[PMID]: | 28056737 |
[Au] Autor: | Pradhan S; Mahaddalkar T; Choudhary S; Manhcukonda N; Nagireddy PR; Kantevari S; Lopus M |
[Ad] Endereço: | Experimental Cancer Therapeutics and Chemical Biology, UM-DAE Centre for Excellence in Basic Sciences, Kalina, Mumbai, India. |
[Ti] Título: | Elucidation of the Tubulin-targeted Mechanism of Action of 9-(3-pyridyl) Noscapine. |
[So] Source: | Curr Top Med Chem;17(22):2569-2574, 2017. |
[Is] ISSN: | 1873-4294 |
[Cp] País de publicação: | Netherlands |
[La] Idioma: | eng |
[Ab] Resumo: | We have recently reported the synthesis and antiproliferative potential of a series of biaryl type α-noscapine congeners. Among them, 9-(3-pyridyl) noscapine 3f (9-PyNos, henceforth), which was synthesized by adding pyridine unit to the tetrahydroisoquinoline part of natural α-noscapine core, was found to be the most effective one to inhibit proliferation of a variety of cancer cell lines. However, details of its interactions with its cellular target, tubulin, remain poorly understood. In this report, we examined the nature of interactions of 9-PyNos with tubulin based on the methodologies of spectrofluorimetry, circular dichroism, and turbidimetry techniques. Far-UV circular dichroism spectra indicated perturbation of tubulin secondary structure in the presence of 9-PyNos, not amounting, however, to the perturbation induced by noscapine. The noscapinoid nevertheless altered the surface configuration of the protein considerably, as indicated by an anilinonaphthalene sulphonate binding assay, and promoted colchicine binding to tubulin, the latter indicating its adjacent binding site with colchicine. 9-PyNos however, did not alter microtubule assembly considerably. Investigating the possible reason behind this apparent lack of strong inhibition of microtubule assembly, we found that the binding interactions of tubulin with 9-PyNos do not involve modification of cysteine residues of tubulin. Taken together, our data suggest that the antiproliferative mechanism of action of 9-PyNos involves disruption of structural integrity of tubulin without strong inhibition of tubulin assembly. |
[Mh] Termos MeSH primário: |
Noscapina/análogos & derivados Moduladores de Tubulina/farmacologia Tubulina (Proteína)/metabolismo
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[Mh] Termos MeSH secundário: |
Seres Humanos Estrutura Molecular Noscapina/síntese química Noscapina/química Noscapina/farmacologia Relação Estrutura-Atividade Tubulina (Proteína)/química Moduladores de Tubulina/síntese química Moduladores de Tubulina/química
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; REVIEW |
[Nm] Nome de substância:
| 0 (9-(3-pyridyl)noscapine); 0 (Tubulin); 0 (Tubulin Modulators); 8V32U4AOQU (Noscapine) |
[Em] Mês de entrada: | 1708 |
[Cu] Atualização por classe: | 170825 |
[Lr] Data última revisão:
| 170825 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170107 |
[St] Status: | MEDLINE |
[do] DOI: | 10.2174/1568026617666170104150304 |
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