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Tubulin Inhibitors
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Tubulin Inhibitors

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 21544

Special Issue Editor

Prof. Dr. Romano Silvestri

E-Mail Website
Guest Editor
Department of Drug Chemistry and Technologies, Universita degli Studi di Roma La Sapienza, Rome, Italy
Interests: drug design and synthesis of new biologically active chemical entities in the areas of antitumor; antiviral or SNC drugs; the drug design is based on molecular models performed by either the internal unit or external research groups; new procedures for the microwave-assisted synthesis and the highly automated purification of relevant pharmaceutical molecules

Special Issue Information

Dear Colleagues,

Microtubule (MTs) play a key role in the division and motility of cells, manage the intracellular trafficking and preserve cell shape. The mitotic spindle generated by the MTs segregate the chromosomes during the cell division.  Both inhibition of tubulin polymerization and stabilization of disassembly alter the MT dynamic equilibrium, and, ultimately, cause lethal injury to the cell. Interfering with the MT dynamic equilibrium has drawn attention as a fruitful strategy to develop anticancer agents. A high proportion of cells treated with a MT targeting agent appear to be arrested in mitosis, show condensed chromosomes, lack of nuclear membrane and have damaged or no mitotic spindle. Over the past decades, an ever-growing number of compounds that bind to tubulin a,b-dimers, oligomers or polymers have been reported. The interference by these agents to the cell division has led the development of a wide variety of potential anticancer agents.

This Special Issue aims to attract contributions on all aspects of the chemistry and biological activity of tubulin binding agents. There's an unmet need for improved anticancer therapies. An exploration through tubulin binding agents and their biological effects may have a great impact on the advance of successful anticancer therapies.

Prof. Dr. Romano Silvestri
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Tubulin
  • Microtubules
  • Interaction
  • Cancer
  • Chemotherapeutics

Published Papers (5 papers)

