7 research outputs found

    Design and Synthesis of Pironetin Analogue/Colchicine Hybrids and Study of Their Cytotoxic Activity and Mechanisms of Interaction with Tubulin

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    We here report the synthesis of a series of 12 hybrid molecules composed of a colchicine moiety and a pironetin analogue fragment. The two fragments are connected through an esterā€“amide spacer of variable length. The cytotoxic activities of these compounds and their interactions with tubulin have been investigated. Relations between the structure and activity are discussed. Since the spacer is not long enough to permit a simultaneous binding of the hybrid molecules to the colchicine and pironetin sites on tubulin, a further feature investigated was whether these molecules would interact with the latter through the pironetin end (irreversible covalent binding) or through the colchicine end (reversible noncovalent binding). It has been found that binding to tubulin may take place preferentially at either of these ends depending on the length of the connecting spacer

    Synthesis, Characterization, and Application in HeLa Cells of an NIR Light Responsive Doxorubicin Delivery System Based on NaYF<sub>4</sub>:Yb,Tm@SiO<sub>2</sub>ā€‘PEG Nanoparticles

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    Herein, we present a phototriggered drug delivery system based on light responsive nanoparticles, which is able to release doxorubicin upon NIR light illumination. The proposed system is based on upconversion fluorescence nanoparticles of Ī²-NaYF<sub>4</sub>:Yb,Tm@SiO<sub>2</sub>-PEG with a mean diameter of 52 Ā± 2.5 nm that absorb the NIR light and emit UV light. The UV radiation causes the degradation of photodegradable <i>ortho</i>-nitrobenzyl alcohol derivates, which are attached on one side to the surface of the nanoparticles and on the other to doxorubicin. This degradation triggers the doxorubicin release. This drug delivery system has been tested ā€œ<i>in vitro</i>ā€ with HeLa cells. The results of this study demonstrated that this system caused negligible cytotoxicity when they were not illuminated with NIR light. In contrast, under NIR light illumination, the HeLa cell viability was conspicuously reduced. These results demonstrated the suitability of the proposed system to control the release of doxorubicin via an external NIR light stimulus

    Novel Colchicine-Site Binders with a Cyclohexanedione Scaffold Identified through a Ligand-Based Virtual Screening Approach

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    Vascular disrupting agents (VDAs) constitute an innovative anticancer therapy that targets the tumor endothelium, leading to tumor necrosis. Our approach for the identification of new VDAs has relied on a ligand 3-D shape similarity virtual screening (VS) approach using the ROCS program as the VS tool and as query colchicine and TN-16, which both bind the Ī±,Ī²-tubulin dimer. One of the hits identified, using TN-16 as query, has been explored by the synthesis of its structural analogues, leading to 2-(1-((2-methoxyphenyl)Ā­amino)Ā­ethylidene)-5-phenylcyclohexane-1,3-dione (compound <b>16c</b>) with an IC<sub>50</sub> = 0.09 Ā± 0.01 Ī¼M in HMEC-1 and BAEC, being 100-fold more potent than the initial hit. Compound <b>16c</b> caused cell cycle arrest in the G2/M phase and interacted with the colchicine-binding site in tubulin, as confirmed by a competition assay with <i><i>N,N</i></i>ā€²<b>-</b>ethylenebisĀ­(iodoacetamide) and by fluorescence spectroscopy. Moreover, <b>16c</b> destroyed an established endothelial tubular network at 1 Ī¼M and inhibited the migration and invasion of human breast carcinoma cells at 0.4 Ī¼M. In conclusion, our approach has led to a new chemotype of promising antiproliferative compounds with antimitotic and potential VDA properties

    Total Synthesis of Amphidinolide K, a Macrolide That Stabilizes Fā€‘Actin

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    The total synthesis of (āˆ’)-amphidinolide K (<b>1</b>) based on asymmetric addition of allylsilane <b>C1</b>ā€“<b>C8</b> to enal <b>C9</b>ā€“<b>C22</b> is reported. The 1,9,18-tris-<i>O</i>-TBDPS ether was converted into the desired 9,18-dihydroxy acid. Its macrolactonization was accomplished by the Shiina method. Compound <b>1</b> together with some of its stereoisomers and analogues were subjected to evaluation of the possible disruption of the Ī±,Ī²-tubulinā€“microtubule and/or G-actinā€“F-actin equilibria. Compound <b>1</b> behaves as a stabilizer of actin filaments (F-actin) in vitro

    Structural and Biochemical Characterization of the Interaction of Tubulin with Potent Natural Analogues of Podophyllotoxin

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    Four natural analogues of podophyllotoxin obtained from the Mexican medicinal plant <i>Bursera fagaroides</i>, namely, acetyl podophyllotoxin (<b>2</b>), 5ā€²-desmethoxy-Ī²-peltatin A methyl ether (<b>3</b>), 7ā€²,8ā€²-dehydro acetyl podophyllotoxin (<b>4</b>), and burseranin (<b>5</b>), have been characterized, and their interactions with tubulin have been investigated. Cytotoxic activity measurements, followed by immunofluorescence microscopy and flow cytometry studies, demonstrated that these compounds disrupt microtubule networks in cells and cause cell cycle arrest in the G2/M phase in the A549 cell line. A tubulin binding assay showed that compounds <b>1</b>ā€“<b>4</b> were potent assembly inhibitors, displaying binding to the colchicine site with <i>K</i><sub>b</sub> values ranging from 11.75 to 185.0 Ɨ 10<sup>5</sup> M<sup>ā€“1</sup>. In contrast, burseranin (<b>5</b>) was not able to inhibit tubulin assembly. From the structural perspective, the ligand-binding epitopes of compounds <b>1</b>ā€“<b>3</b> have been mapped using STD-NMR, showing that B and E rings are the major points for interaction with the protein. The obtained results indicate that the inhibition of tubulin assembly of this family of compounds is more effective when there are at least two methoxyl groups at the E ring, along with a <i>trans</i> configuration of the lactone ring in the aryltetralin lignan core

    Endowing Indole-Based Tubulin Inhibitors with an Anchor for Derivatization: Highly Potent 3ā€‘Substituted Indolephenstatins and Indoleisocombretastatins

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    Colchicine site ligands with indole B rings are potent tubulin polymerization inhibitors. Structural modifications at the indole 3-position of 1-methyl-5-indolyl-based isocombretastatins (1,1-diarylethenes) and phenstatins endowed them with anchors for further derivatization and resulted in highly potent compounds. The substituted derivatives displayed potent cytotoxicity against several human cancer cell lines due to tubulin inhibition, as shown by cell cycle analysis, confocal microscopy, and tubulin polymerization inhibitory activity studies and promoted cell killing mediated by caspase-3 activation. Binding at the colchicine site was confirmed by means of fluorescence measurements of MTC displacement. Molecular modeling suggests that the tropolone-binding region of the colchicine site of tubulin can adapt to hosting small polar substituents. Isocombretastatins accepted substitutions better than phenstatins, and the highest potencies were achieved for the cyano and hydroxyiminomethyl substituents, with TPI values in the submicromolar range and cytotoxicities in the subnanomolar range. A 3,4,5-trimethoxyphenyl ring usually afforded more potent derivatives than a 2,3,4-trimethoxyphenyl ring

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

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    Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl group with either the 7Ī± (podo) or 7Ī² (epipodo) configuration. Along with pinacols, some C-7 alkylidene and C-7 alkyl derivatives were also prepared. Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7Ī²-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7Ī±-isopropyl-7-deoxypodophyllotoxin (<b>20</b>), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series
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