Modified Taxols, 9. Synthesis and Biological Evaluation of 7-Substituted Photoaffinity Analogues of Taxol

Rimoldi, John M.; Kingston, David G. L.; Chaudhary, Ashok; Samaranayake, Gamini; Grover, S. K.; Hamel, Ernest

doi:10.1021/np50098a016

Cited by 33 publications

(17 citation statements)

References 32 publications

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“…Previous studies have shown that the N-benzoyl, 2-benzoyl, 3′-phenyl, 7-OH, and the 10-acetyl groups of paclitaxel can tolerate a number of substitutions without causing large changes in the activity of the drug Georg et al, 1995b,c). However, modifications of the 7-hydroxy group with bulky substituents can decrease activity significantly (Georg et al, 1992;Riomoldi et al, 1993). Our results with the dimethylamino derivatives, showing a larger decrease in tubulin assemblypromoting activity for 7-mDMAT compared to those of the other analogues (Table 1), are consistent with the past results.…”

Section: Discussionsupporting

confidence: 92%

Probing the Environment of Tubulin-Bound Paclitaxel Using Fluorescent Paclitaxel Analogues

et al. 1997

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To determine the environment of different positions in the paclitaxel molecule when bound to tubulin, we have synthesized six fluorescent analogues in which a (dimethylamino)benzoyl group has been introduced into the 7- and 10-positions, and the benzoyl groups at the 2- and N- as well as the 3'-phenyl ring have been modified with dimethylamino functions. In a tubulin assembly assay, the N-m- and N-p-(dimethylamino)benzoyl derivatives had activities comparable to the activity of paclitaxel. The 2-, 3'-, and 10-analogues had slightly reduced activity, and the 7-derivative was about 5% as active as paclitaxel. On the basis of the results of studies of the effect of solvents on the fluorescence emission spectra, it is proposed that the unbound analogues form hydrogen bonds with protic solvents. But the 7- and 10-substituted analogues appear to be more affected by protic solvents than the other analogues. Previously, we studied the binding of the N-meta derivative to tubulin and microtubules [Sengupta, S., et al. (1995) Biochemistry 34, 11889-11894]. In this study, we extended the studies to include the 2-, 7-, and 10-derivatives. Similar to the N-substituted analogue, binding of the 2-derivative to tubulin was accompanied by a large blue shift, whereas a very small shift occurred when the 7- and 10-substituted derivatives bound. The 2- and N-substituted analogues bind to microtubules with an increase in fluorescence intensity over that which was observed with tubulin, whereas binding of the 7- and 10-substituted analogues was accompanied by a large quenching in fluorescence. This quenching may be due to the presence of charged residues in the protein near the 7- and 10-(dimethylamino)benzoyl groups or to pi stacking of the groups with an aromatic side chain. The presence of paclitaxel with microtubules prevented the fluorescence increase of the 2- and N-derivatives and quenching of the 7- and 10-derivatives. The difference in behavior of the fluorescent analogues upon binding to polymerized tubulin, coupled with the solvent studies on the free drugs, suggests that the 2- and N-benzoyl groups of paclitaxel bind in a hydrophobic pocket of tubulin but could participate in hydrogen bonding, and the 7- and 10-positions are in a more hydrophilic environment.

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Section: Discussionsupporting

confidence: 92%

Probing the Environment of Tubulin-Bound Paclitaxel Using Fluorescent Paclitaxel Analogues

et al. 1997

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“…As mentioned earlier, because of its high instability in aqueous solution, the hydroxyl group of paclitaxel at the 7 position rapidly undergoes epimerization, giving rise to 7-Epitaxol, which is more thermodynamically stable and more cytotoxic than paclitaxel [38,39]. In this context, a recent study has revealed that, in standard cell culture conditions, bone marrow-derived mesenchymal stem cells are able to incorporate paclitaxel for targeted cellular delivery.…”

Section: Discussionmentioning

confidence: 96%

7-Epitaxol Induces Apoptosis and Autophagy in Head and Neck Squamous Cell Carcinoma through Inhibition of the ERK Pathway

