Microtubules destabilizing agents binding sites in tubulin

Alpízar-Pedraza, Daniel; Veulens, Ania de la Nuez; Araujo, Enrique Colina; Piloto-Ferrer, Janet; Sánchez-Lamar, Ángel

doi:10.1016/j.molstruc.2022.132723

Cited by 19 publications

(13 citation statements)

References 79 publications

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“…In this sense, a superposition study based on the sequence identity homology shared by α-and β-tubulin, the 3D structures similarities, and the disposition of pironetin and colchicine binding sites in their respective subunits reveal that these are equivalent sites from different subunits. They share the same fold and their sequences are similar, with 34% of sequence identity and many of the observed amino acid changes are conservative (29%) [50]. All mentioned above, make stronger our previous suggestion of two possible binding sites in tubulin for xanthanolides.…”

Section: Discussionmentioning

confidence: 66%

“…The colchicine and pironetin binding sites are two well-de ned hydrophobic pockets that bind small molecular weight molecules. However, despite the high similarity in their 3D structure, they present some differences in their amino acid composition [50]. These differences in the primary sequence could contribute to the lower stability observed for the xanthanolides inside the pironetin binding site.…”

Section: Discussionmentioning

confidence: 99%

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Xanthatin and 8-epi-xanthatin as new potential colchicine binding site inhibitors: a computational study

et al. 2023

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Phytocompounds xanthatin and 8-epi-xanthatin, obtained from Xanthium chinese Mill, showed antitumoral activity in vitro, related to the microtubules destabilizing properties of these phytocompounds. However, the exact binding pocket on tubulin of these isomers remains unknown. The aim of this work is, to develop a comprehensive computational strategy to understand and eventually predict the structure-activity relationship of xanthatin and 8-epi-xanthatin, with the destabilizingantimitotic binding domain in tubulin heterodimer and to propose a putative binding site for these phytocompounds into the microtubule destabilizing agents binding sites in the tubulin heterodimer. A molecular docking was performed using the xanthanolides conformers as ligands and several tubulin structures obtained from the Protein Data Bank as receptor. The xanthanolides-tubulin complexes were energy minimized by molecular dynamics simulations at vacuum and their stability was evaluated by solvated molecular dynamics simulations during 100 ns. Xanthanolides showed higher stability into the colchicine and pironetin binding sites, whit a greater a nity for the former. In addition, the xanthanolides and non-classical colchicine binding site inhibitors share a high structural similarity.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Xanthatin and 8-epi-xanthatin as new potential colchicine binding site inhibitors: a computational study

et al. 2023

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“…The stereodiads formed via ruthenium-catalyzed coupling of 1,4-pentadiene 1a represent polyketide “butyrate” substructures . This motif is evident in (−)-pironetin, ,, a microtubule destabilizing agent that arrests cell cycle progression at the G2/M phase. , Many FDA-approved anticancer drugs perturb microtubule dynamics; however, pironetin is unique as it is the only microtubule destabilizing agent that binds α-tubulin. , Consequently, pironetin has attracted the attention of synthetic chemists, resulting in over a dozen total syntheses, as well as the synthesis and evaluation of simplified analogues . To illustrate the utility of the present ruthenium-catalyzed coupling of 1,4-pentadiene 1a , a known C1–C7 substructure of pironetin was prepared using this method (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Dual Ruthenium-Catalyzed Alkene Isomerization–Hydrogen Auto-Transfer Unlocks Skipped Dienes as Pronucleophiles for Enantioselective Alcohol C–H Allylation

et al. 2023

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The first use of 1,4-pentadiene and 1,5-hexadiene as allylmetal pronucleophiles in regio-, anti-diastereo-, and enantioselective carbonyl addition from alcohol proelectrophiles is described. As corroborated by deuterium labeling experiments, primary alcohol dehydrogenation delivers a ruthenium hydride that affects alkene isomerization to furnish a conjugated diene, followed by transfer hydrogenative carbonyl addition. Hydrometalation appears to be assisted by the formation of a fluxional olefin-chelated homoallylic alkylruthenium complex II, which exists in equilibrium with its pentacoordinate η1 form to enable β-hydride elimination. This effect confers remarkable chemoselectivity: while 1,4-pentadiene and 1,5-hexadiene are competent pronucleophiles, higher 1,n-dienes are not, and the olefinic functional groups of the products remain intact under conditions in which the 1,4- and 1,5-dienes isomerize. A survey of halide counterions reveals iodide-bound ruthenium-JOSIPHOS catalysts are uniquely effective in these processes. This method was used to prepare a previously reported C1–C7 substructure of (−)-pironetin in 4 vs 12 steps.

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“…Microtubule targeting agents (MTAs) can generally be divided into tubulin depolymerization inhibitors and tubulin polymerization inhibitors, which disrupt microtubule dynamics by binding to tubulin and causing cell death. MTAs are currently known to interact with tubulin through several binding sites: the vinca, laulimalide, maytansine, pironetin, taxane, and colchicine sites (Alpizar-Pedraza et al, 2022;Pal et al, 2022). Clinically applied microtubule targeting agents have been very successful in binding to vinca or taxane sites.…”

Section: Introductionmentioning

confidence: 99%

Research progress on antitumor activity of XRP44X and analogues as microtubule targeting agents

Wang

Shi²,

Yang³

et al. 2023

Front. Chem.

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Cancer threatens human health and life. Therefore, it is particularly important to develop safe and effective antitumor drugs. Microtubules, the main component of cytoskeleton, play an important role in maintaining cell morphology, mitosis, and signal transduction, which are one of important targets of antitumor drug research and development. Colchicine binding site inhibitors have dual effects of inhibiting proliferation and destroying blood vessels. In recent years, a series of inhibitors targeting this target have been studied and some progress has been made. XRP44X has a novel structure and overcomes some disadvantages of traditional inhibitors. It is also a multifunctional molecule that regulates not only the function of tubulin but also a variety of biological pathways. Therefore, the structure, synthesis, structure-activity relationship, and biological activity of XRP44X analogues reported in recent years were summarized in this paper, to provide a useful reference for the rational design of efficient colchicine binding site inhibitors.

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Microtubules destabilizing agents binding sites in tubulin

Cited by 19 publications

References 79 publications

Xanthatin and 8-epi-xanthatin as new potential colchicine binding site inhibitors: a computational study

Xanthatin and 8-epi-xanthatin as new potential colchicine binding site inhibitors: a computational study

Dual Ruthenium-Catalyzed Alkene Isomerization–Hydrogen Auto-Transfer Unlocks Skipped Dienes as Pronucleophiles for Enantioselective Alcohol C–H Allylation

Research progress on antitumor activity of XRP44X and analogues as microtubule targeting agents

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