Understanding Tubulin/Microtubule−Taxane Interactions: A Quantitative Structure–Activity Relationship Study

Hansch, Corwin; Verma, Rajeshwar P.

doi:10.1021/mp700119e

Cited by 14 publications

(14 citation statements)

References 41 publications

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“…Studies on several types of lung cancer cells have shown that microtubule polymerization has an impact on its binding to chemotherapeutic agents. The enhanced microtubule polymerization increases the binding of microtubules to paclitaxel instead of vinblastine, affecting the response to chemotherapeutics in patients with lung cancer (18,19). …”

Section: Discussionmentioning

confidence: 99%

Correlation between microtubule-associated gene expression and chemosensitivity of patients with stage II non-small cell lung cancer

Jiang¹,

Xiao-fang³

et al. 2013

Experimental and Therapeutic Medicine

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The aim of this study was to explore the correlation between mRNA expression of β-tubulin-III and stathmin in patients with stage II non-small cell lung cancer (NSCLC) and the chemosensitivity to Navelbine plus cisplatin (NP), as well as to provide a basis for personalized treatment. A single-gene quantitative test was performed to detect the mRNA expression of β-tubulin-III and stathmin in the tumor tissue of patients with stage II NSCLC. All the patients underwent NP treatment following surgery and were followed-up to record their disease-free survival (DFS) and overall survival (OS). Statistical analyses were conducted to investigate the correlation between β-tubulin-III and stathmin mRNA expression and DFS and OS in the patients. β-tubulin-III mRNA expression was associated with OS in the 73 patients (P=0.003) and DFS was correlated with β-tubulin-III mRNA expression and lymphatic metastasis (P<0.01). Stathmin mRNA expression was not correlated with OS or DFS (P>0.05). OS and DFS were longer in the patients with low β-tubulin-III mRNA expression than in those with high β-tubulin-III mRNA expression (P<0.01); there was no significant change in OS and DFS between the patients with high and low mRNA expression of stathmin (P>0.05). The mRNA expression levels of β-tubulin-III in the tumor tissue of patients with stage II NSCLC may be considered as an index of prognosis and chemosensitivity, as well as a reference for personalized chemotherapeutic applications in patients.

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Section: Discussionmentioning

confidence: 99%

Correlation between microtubule-associated gene expression and chemosensitivity of patients with stage II non-small cell lung cancer

Jiang¹,

Xiao-fang³

et al. 2013

Experimental and Therapeutic Medicine

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“…where Q is the quality factor, and (vii) low value of s, where s is the standard deviation [15h, [22][23][24][25][26]. On the other hand, the internal validation was carried out by the cross-validation and Y-randomization tests [23b, 27].…”

Section: Methodsmentioning

confidence: 99%

A QSAR Study on the Cytotoxicity of Podophyllotoxin Analogues Against Various Cancer Cell Lines

Verma¹,

Hansch²

2010

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The powerful inhibitory activity of podophyllotoxin (a natural product) on cell growth led to the development of clinically useful anticancer agents such as etoposide, teniposide, and etopophos. Although, these podophyllotoxin derivatives show good clinical effects against various cancers, its use often results in various undesired side effects, drug resistance, and cytotoxicity towards the normal cells. In order to overcome these limitations, it is essential to search new podophyllotoxin analogues with improved anticancer activity and fewer side effects to gain the maximum benefits for the cancer patients. With this purpose, the cytotoxicity data of two series of podophyllotoxin derivatives against four different cancer cell lines was used to develop 4 QSAR models. Hydrophobic property of the molecules was found one of the most important determining factors for their activity. The developed QSAR models showed a good correlative and predictive abilities having r(2) = 0.960 to 0.836 and q(2) = 0.911 to 0.705. On the basis of QSAR 1, two compounds (10-10 and 10-11) are suggested as potential synthetic targets. Statistical diagnostics and internal validation (cross validation and Y-randomization) tests have validated all the QSAR models. These QSAR models could be useful in the rational design of potential drug molecules with an enhanced inhibitory potency.

