Evaluation of the Tubulin-Bound Paclitaxel Conformation:  Synthesis, Biology, and SAR Studies of C-4 to C-3‘ Bridged Paclitaxel Analogues

Ganesh, Thota; Yang, Chao; Norris, Andrew; Glass, T. E.; Bane, Susan; Ravindra, Rudravajhala; Banerjee, Abhijit; Metaferia, Belhu; Thomas, S.; Giannakakou, Paraskevi; Alcaraz, Ana A.; Lakdawala, Ami S.; Snyder, James P.; Kingston, David G. I.

doi:10.1021/jm061071x

Cited by 67 publications

(87 citation statements)

References 70 publications

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“…By rigidifying the conformation of PTX to that found in the EC binding site, activity is seen to increase 100-fold against the parental 1A9 cell lines and over 1000-fold against cell line with resistance that was acquired though a Phe270Val mutation in the beta tubulin site ( Fig. 10 ) [25] .…”

Section: Conformation and Controversymentioning

confidence: 99%

The Tubulin Binding Mode of Microtubule Stabilizing Agents Studied by Electron Crystallography

Nettles

Downing

2008

Topics in Current Chemistry

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Since tubulin was discovered in 1967, drug probes have been used to manipulate mechanisms of microtubule polymerization and disassembly. In parallel, advances in optical imagery, electron microscopy, along with both electron and X-ray diffraction have provided ability to "see" the molecular underpinning of these machines. Nanoscale mapping of different tubulin polymers formed in the presence of different drugs and cofactors provide a context for examining the dynamic features relevant to their biological activity. Models built from EM maps have been used to understand the binding of stabilizing drugs such as taxanes and epothilones, to predict more effective molecules, and to explain mutation based resistance. Here, we discuss drug binding in the context of different polymeric forms and propose a trigger mechanism associated with microtubules' dynamic instability.

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Section: Conformation and Controversymentioning

confidence: 99%

The Tubulin Binding Mode of Microtubule Stabilizing Agents Studied by Electron Crystallography

Nettles

Downing

2008

Topics in Current Chemistry

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“…Taxol strongly binds to the b-subunit of tubulin, the building block of microtubules, to affect microtubule dynamics in the highly replicating cancer cells [7]. The dynamic instability of microtubules affects the positioning of chromosomes during replication and finally inhibits cell division.…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 siRNA Augments Taxol Mediated Apoptotic Death in Human Glioblastoma U138MG and U251MG Cells

2008

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The anti-neoplastic drug taxol binds to beta-tubulin to prevent tumor cell division, promoting cell death. However, high dose taxol treatment may induce cell death in normal cells too. The anti-apoptotic molecule Bcl-2 is upregulated in many cancer cells to protect them from apoptosis. In the current study, we knocked down Bcl-2 expression using cognate siRNA during low-dose taxol treatment to induce apoptosis in two human glioblastoma U138MG and U251MG cell lines. The cells were treated with either 100 nM taxol or 100 nM Bcl-2 siRNA or both for 72 h. Immunofluorescent stainings for calpain and active caspase-3 showed increases in expression and co-localization of these proteases in apoptotic cells. Fluorometric assays demonstrated increases in intracellular free [Ca(2+)], calpain, and caspase-3 indicating augmentation of apoptosis. Western blotting demonstrated dramatic increases in the levels of Bax, Bak, tBid, active caspases, DNA fragmentation factor-40 (DFF40), cleaved fragments of lamin, fodrin, and poly(ADP-ribose) polymerase (PARP) during apoptosis. The events related to apoptosis were prominent more in combination therapy than in either treatment alone. Our current study demonstrated that Bcl-2 siRNA significantly augmented taxol mediated apoptosis in different human glioblastoma cells through induction of calpain and caspase proteolytic activities. Thus, combination of taxol and Bcl-2 siRNA offers a novel therapeutic strategy for controlling the malignant growth of human glioblastoma cells.

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“…Compound 33 had very similar cytotoxicity and tubulin-assembly activities to those of taxol (1), but the big surprise was compound 34, with a ring size one atom smaller. This compound was up to 20 times more active than taxol (1), depending on the assay used (Ganesh et al, 2004), and it was also much more active than taxol (1) against two taxol-resistant cell lines and an epothilone-resistant cell line (Ganesh et al, 2007). Molecular modeling of the complex of 34 with b-tubulin showed that the unfavorable interaction with Phe272 of b-tubulin had indeed been removed.…”

Section: The Interaction Of Taxol With Tubulinmentioning

confidence: 96%

The shape of things to come: Structural and synthetic studies of taxol and related compounds

Kingston

2007

Phytochemistry

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The history of the development of Taxol (paclitaxel) as an anticancer drug is reviewed, and some aspects of the phytochemistry of Taxus species and of the medicinal chemistry of taxol are discussed. The nature of the taxol-tubulin interaction is then described, with an emphasis on studies that led to the discovery and experimental proof of the T-taxol conformation as the tubulin-binding conformation of taxol. The implications of this conformation for future drug development are also briefly covered.

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Evaluation of the Tubulin-Bound Paclitaxel Conformation: Synthesis, Biology, and SAR Studies of C-4 to C-3‘ Bridged Paclitaxel Analogues

Cited by 67 publications

References 70 publications

The Tubulin Binding Mode of Microtubule Stabilizing Agents Studied by Electron Crystallography

The Tubulin Binding Mode of Microtubule Stabilizing Agents Studied by Electron Crystallography

Bcl-2 siRNA Augments Taxol Mediated Apoptotic Death in Human Glioblastoma U138MG and U251MG Cells

The shape of things to come: Structural and synthetic studies of taxol and related compounds

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