Velmurugan

Hsieh

Mahalakshmi³

et al. 2021

Cells

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As the main derivative of paclitaxel, 7-Epitaxol is known to a have higher stability and cytotoxicity. However, the anticancer effect of 7-Epitaxol is still unclear. The purpose of this study was to explore the anticancer effects of 7-Epitaxol in squamous cell carcinoma of the head and neck (HNSCC). Our study findings revealed that 7-Epitaxol potently suppressed cell viability in SCC-9 and SCC-47 cells by inducing cell cycle arrest. Flow cytometry and DAPI staining demonstrated that 7-Epitaxol treatment induced cell death, mitochondrial membrane potential and chromatin condensation in OSCC cell lines. The compound regulated the proteins of extrinsic and intrinsic pathways at the highest concentration, and also increased the activation of caspases 3, 8, 9, and PARP in OSCC cell lines. Interestingly, a 7-Epitaxol-mediated induction of LC3-I/II expression and suppression of p62 expression were observed in OSCC cells lines. Furthermore, the MAPK inhibitors indicated that 7-Epitaxol induces apoptosis and autophagy marker proteins (cleaved-PARP and LC3-I/II) by reducing the phosphorylation of ERK1/2. In conclusion, these findings indicate the involvement of 7-Epitaxol in inducing apoptosis and autophagy through ERK1/2 signaling pathway, which identify 7-Epitaxol as a potent cytotoxic agent in HNSCC.

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“…Several attempts to covalently label the taxoids binding site on tubulin have been reported in the literature. A series of photosensitive 7-acyl-Taxol derivatives (Georg et al, 1992;Carboni et al, 1993;Rimoldi et al, 1993) have been synthesized as potential labels for the taxoid binding site on polymerized tubulin. However, the probes which could be synthesized in a radiolabeled form failed to covalently label, in a specific manner, polymerized tubulin.…”

Section: Discussionmentioning

confidence: 99%

“…One study has been performed using direct photoaffinity labeling of tubulin by Taxol which indicated selective binding of Taxol to /3-tubulin (Rao et al, 1992). Many workers in the field have been interested in designing Taxol-derived photoaffinity probes, modified on the C-7 position (Georg et al, 1992;Carboni et al, 1993;Rimoldi et al, 1993), but no successful irradiation experiment has been reported so far.…”

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confidence: 99%

Predominant Labeling of .beta.- over .alpha.-Tubulin from Porcine Brain by a Photoactivatable Taxoid Derivative

Combeau¹,

Commerçon²,

Mioskowski³

et al. 1994

Biochemistry

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An [(azidophenyl)ureido]taxoid (TaxAPU) was synthesized in a radiolabeled form by coupling an aminotaxoid to tritiated N-methyl-N-(chloroformyl)-p-azidoaniline. TaxAPU was used to photolabel polymerized porcine brain tubulin. This newly synthesized probe possesses taxoid properties as demonstrated by its effect, in the absence of light, on the kinetics of tubulin assembly and microtubule disassembly and on the critical concentration of tubulin. TaxAPU apparently competes with Taxol for the same binding site with an equilibrium dissociation constant of 6 microM. The photoactivation of 266 nm of the radiolabeled probe in the presence of microtubules led to a covalent incorporation of radioactivity. Analysis of the radiolabeled polypeptides by electrophoresis under denaturing conditions revealed a specific incorporation of tritium in both the alpha-and beta-subunits of tubulin. A dependence on probe concentration was observed for the irreversible radioactivity incorporated into both subunits and maintained essentially a ratio of 2.5:1 between beta/alpha. Therefore, TaxAPU constitutes a true photoaffinity probe for the taxoid binding site on microtubules. Our results complement those reported by Rao et al. (1992) of photo-cross-linking experiments with unmodified Taxol.

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Modified Taxols, 9. Synthesis and Biological Evaluation of 7-Substituted Photoaffinity Analogues of Taxol

Cited by 33 publications

References 32 publications

Probing the Environment of Tubulin-Bound Paclitaxel Using Fluorescent Paclitaxel Analogues

Probing the Environment of Tubulin-Bound Paclitaxel Using Fluorescent Paclitaxel Analogues

7-Epitaxol Induces Apoptosis and Autophagy in Head and Neck Squamous Cell Carcinoma through Inhibition of the ERK Pathway

Predominant Labeling of .beta.- over .alpha.-Tubulin from Porcine Brain by a Photoactivatable Taxoid Derivative

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