Synthesis and Antimitotic and Tubulin Interaction Profiles of Novel Pinacol Derivatives of Podophyllotoxins

Abad, Antonio; López-Pérez, Jose Luis; Olmo, Esther del; García‐Fernández, Luis; Francesch, Andrés; Trigili, Chiara; Barasoaín, Isabel; Andreu, José Manuel; Díaz, J. Fernando; Feliciano, Arturo San

doi:10.1021/jm2017573

Cited by 76 publications

(30 citation statements)

References 56 publications

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“…During a normal cell cycle, the progression of cells in the G 2 phase to the M phase is triggered by activation of the cyclin B1 dependent kinase . We further investigated the expression levels of cyclin B1.…”

Section: Resultsmentioning

confidence: 99%

2‐Anilino‐3‐Aroylquinolines as Potent Tubulin Polymerization Inhibitors

et al. 2016

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Several 2-anilino-3-aroylquinolines were designed, synthesized, and screened for their cytotoxic activity against five human cancer cell lines: HeLa, DU-145, A549, MDA-MB-231, and MCF-7. Their IC50 values ranged from 0.77 to 23.6 μm. Among the series, compounds 7 f [(4-fluorophenyl)(2-((4-fluorophenyl)amino)quinolin-3-yl)methanone] and 7 g [(4-chlorophenyl)(2-((4-fluorophenyl)amino)quinolin-3-yl)methanone] showed remarkable antiproliferative activity against human lung cancer and prostate cancer cell lines. The IC50 values for inhibiting tubulin polymerization were 2.24 and 2.10 μm for compounds 7 f and 7 g, respectively, and were much lower than that of the reference compound E7010 [N-(2-(4-hydroxyphenylamino)pyridin-3-yl)-4-methoxybenzenesulfonamide]. Furthermore, flow cytometric analysis revealed that these compounds arrest the cell cycle at the G2 /M phase, leading to apoptosis. Apoptosis was also confirmed by mitochondrial membrane potential, Annexin V-FITC assay, and intracellular ROS generation. Immunohistochemistry, western blot, and tubulin polymerization assays showed that these compounds disrupt tubulin polymerization. Molecular docking studies revealed that these compounds bind efficiently to β-tubulin at the colchicine binding site.

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Section: Resultsmentioning

confidence: 99%

2‐Anilino‐3‐Aroylquinolines as Potent Tubulin Polymerization Inhibitors

et al. 2016

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“…This decrease in activity was previously observed on other cell lines, (Castro et al., 2003, López-Pérez et al., 2004, Abad et al., 2012), and could be due to additional spatial hindering for the binding to tubulin. However, relevant exceptions of highly potent polymerization inhibition of mammalian tubulin were demonstrated for some 7α-alkyl and 7α-hydroxycycloalkyl derivatives, as for 7α-isopropyl derivative 4 and for the glycolic pyranyl derivative 13 (Abad et al., 2012) included in this research (Table 1). …”

Section: Discussionmentioning

confidence: 99%

“…1) and the derivatives evaluated in this work are compiled in Table 1, Table 2, Table 3, Table 4. Compounds were prepared according to previous reports (Castro et al., 2004, Castro et al., 2010, Castro et al., 2012, Abad et al., 2012) and to unpublished procedures (chemical data not shown here). Their structures were respectively confirmed or assigned by either direct comparison with authentic samples, or through complete analysis of One- and Two-Dimensional 1 H and 13 C nuclear magnetic resonance (1D- and 2D-NMR, respectively), infrared (IR) and mass (MS) spectra for the new compounds.…”

Section: Methodsmentioning

confidence: 99%

Antileishmanial activity and tubulin polymerization inhibition of podophyllotoxin derivatives on Leishmania infantum

