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Pregled bibliografske jedinice broj: 1103326

N-substituted benzimidazoles as tubulin polymerization inhibitors


Hok, Lucija; Perin, Nataša; Beč, Anja; Persoons, Leentje; Vanstreels, Els; Daelemans, Dirk; Vianello, Robert; Hranjec, Marijana
N-substituted benzimidazoles as tubulin polymerization inhibitors // Virtual NGSymposium
online, 2020. (predavanje, nije recenziran, neobjavljeni rad, znanstveni)


CROSBI ID: 1103326 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
N-substituted benzimidazoles as tubulin polymerization inhibitors

Autori
Hok, Lucija ; Perin, Nataša ; Beč, Anja ; Persoons, Leentje ; Vanstreels, Els ; Daelemans, Dirk ; Vianello, Robert ; Hranjec, Marijana

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, neobjavljeni rad, znanstveni

Skup
Virtual NGSymposium

Mjesto i datum
Online, 24.09.2020. - 25.09.2020

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Nije recenziran

Ključne riječi
acrylonitriles ; amination ; antiproliferative activity ; benzimidazoles ; docking simulations ; tubulin polymerization

Sažetak
The benzimidazole scaffold, as a small nitrogen-containing heterocycle, has become a fundamental building block widely incorporated in the structure of numerous synthetic molecules. Due to the fact that benzimidazole nucleus is a bioisoster of the naturally occurring purine, its derivatives may interact with different biomolecules and achieve many biological effects, of which the most important is their promising and strong antiproliferative activity [1]. In this work, the novel N- substituted-2- benzimidazolyl acrylonitriles were synthesized and tested for the antiproliferative activity in vitro on eight human cancer cell lines and one reference non- cancerous assay. Of all evaluated derivatives, the N, N-dimethylamino substituted acrylonitriles bearing N-isobutyl and cyano moieties showed the strongest and the most selective antitumor activity in the submicromolar range of inhibitory concentrations, while being significantly less toxic than the reference systems docetaxel and staurosporine. Further mechanistic studies demonstrated that the most active derivatives inhibit cancer cell proliferation by disintegration of the microtubule network, comparable with the effect of the microtubule destabilizing compounds vincristine and colchicine. With the aim of obtaining a deeper insight into the binding of the tested molecules, we employed docking simulations and quantum- chemical calculations using the SwissDock web server and the Gaussian 16 software. Computational analysis confirmed the suitability of the employed benzimidazole- acrylonitrile skeleton for the binding within the colchicine binding site in tubulin, thus rationalizing the observed antitumor activity. It also provided structural determinants affecting both the binding position and the matching affinities, identifying the attached N, N-dimethylamino group as the most dominant in promoting the binding, which allows ligands to optimize favorable cation∙∙∙π and hydrogen bonding interactions with Lys352. This initial research represents a valuable foundation for the further development and the rational design of the benzimidazole-based antiproliferative substances. [1] W. Akhtar, M. Faraz Khan, G. Verma, M. Shaquiquzzaman, M. A. Rizvi, S. H. Mehdi, M. Akhter, M. Mumtaz Alam, Therapeutic evolution of benzimidazole derivatives in the last quinquennial period, Eur. J. Med. Chem. 126 (2017) 705–753. DOI: 10.1016/j.ejmech.2016.12.010

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Interdisciplinarne prirodne znanosti



POVEZANOST RADA


Ustanove:
Institut "Ruđer Bošković", Zagreb,
Fakultet kemijskog inženjerstva i tehnologije, Zagreb

Profili:

Avatar Url Anja Beč (autor)

Avatar Url Robert Vianello (autor)

Avatar Url Marijana Hranjec (autor)

Avatar Url Nataša Perin (autor)

Avatar Url Lucija Hok (autor)

Poveznice na cjeloviti tekst rada:

ngschool.eu

Citiraj ovu publikaciju:

Hok, Lucija; Perin, Nataša; Beč, Anja; Persoons, Leentje; Vanstreels, Els; Daelemans, Dirk; Vianello, Robert; Hranjec, Marijana
N-substituted benzimidazoles as tubulin polymerization inhibitors // Virtual NGSymposium
online, 2020. (predavanje, nije recenziran, neobjavljeni rad, znanstveni)
Hok, L., Perin, N., Beč, A., Persoons, L., Vanstreels, E., Daelemans, D., Vianello, R. & Hranjec, M. (2020) N-substituted benzimidazoles as tubulin polymerization inhibitors. U: Virtual NGSymposium.
@article{article, author = {Hok, Lucija and Perin, Nata\v{s}a and Be\v{c}, Anja and Persoons, Leentje and Vanstreels, Els and Daelemans, Dirk and Vianello, Robert and Hranjec, Marijana}, year = {2020}, keywords = {acrylonitriles, amination, antiproliferative activity, benzimidazoles, docking simulations, tubulin polymerization}, title = {N-substituted benzimidazoles as tubulin polymerization inhibitors}, keyword = {acrylonitriles, amination, antiproliferative activity, benzimidazoles, docking simulations, tubulin polymerization}, publisherplace = {online} }
@article{article, author = {Hok, Lucija and Perin, Nata\v{s}a and Be\v{c}, Anja and Persoons, Leentje and Vanstreels, Els and Daelemans, Dirk and Vianello, Robert and Hranjec, Marijana}, year = {2020}, keywords = {acrylonitriles, amination, antiproliferative activity, benzimidazoles, docking simulations, tubulin polymerization}, title = {N-substituted benzimidazoles as tubulin polymerization inhibitors}, keyword = {acrylonitriles, amination, antiproliferative activity, benzimidazoles, docking simulations, tubulin polymerization}, publisherplace = {online} }




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