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Research

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18 pages, 2510 KiB  
Article
Synthesis and Biological Evaluation of 2-Substituted Benzyl-/Phenylethylamino-4-amino-5-aroylthiazoles as Apoptosis-Inducing Anticancer Agents
by Paola Oliva, Valentina Onnis, Elisa Balboni, Ernest Hamel, Francisco Estévez-Sarmiento, José Quintana, Francisco Estévez, Andrea Brancale, Salvatore Ferla, Stefano Manfredini and Romeo Romagnoli
Molecules 2020, 25(9), 2177; https://doi.org/10.3390/molecules25092177 - 6 May 2020
Cited by 6 | Viewed by 3078
Abstract
Induction of apoptosis is a common chemotherapeutic mechanism to kill cancer cells The thiazole system has been reported over the past decades as a building block for the preparation of anticancer agents. A novel series of 2-arylalkylamino-4-amino-5-(3′,4′,5′-trimethoxybenzoyl)-thiazole derivatives designed as dual inhibitors of [...] Read more.
Induction of apoptosis is a common chemotherapeutic mechanism to kill cancer cells The thiazole system has been reported over the past decades as a building block for the preparation of anticancer agents. A novel series of 2-arylalkylamino-4-amino-5-(3′,4′,5′-trimethoxybenzoyl)-thiazole derivatives designed as dual inhibitors of tubulin and cyclin-dependent kinases (CDKs) were synthesized and evaluated for their antiproliferative activity in vitro against two cancer cell lines and, for selected highly active compounds, for interactions with tubulin and cyclin-dependent kinases and for cell cycle and apoptosis effects. Structure-activity relationships were elucidated for various substituents at the 2-position of the thiazole skeleton. Among the synthesized compounds, the most active analogues were found to be the p-chlorobenzylamino derivative 8e as well as the p-chloro and p-methoxyphenethylamino analogues 8f and 8k, respectively, which inhibited the growth of U-937 and SK-MEL-1 cancer cell lines with IC50 values ranging from 5.7 to 12.2 μM. On U-937 cells, the tested compounds 8f and 8k induced apoptosis in a time and concentration dependent manner. These two latter molecules did not affect tubulin polymerization (IC50 > 20 μM) nor CDK activity at a single concentration of 10 μM, suggesting alternative targets than tubulin and CDK for the compounds. Full article
(This article belongs to the Special Issue Tubulin Inhibitors)
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23 pages, 3944 KiB  
Article
Synthesis and Biological Evaluation of New Antitubulin Agents Containing 2-(3′,4′,5′-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine Scaffold
by Romeo Romagnoli, Filippo Prencipe, Paola Oliva, Barbara Cacciari, Jan Balzarini, Sandra Liekens, Ernest Hamel, Andrea Brancale, Salvatore Ferla, Stefano Manfredini, Matteo Zurlo, Alessia Finotti and Roberto Gambari
Molecules 2020, 25(7), 1690; https://doi.org/10.3390/molecules25071690 - 7 Apr 2020
Cited by 11 | Viewed by 3488
Abstract
Two novel series of compounds based on the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4,5,6,7-tetrahydrobenzo[b]thiophene molecular skeleton, characterized by the presence of a 3′,4′,5′-trimethoxyanilino moiety and a cyano or an alkoxycarbonyl group at its 2- or 3-position, respectively, were designed, synthesized, and evaluated [...] Read more.
Two novel series of compounds based on the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4,5,6,7-tetrahydrobenzo[b]thiophene molecular skeleton, characterized by the presence of a 3′,4′,5′-trimethoxyanilino moiety and a cyano or an alkoxycarbonyl group at its 2- or 3-position, respectively, were designed, synthesized, and evaluated for antiproliferative activity on a panel of cancer cell lines and for selected highly active compounds, inhibition of tubulin polymerization, and cell cycle effects. We have identified the 2-(3′,4′,5′-trimethoxyanilino)-3-cyano-6-methoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivative 3a and its 6-ethoxycarbonyl homologue 3b as new antiproliferative agents that inhibit cancer cell growth with IC50 values ranging from 1.1 to 4.7 μM against a panel of three cancer cell lines. Their interaction with tubulin at micromolar levels leads to the accumulation of cells in the G2/M phase of the cell cycle and to an apoptotic cell death. The cell apoptosis study found that compounds 3a and 3b were very effective in the induction of apoptosis in a dose-dependent manner. These two derivatives did not induce cell death in normal human peripheral blood mononuclear cells, suggesting that they may be selective against cancer cells. Molecular docking studies confirmed that the inhibitory activity of these molecules on tubulin polymerization derived from binding to the colchicine site. Full article
(This article belongs to the Special Issue Tubulin Inhibitors)
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27 pages, 3612 KiB  
Article
The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors
by Myriam González, Younes Ellahioui, Raquel Álvarez, Laura Gallego-Yerga, Esther Caballero, Alba Vicente-Blázquez, Laura Ramudo, Miguel Marín Folgado, Cristina Sanz, Manuel Medarde and Rafael Pelaéz
Molecules 2019, 24(23), 4319; https://doi.org/10.3390/molecules24234319 - 26 Nov 2019
Cited by 18 | Viewed by 3303
Abstract
Colchicine site ligands suffer from low aqueous solubility due to the highly hydrophobic nature of the binding site. A new strategy for increasing molecular polarity without exposing polar groups—termed masked polar group incorporation (MPGI)—was devised and applied to nitrogenated combretastatin analogues. Bulky ortho [...] Read more.
Colchicine site ligands suffer from low aqueous solubility due to the highly hydrophobic nature of the binding site. A new strategy for increasing molecular polarity without exposing polar groups—termed masked polar group incorporation (MPGI)—was devised and applied to nitrogenated combretastatin analogues. Bulky ortho substituents to the pyridine nitrogen hinder it from the hydrophobic pocket while increasing molecular polarity. The resulting analogues show improved aqueous solubilities and highly potent antiproliferative activity against several cancer cell lines of different origin. The more potent compounds showed moderate tubulin polymerization inhibitory activity, arrested the cell cycle of treated cells at the G2/M phase, and subsequently caused apoptotic cell death represented by the cells gathered at the subG0/G1 population after 48 h of treatment. Annexin V/Propidium Iodide (PI) double-positive cells observed after 72 h confirmed the induction of apoptosis. Docking studies suggest binding at the colchicine site of tubulin in a similar way as combretastatin A4, with the polar groups masked by the vicinal substituents. These results validate the proposed strategy for the design of colchicine site ligands and open a new road to increasing the aqueous solubility of ligands binding in apolar environments. Full article
(This article belongs to the Special Issue Tubulin Inhibitors)
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18 pages, 2489 KiB  
Article
Design and Synthesis of New 6-Nitro and 6-Amino-3,3a,4,5-Tetrahydro-2H-Benzo[g]indazole Derivatives: Antiproliferative and Antibacterial Activity
by Viviana Cuartas, María del Pilar Crespo, Eva-María Priego, Leentje Persoons, Dirk Daelemans, María-José Camarasa, Braulio Insuasty and María-Jesús Pérez-Pérez
Molecules 2019, 24(23), 4236; https://doi.org/10.3390/molecules24234236 - 21 Nov 2019
Cited by 5 | Viewed by 3011
Abstract
New substituted benzo[g]indazoles functionalized with a 6-nitro and 6-amino groups have been synthesized by the reaction of benzylidene tetralones with hydrazine in acetic acid. The resulting conformationally-constrained compounds were evaluated for their antiproliferative activity against selected cancer cell lines. The nitro-based indazoles 11a [...] Read more.
New substituted benzo[g]indazoles functionalized with a 6-nitro and 6-amino groups have been synthesized by the reaction of benzylidene tetralones with hydrazine in acetic acid. The resulting conformationally-constrained compounds were evaluated for their antiproliferative activity against selected cancer cell lines. The nitro-based indazoles 11a, 11b, 12a and 12b have shown IC50 values between 5–15 μM against the lung carcinoma cell line NCI-H460. Moreover, the nitro compounds were tested for antibacterial activity where compounds 12a and 13b have shown MIC values of 250 and 62.5 μg/mL against N. gonorrhoeae with no hemolytic activity in human red blood cells (RBC). Full article
(This article belongs to the Special Issue Tubulin Inhibitors)
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Review