Escudero-Martínez

Pérez-Pertejo

Reguera

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages. Microtubules result from the self-assembly of alpha and beta tubulins, two phylogenetically conserved and very abundant eukaryotic proteins in kinetoplastids. The colchicine binding domain has inspired the discovery and development of several drugs currently in clinical use against parasites. However, this domain is less conserved in kinetoplastids and may be selectively targeted by new compounds. This report shows the antileishmanial effect of several series of compounds (53), derived from podophyllotoxin (a natural cyclolignan isolated from rhizomes of Podophyllum spp.) and podophyllic aldehyde, on a transgenic, fluorescence-emitting strain of Leishmania infantum. These compounds were tested on both promastigotes and amastigote-infected mouse splenocytes, and in mammalian – mouse non-infected splenocytes and liver HepG2 cells – in order to determine selective indexes of the drugs. Results obtained with podophyllotoxin derivatives showed that the hydroxyl group at position C-7α was a structural requisite to kill the parasites. On regards podophyllic aldehyde, derivatives with C9-aldehyde group integrated into a bicyclic heterostructure displayed more potent antileishmanial effects and were relatively safe for host cells. Docking studies of podophyllotoxin and podophyllic aldehyde derivatives showed that these compounds share a similar pattern of interaction at the colchicine site of Leishmania tubulin, thus pointing to a common mechanism of action. However, the results obtained suggested that despite tubulin is a remarkable target against leishmaniasis, there is a poor correlation between inhibition of tubulin polymerization and antileishmanial effect of many of the compounds tested, fact that points to alternative pathways to kill the parasites.

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“…[12][13][14] Although COL has been shown to possess antitumor properties, 15,16 its therapeutic use is limited by toxicity problems; this has led to the consideration of analogs. [17][18][19] When COL binds to TU, it inhibits the assembly into microtubules and microtubule dynamics. 20 The binding process is slow and strongly temperature-dependent, 21 while dissociation is kinetically unfavorable due to its high activation energy.…”

Section: Introductionmentioning

confidence: 99%

Drug–tubulin interactions interrogated by transient absorption spectroscopy

et al. 2015

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Colchicine (COL) is a bioactive molecule with antitumor properties. When COL binds to tubulin (TU), it inhibits microtubule assembly dynamics. We have investigated COL-TU interactions using laser flash photolysis (LFP) technique and performing fully flexible molecular dynamics simulations. Excitation of COL at 355 nm in aqueous medium did not lead to any transient absorption spectrum. By contrast, in the presence of TU a transient peaking at l max ca. 420 nm was registered and assigned as triplet excited COL complexed with TU ( 3 COL*@TU). In aerated medium, the lifetime was s ca.160 ms and the quantum yield was 0.138. Likewise, when the bicyclic COL analog MTC was submitted to LFP in the presence of TU, 3 MTC@TU* was detected with a lifetime of ca. 62 ms and a quantum yield of 0.296, Aqueous solutions of MTC did not produce any signal in the microsecond timescale. The triplet energy of MTC was obtained by means of emission measurements and found to be ca. 200 kJ mol À1 , a value that matches with that previously reported for COL (188 kJ mol À1 ).Molecular dynamic simulations, both with the ground and triplet excited state, reveal a strong interaction between COL and TU to give stabilized complexes with restricted mobility inside the protein binding site. These results demonstrate that LFP is a useful methodology to study the binding of COL derivatives to TU and open a new way to evaluate the interactions of nonfluorescent anticancer drugs with this protein.

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Synthesis and Antimitotic and Tubulin Interaction Profiles of Novel Pinacol Derivatives of Podophyllotoxins

Cited by 76 publications

References 56 publications

2‐Anilino‐3‐Aroylquinolines as Potent Tubulin Polymerization Inhibitors

2‐Anilino‐3‐Aroylquinolines as Potent Tubulin Polymerization Inhibitors

Antileishmanial activity and tubulin polymerization inhibition of podophyllotoxin derivatives on Leishmania infantum

Drug–tubulin interactions interrogated by transient absorption spectroscopy

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