Recent developments in tubulin polymerization inhibitors: An overview

Kaur, Ramandeep; Kaur, Gurneet; Gill, Rupinder Kaur; Soni, Richard; Bariwal, Jitender

doi:10.1016/j.ejmech.2014.09.051

Cited by 273 publications

(216 citation statements)

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ABSTRACT: A series of 3,6-diaryl- [1,2,4]triazolo [4,3-b]pyridazines were designed as a class of vinylogous CA-4 analogues. The easily isomerized (Z,E)-butadiene linker of vinylogous CA-4 was replaced by a rigid [1,2,4]triazolo [4,3-b]pyridazine scaffold.

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confidence: 99%

“…The easily isomerized (Z,E)-butadiene linker of vinylogous CA-4 was replaced by a rigid [1,2,4]triazolo [4,3-b]pyridazine scaffold. Twentyone target compounds were synthesized and exhibited moderate to potent antiproliferative activity.…”

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confidence: 99%

“…14,15 Over the years, researchers have been highly interested in compounds containing the [1,2,4]triazolo [4,3-b]pyridazine scaffold, on account of their characteristic chemical structure and various biological properties including anticancer activity. 16−19 As part of our search for new antitubulin agents, 20−24 we hypothesized that the replacement of the easily isomerized (Z,E)-butadiene linker of vinylogous CA-4 analogues with a rigid [1,2,4]triazolo [4,3-b]pyridazine scaffold could be a successful strategy to unravel a class of antitubulin agents ( Figure 1). Thus, a series of 3,6-diaryl- [1,2,4]triazolo [4,3-b]pyridazines were synthesized and distinguished into two types.…”

mentioning

confidence: 99%

“…16−19 As part of our search for new antitubulin agents, 20−24 we hypothesized that the replacement of the easily isomerized (Z,E)-butadiene linker of vinylogous CA-4 analogues with a rigid [1,2,4]triazolo [4,3-b]pyridazine scaffold could be a successful strategy to unravel a class of antitubulin agents ( Figure 1). Thus, a series of 3,6-diaryl- [1,2,4]triazolo [4,3-b]pyridazines were synthesized and distinguished into two types. Type I target compounds (4a−q) include a 3,4,5-trimethoxyphenyl unit as the A-ring, which is an essential component to induce cytotoxicity in the compounds based on CA-4 pharmacophores, while type II target compounds (5a−d) include a 2,3,4-trimethoxy substitution on the A-ring for comparison ( Figure 1).…”

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confidence: 99%

“…For compound 4q, the oxygen atom of the paramethoxy group on A-ring formed a hydrogen bond with the thiol group of Cys β241, and the amino nitrogen atom on Bring formed another hydrogen bond with the sulfur atom of Met β259 ( Figure 5B). Additionally, the Ala β250 residue formed a direct hydrogen bond with the [1,2,4]triazolo [4,3-b]pyridazine linker. The docking study and tubulin polymerization assay suggested that 4q could bind at the colchicine binding site of tubulin.…”

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confidence: 99%

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Synthesis and Bioevaluation of 3,6-Diaryl-[1,2,4]triazolo[4,3-b] Pyridazines as Antitubulin Agents

Sun

et al. 2016

ACS Med. Chem. Lett.

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A series of 3,6-diaryl- [1,2,4]triazolo [4,3-b]pyridazines were designed as a class of vinylogous CA-4 analogues. The easily isomerized (Z,E)-butadiene linker of vinylogous CA-4 was replaced by a rigid [1,2,4]triazolo [4,3-b]pyridazine scaffold. Twentyone target compounds were synthesized and exhibited moderate to potent antiproliferative activity. The compound 4q with a 3-amino-4-methoxyphenyl moiety as the B-ring, comparable to CA-4 (IC 50 = 0.009−0.012 μM), displayed the highly active antiproliferative activity against SGC-7901, A549, and HT-1080 cell lines with IC 50 values of 0.014, 0.008, and 0.012 μM, respectively. Tubulin polymerization experiments indicated that 4q effectively inhibited tubulin polymerization, and immunostaining assay revealed that 4q significantly disrupted tubulin microtubule dynamics. Moreover, cell cycle studies revealed that compound 4q dramatically arrested cell cycle progression at G2/M phase in A549 cells. Molecular modeling studies showed that 4q could bind to the colchicine binding site on microtubules.

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Synthesis and Bioevaluation of 3,6-Diaryl-[1,2,4]triazolo[4,3-b] Pyridazines as Antitubulin Agents

Sun

et al. 2016

ACS Med. Chem. Lett.

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Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistance

Hsieh,

Du,

Yang

2023

Molecular Oncology

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Microtubule‐targeting agents represent one of the most successful classes of anticancer agents. However, the development of drug resistance and the appearance of adverse effects hamper their clinical implementation. Novel microtubule‐targeting agents without such limitations are urgently needed. By employing a gene expression‐based drug repositioning strategy, this study identifies VU‐0365114, originally synthesized as a positive allosteric modulator of human muscarinic acetylcholine receptor M5 (M5 mAChR), as a novel type of tubulin inhibitor by destabilizing microtubules. VU‐0365114 exhibits a broad‐spectrum in vitro anticancer activity, especially in colorectal cancer cells. A tumor xenograft study in nude mice shows that VU‐0365114 slowed the in vivo colorectal tumor growth. The anticancer activity of VU‐0365114 is not related to its original target, M5 mAChR. In addition, VU‐0365114 does not serve as a substrate of multidrug resistance (MDR) proteins, and thus it can overcome MDR. Furthermore, a kinome analysis shows that VU‐0365114 did not exhibit other significant off‐target effects. Taken together, our study suggests that VU‐0365114 primarily targets microtubules, offering potential for repurposing in cancer treatment, although more studies are needed before further drug development.

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The Mechanism of the Interactions of Pironetin Analog/Combretastatin A‐4 Hybrids with Tubulin

Torijano-Gutiérrez

Vilanova

Díaz‐Oltra

et al. 2015

Archiv der Pharmazie

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Registro de acceso restringido Este recurso no está disponible en acceso abierto por política de la editorial. No obstante, se puede acceder al texto completo desde la Universitat Jaume I o si el usuario cuenta con suscripción. Registre d'accés restringit Aquest recurs no està disponible en accés obert per política de l'editorial. No obstant això, es pot accedir al text complet des de la Universitat Jaume I o si l'usuari compta amb subscripció. Restricted access item This item isn't open access because of publisher's policy. The full--text version is only available from Jaume I University or if the user has a running suscription to the publisher's contents.

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Recent developments in tubulin polymerization inhibitors: An overview

Cited by 273 publications

References 118 publications

Synthesis and Bioevaluation of 3,6-Diaryl-[1,2,4]triazolo[4,3-b] Pyridazines as Antitubulin Agents

Synthesis and Bioevaluation of 3,6-Diaryl-[1,2,4]triazolo[4,3-b] Pyridazines as Antitubulin Agents

Repositioning VU‐0365114 as a novel microtubule‐destabilizing agent for treating cancer and overcoming drug resistance

The Mechanism of the Interactions of Pironetin Analog/Combretastatin A‐4 Hybrids with Tubulin

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