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36 pages, 4762 KiB  
Review
Intrinsic and Extrinsic Factors Affecting Microtubule Dynamics in Normal and Cancer Cells
by Filip Borys, Ewa Joachimiak, Hanna Krawczyk and Hanna Fabczak
Molecules 2020, 25(16), 3705; https://doi.org/10.3390/molecules25163705 - 14 Aug 2020
Cited by 36 | Viewed by 8275
Abstract
Microtubules (MTs), highly dynamic structures composed of α- and β-tubulin heterodimers, are involved in cell movement and intracellular traffic and are essential for cell division. Within the cell, MTs are not uniform as they can be composed of different tubulin isotypes that are [...] Read more.
Microtubules (MTs), highly dynamic structures composed of α- and β-tubulin heterodimers, are involved in cell movement and intracellular traffic and are essential for cell division. Within the cell, MTs are not uniform as they can be composed of different tubulin isotypes that are post-translationally modified and interact with different microtubule-associated proteins (MAPs). These diverse intrinsic factors influence the dynamics of MTs. Extrinsic factors such as microtubule-targeting agents (MTAs) can also affect MT dynamics. MTAs can be divided into two main categories: microtubule-stabilizing agents (MSAs) and microtubule-destabilizing agents (MDAs). Thus, the MT skeleton is an important target for anticancer therapy. This review discusses factors that determine the microtubule dynamics in normal and cancer cells and describes microtubule–MTA interactions, highlighting the importance of tubulin isoform diversity and post-translational modifications in MTA responses and the consequences of such a phenomenon, including drug resistance development. Full article
(This article belongs to the Special Issue Tubulin Inhibitors)
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