol of alpha or beta monomer. These results are consistent with the hypothesis that CO2 competed with formaldehyde or cyanate for uncharged amino groups and led to the reversible formation of carbamates. The complete antagonism of the inhibition of microtubule assembly by reductive methylation by CO2, even though the number of methyl groups incorporated was reduced by only 0.5 mol/tubulin monomer, was consistent with the possibility that reductive methylation opened up additional residues for attack. Indeed, using an adaptation of the method of Gros et al. for measurement of carbamates [Gros, G., Forster, R.E., & Lin, L. (1976) J. Biol. Chem. 251, 4398-4407], we found that reductive methylation with 2 mM formaldehyde (assembly blocked) did not decrease carbamate formation (carbamate formation was inhibited at higher formaldehyde concentrations).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Ethoxyformylation of tubulin with [3H]diethyl pyrocarbonate: a reexamination of the mechanism of assembly inhibition.

In this study we reexamined the basis for the profound inhibitory effects of low concentrations of diethyl pyrocarbonate (DEP) on tubulin's ability to assemble into microtubules [cf. Lee, Y. C., Houston, L. I., & Himes, R. H. (1976) Biochem. Biophys. Res. Commun. 70, 50-56]. Assembly inhibition at low DEP concentrations can be resolved into two components: a component reversible with hydroxylamine (attributed to monoethoxyformylation of histidyl residues) that contributes approximately 40% of the inhibition and a hydroxylamine-resistant component (attributed to ethoxyformylation of non-histidyl residues) that contributes approximately 60% of the inhibition. Comparisons between the extent of assembly inhibition associated with each component and the degree of residue modification argue for the involvement of a small number of highly reactive residues in the inhibition process. To identify these residues, tubulin was reacted with limiting concentrations of [3H]DEP and subjected to tryptic digestion and HPLC analysis. Only one moderately reactive histidyl residue was detected. This residue (approximately 2-3-fold more reactive than the bulk histidyl residues) eluted in an apparently large, hydrophobic fragment. We failed to detect any non-histidyl residues that were exceptionally reactive to [3H]DEP. However, we did observe that the N-terminal methionyl residues in native protein were ethoxyformylated at rates comparable to that of the bulk histidyl residues. In denatured protein these methionyl residues were ethoxyformylated to a much larger extent (approximately 3-4-fold) than the bulk histidyl residues. We suggest that the N-terminal methionyl residues in tubulin are partly buried or are in a salt-bridge interaction in native protein and that ethoxyformylation of these residues disrupts tubulin structure and interferes with microtubule assembly.

Amino Acid Sequence↗