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Section: -15mentioning

confidence: 99%

“…[19][20][21][22][23][24][25][26] However, there is only a small number of QSAR studies found in the literature for taxoid-site tubulin modulators and, to the best of our knowledge, no 3D QSAR investigation of discodermolide analogs has been reported to date. 25,[27][28][29][30] This proves the importance of QSAR studies involving this class of tubulin modulators.As part of our ongoing research program aimed at designing new β-tubulin modulators, a rational structurebased design strategy was employed to investigate the molecular recognition patterns required for specific β-tubulin binding, as schematically shown in Figure 2. In the present study, three-dimensional QSAR comparative molecular field analysis (3D QSAR CoMFA) 31 models were developed for a series of synthetic discodermolide analogs using two different structural alignment methods in order to explore the high conformational flexibility of the compounds.…”

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confidence: 99%

“…The results of the receptor-based CoMFA model are in accordance with previous classical and 3D QSAR studies on the interaction of taxanes in the tubulin/microtubule system, which indicated that the hydrophobic feature of the substituents along with the steric parameters/fields are the most important determinants of biological activity and directly reflect the chemical environment of the tubulin binding pocket. 27,28 In addition to prediction of property values for the test set molecules, the derived 3D QSAR CoMFA models should also provide insights into molecular properties intrinsically related to receptor-binding affinity and biological activity. One prominent feature of the CoMFA method is the easy visualization of the steric and electrostatic regions in space responsible for increases and decreases in the values of a particular type of dependent variable (e.g., pIC 50 ).…”

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confidence: 99%

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Structural and chemical basis for anticancer activity of a series of²-tubulin ligands: molecular modeling and 3D QSAR studies

Salum¹,

Dias²,

Andricopulo³

2009

J. Braz. Chem. Soc.

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Uma estratégia importante para a terapia do câncer é o planejamento de modulares que interferem na dinâmica dos microtúbulos através de sua ligação específica à subunidade β da tubulina. No presente trabalho, estudos de análise comparativa dos campos moleculares (CoMFA) foram realizados com uma série de análogos do discodermolídeo com ação antimitótica. Resultados significativos foram obtidos (CoMFA (i) , q 2 = 0,68, r 2 = 0,94; CoMFA (ii) , q 2 = 0,63, r 2 = 0,91), indicando a elevada consistência interna e externa dos modelos gerados empregando duas estratégias independentes de alinhamento estrutural. Os modelos foram validados externamente com um conjunto teste e os valores preditos apresentaram boa concordância com os resultados experimentais. Os modelos de QSAR e os mapas de contorno 3D forneceram importantes informações sobre as bases químicas e estruturais envolvidas no processo de reconhecimento molecular dessa família de análogos do discodermolídeo, sendo uma valiosa ferramenta no planejamento de novos moduladores específicos da β-tubulina com potente atividade antitumoral.An important approach to cancer therapy is the design of small molecule modulators that interfere with microtubule dynamics through their specific binding to the β-subunit of tubulin. In the present work, comparative molecular field analysis (CoMFA) studies were conducted on a series of discodermolide analogs with antimitotic properties. Significant correlation coefficients were obtained (CoMFA (i) , q 2 = 0.68, r 2 = 0.94; CoMFA (ii) , q 2 = 0.63, r 2 = 0.91), indicating the good internal and external consistency of the models generated using two independent structural alignment strategies. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the 3D contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of discodermolide analogs, and should be useful for the design of new specific β-tubulin modulators with potent anticancer activity.Keywords: cancer, drug design, discodermolide, microtubule, β-tubulin IntroductionA rational approach to cancer therapy involves the design of small molecule ligands that interfere with microtubule dynamics through their specific binding to the β-subunit of tubulin, leading to mitotic arrest and cell death.1-6 Taxol (paclitaxel, Figure 1), a highly functionalized diterpenoid isolated from Taxus brevifolia (Pacific Yew tree), was the first compound recognized to interact specifically and reversibly with the β-subunit of the tubulin heterodimer, promoting microtubule stabilization and consequently, blocking cells in the mitotic phase of the cell cycle. The unique mechanism of action as a microtubule-stabilizing antimitotic agent (MSAA) is responsible by the extraordinary clinical success achieved by Taxol and related taxanes in the treatment of a variety of cancers. Although taxanes are the most prominent amon...

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Understanding Tubulin/Microtubule−Taxane Interactions: A Quantitative Structure–Activity Relationship Study

Cited by 14 publications

References 41 publications

Correlation between microtubule-associated gene expression and chemosensitivity of patients with stage II non-small cell lung cancer

Correlation between microtubule-associated gene expression and chemosensitivity of patients with stage II non-small cell lung cancer

A QSAR Study on the Cytotoxicity of Podophyllotoxin Analogues Against Various Cancer Cell Lines

Structural and chemical basis for anticancer activity of a series of²-tubulin ligands: molecular modeling and 3D QSAR studies

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