Tubulin as a target for anticancer drugs: Agents which interact with the mitotic spindle

Jordan, Allan M.; Hadfield, John A.; Lawrence, Nicholas J.; McGown, Alan T.

doi:10.1002/(sici)1098-1128(199807)18:4<259::aid-med3>3.0.co;2-u

Cited by 590 publications

(195 citation statements)

References 147 publications

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“…In addition to the widely used vinca alkaloids and taxoids, many other antimitotic agents are currently in clinical or preclinical development. 3 Newer potential targets that may cause mitotic arrest are in development as well. Although cancer chemotherapy is a very important goal being extensively investigated, the mechanism of action of the naturally occurring peptides that inhibit tubulin polymerization remains a challenging problem.…”

Section: Antimitotic Agentsmentioning

confidence: 99%

“…5 The structures of the ustiloxin congeners contain a 13-membered heterodetic peptide macrocycle that includes a rare chiral tertiary alkyl-aryl ether linkage. The ustiloxin congeners (1)(2)(3)(4)(5) are composed of permutations of two separate sites: the side chain attached to the macrocyclic aromatic ring para to the ether linkage (see R 1 in Error! Reference source not found.)…”

Section: Ustiloxinsmentioning

confidence: 99%

“…In addition to the widely used vinca alkaloids and taxoids, many other antimitotic agents are currently in clinical or preclinical development. 3 Newer potential targets …”

mentioning

confidence: 99%

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Evolution of the Total Syntheses of Ustiloxin Natural Products and Their Analogues

Evans

et al. 2008

J. Am. Chem. Soc.

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Ustiloxins A-F are antimitotic heterodetic cyclopeptides containing a 13-membered cyclic core structure with a synthetically challenging chiral tertiary alkyl-aryl ether linkage. The first total synthesis of ustiloxin D was achieved in 31 linear steps using an S N Ar reaction. An nOe study of this synthetic product showed that ustiloxin D existed as a single atropisomer. Subsequently, highly concise and convergent syntheses of ustiloxins D and F were developed by utilizing a newly discovered ethynyl aziridine ring-opening reaction in a longest linear sequence of 15 steps. The approach was further optimized to achieve a better macrolactamization strategy. Ustiloxins D, F and eight analogues (14-MeO-ustiloxin D, four analogues with different amino acid residues at the C-6 position, and three (9R, 10S)-epi-ustiloxin analogues) were prepared via the second generation route. Evaluation of these compounds as inhibitors of tubulin polymerization demonstrated that variation at the C-6 position is tolerated to a certain extent. In contrast, the S configuration of the C-9 methylamino group and a free phenolic hydroxyl group are essential for inhibition of tubulin polymerization. Antimitotic agentsAntimitotic agents have long been of interest to scientists and physicians, even before their precise mechanism of action could be articulated. Most of these compounds interfere with microtubule assembly and functions thus resulting in mitotic arrest of eukaryotic cells. There are a number of natural and synthetic compounds that interfere with tubulin function to inhibit the formation of microtubules. 1 Such antimitotic agents exhibit a broad range of biological activities and can be used for medicinal and agrochemical purposes, acting as anticancer, antifungal, or anthelmintic agents. Moreover, tubulin binding compounds are valuable for understanding basic mechanisms involved in the dynamics of the microtubule network. 2 Mitotic arrest is of importance in cancer chemotherapy, since tubulin is an established chemotherapeutic target. In addition to the widely used vinca alkaloids and taxoids, many other antimitotic agents are currently in clinical or preclinical development. 3 Newer potential targets NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript that may cause mitotic arrest are in development as well. Although cancer chemotherapy is a very important goal being extensively investigated, the mechanism of action of the naturally occurring peptides that inhibit tubulin polymerization remains a challenging problem. Attempts to establish a relationship among the tubulin binding peptides have only had limited success. [4][5][6][7][8] As a result, the mechanism of action of peptidic antimitotic agents is not completely elucidated and deserves further investigation. UstiloxinsThe first peptide shown to interact with tubulin was phomopsin A (Error! Reference source not found.). [9][10][11][12][13] Since then, a number of peptides and depsipeptides were found to disrupt cellular microtubules. These compo...

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Section: Antimitotic Agentsmentioning

confidence: 99%

Section: Ustiloxinsmentioning

confidence: 99%

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Evolution of the Total Syntheses of Ustiloxin Natural Products and Their Analogues

Evans

et al. 2008

J. Am. Chem. Soc.

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“…VBL and VCR are structurally very similar, whereas the structure of VDS differs from those of the other two. 27 This structural difference may be responsible for the different genomic responses. Vinca alkaloids and dolastatins are known to bind at so-called Vinca-binding domains in tubulin.…”

Section: Characterization Of Tzt-1027 In Reference Profilingmentioning

confidence: 99%

Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro

et al. 2006

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“…The proper orientation and segregation of chromosomes require highly coordinated microtubule dynamics. Therefore, microtubules are intimately involved with the replication of cells [7]. In all, the correct arrangement of microtubules is essential for intracellular trafficking, cellular motility and mitotic chromosome segregation.…”

mentioning

confidence: 99%

Modernization of traditional Chinese medicine

Guo

Lü

Liu

2012

Journal of Ethnopharmacology

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Tubulin as a target for anticancer drugs: Agents which interact with the mitotic spindle

Cited by 590 publications

References 147 publications

Evolution of the Total Syntheses of Ustiloxin Natural Products and Their Analogues

Evolution of the Total Syntheses of Ustiloxin Natural Products and Their Analogues

Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro

Modernization of traditional Chinese medicine

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