Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents

Monk, Keith A.; Siles, Rogelio; Hadimani, Mallinath B.; Mugabe, Benon E.; Ackley, J. Freeland; Studerus, Scott W.; Edvardsen, Klaus; Trawick, Mary Lynn; Garner, Charles M.; Rhodes, Monte R.; Pettit, George R.; Pinney, Kevin G.

doi:10.1016/j.bmc.2005.12.033

Cited by 75 publications

(48 citation statements)

References 44 publications

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“…Decoy-set method An internal database was developed using 800 compounds containing 43 active structures collected from the reported literature [22][23][24][25][26][27][28][29][30][31][32] . The database was used to evaluate the discriminative ability of the best pharmacophore model when distinguishing the active compounds from the inactive compounds.…”

Section: Fischer Randomization Methodsmentioning

confidence: 99%

Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking

et al. 2014

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Aim:To construct a quantitative pharmacophore model of tubulin inhibitors and to discovery new leads with potent antitumor activities. Methods: Ligand-based pharmacophore modeling was used to identify the chemical features responsible for inhibiting tubulin polymerization. A set of 26 training compounds was used to generate hypothetical pharmacophores using the HypoGen algorithm. The structures were further validated using the test set, Fischer randomization method, leave-one-out method and a decoy set, and the best model was chosen to screen the Specs database. Hit compounds were subjected to molecular docking study using a Molecular Operating Environment (MOE) software and to biological evaluation in vitro. Results: Hypo1 was demonstrated to be the best pharmacophore model that exhibited the highest correlation coefficient (0.9582), largest cost difference (70.905) and lowest RMSD value (0.6977). Hypo1 consisted of one hydrogen-bond acceptor, a hydrogen-bond donor, a hydrophobic feature, a ring aromatic feature and three excluded volumes. Hypo1 was validated with four different methods and had a goodness-of-hit score of 0.81. When Hypo1 was used in virtual screening of the Specs database, 952 drug-like compounds were revealed. After docking into the colchicine-binding site of tubulin, 5 drug-like compounds with the required interaction with the critical amino acid residues and the binding free energies <-4 kcal/mol were selected as representative leads. Compounds 1 and 3 exhibited inhibitory activity against MCF-7 human breast cancer cells in vitro. Conclusion: Hypo1 is a quantitative pharmacophore model for tubulin inhibitors, which not only provides a better understanding of their interaction with tubulin, but also assists in discovering new potential leads with antitumor activities.

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Section: Fischer Randomization Methodsmentioning

confidence: 99%

Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking

et al. 2014

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“…6, compound 7) and with an amino group in the ortho position in the B ring (Fig. 6, compound 8) are worth mentioning as very potent tubulin polymerization inhibitors and highly cytotoxic against the NCI-H460 and DU-145 cell lines [65,66]. The trifluorostilbene 3'-amino-4'-methoxy-3,4,5-trifluoro-cis-stilbene (Fig.…”

Section: Other Synthetic Stilbene Derivatives As Tubulin-interactive mentioning

confidence: 99%

Tubulin-interactive stilbene derivatives as anticancer agents

Mikstacka

Stefański

Różański

2013

Cellular and Molecular Biology Letters

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Microtubules are dynamic polymers that occur in eukaryotic cells and play important roles in cell division, motility, transport and signaling. They form during the process of polymerization of α- and β-tubulin dimers. Tubulin is a significant and heavily researched molecular target for anticancer drugs. Combretastatins are natural cis-stilbenes that exhibit cytotoxic properties in cultured cancer cells in vitro. Combretastatin A-4 (3′-hydroxy-3,4,4′, 5-tetramethoxy-cis-stilbene; CA-4) is a potent cytotoxic cis-stilbene that binds to β-tubulin at the colchicine-binding site and inhibits tubulin polymerization. The prodrug CA-4 phosphate is currently in clinical trials as a chemotherapeutic agent for cancer treatment. Numerous series of stilbene analogs have been studied in search of potent cytotoxic agents with the requisite tubulin-interactive properties. Microtubule-interfering agents include numerous CA-4 and transresveratrol analogs and other synthetic stilbene derivatives. Importantly, these agents are active in both tumor cells and immature endothelial cells of tumor blood vessels, where they inhibit the process of angiogenesis. Recently, computer-aided virtual screening was used to select potent tubulin-interactive compounds. This review covers the role of stilbene derivatives as a class of antitumor agents that act by targeting microtubule assembly dynamics. Additionally, we present the results of molecular modeling of their binding to specific sites on the α- and β-tubulin heterodimer. This has enabled the elucidation of the mechanism of stilbene cytotoxicity and is useful in the design of novel agents with improved anti-mitotic activity. Tubulin-interactive agents are believed to have the potential to play a significant role in the fight against cancer.

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“…106 Nitro and amine derivatives 66 and 67 were inactive as tubulin inhibitors and as cytotoxic agents.…”

Section: 108mentioning

confidence: 99%

ortho-Formylation of oxygenated phenols

Akselsen

Skattebøl

Hansen

2009

Tetrahedron Letters

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Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents

Cited by 75 publications

References 44 publications

Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking

Tubulin inhibitors: pharmacophore modeling, virtual screening and molecular docking

Tubulin-interactive stilbene derivatives as anticancer agents

ortho-Formylation of oxygenated phenols

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