Exploration of Fluorine Chemistry at the Multidisciplinary Interface of Chemistry and Biology

Ojima, Iwao

doi:10.1021/jo400301u

Cited by 174 publications

(71 citation statements)

References 174 publications

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“…We have been designing and applying “fluorine-probes” for structural analysis of paclitaxel and taxoids in the absence and presence of microtubules by 19 F NMR in solution and solid state, as well as in combination with computational analysis [41, 42, 68–71] We also applied time-resolved 19 F NMR spectroscopy to show a proof of concept for the mechanism-based drug release through thiol-triggered cleavage of a self-immolative disulfide linker and subsequent thiolactionization, using a model system [15] (Fig. 5).…”

Section: Fluorine-labeled Taxoids As 19f Nmr Probes For the Metabomentioning

confidence: 99%

Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies

Ojima

2017

Journal of Fluorine Chemistry

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This account exemplifies our recent progress on the strategic incorporation of fluorine and organofluorine groups to taxoid anticancer agents and their tumor-targeted drug delivery systems (TTDDSs) for medicinal chemistry and chemical biology studies. Novel 3′-difluorovinyltaxoids were strategically designed to block the metabolism by cytochrome P-450, synthesized, and evaluated for their cytotoxicity against drug-sensitive and multidrug-resistant (MDR) human cancer cell lines. 3′-Difluorovinyltaxoids exhibited impressive activities against these cancer cell lines. More significantly, a representative 3′-difluorovinyltaxoid exhibited 230-33,000 times higher potency than conventional anticancer drugs against cancer stem cell-enriched HCT-116 cell line. Studies on the mechanism of action (MOA) of these fluorotaxoids were performed by tubulin polymerization assay, morphology analysis by electron microscopy (EM) and protein binding assays. Novel 19F NMR probes, BLT-F2 and BLT-S-F6, were designed by strategically incorporating fluorine, CF3 and CF3O groups into tumor-targeting drug conjugates. These 19F-probes were designed and synthesized to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time 19F NMR analysis. Time-resolved 19F NMR study on probe BLT-F2 revealed a stepwise mechanism for the release of a fluorotaxoid, which might not be detected by other analytical methods. Probe BLT-S-F6 were very useful to study the stability and reactivity of the drug delivery system in human blood plasma by 19F NMR. The clean analysis of the linker stability and reactivity of drug conjugates in blood plasma by HPLC and 1H NMR is very challenging, but the use of 19F NMR and suitable 19F probes can provide a practical solution to this problem.

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Section: Fluorine-labeled Taxoids As 19f Nmr Probes For the Metabomentioning

confidence: 99%

Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies

Ojima

2017

Journal of Fluorine Chemistry

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“…[1][2][3] Fluorine substitution can also be used to fine-tune the stereo-electronic properties of a molecule and in doing so allow conformational control. 4,5 On the other hand, the chemistry of steroids and spirothiazolidinone-steriods has received considerable attention in recent years due to their usefulness in different areas of biological activities and as industrial intermediates. 6 Steroids and spirothiazolidinone steriods hybrids are well known type of compounds and are biosynthetically derived either from the sterol lanosterol (animals and fungi) and/or the sterolcycloartenol (plants).…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Voltammetric and Analytical Applications of Some Fluorine Substituted Spirosteroidalthiazolidin‐4‐one Derivatives of Sulfa Drugs

Makki

Al-Footy

Abdel‐Rahman

et al. 2016

J Chinese Chemical Soc

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A new 5-arylidene-4-oxo-(sulfonamoyl phenyl)-spiro[thiazolidinone-2, 2¢-steroids] series (7-10) was prepared by condensation of sulfanilamide, sulfapyridine and sulfadiazine sulfa drugs with testosterone, epiandrosterone and progesterone steroids, respectively. The resultant imino derivatives 1-3 upon cycloaddition with thioacetic acid in dry 1,4-dioxane afforded 3-sulfo-namoylphenylspiro[4-oxothiazolidin-2, 2¢steroids] (4-6). The latter compounds (4-6) upon condensation with p-fluorobenzaldehyde in ethanol-piperidine yielded the corresponding 4-fluoroarylidene derivatives 7, 8 & 9, respectively. All the newly synthesized compounds were confirmed by UV, IR, 1 H NMR, 13 C NMR, mass spectral data, elemental analysis and molecular weight determination. In vitro antimicrobial screening of some of the synthesized compounds showed good antimicrobial activities towards some pathogenic Gram-positive, Gram-negative bacteria and fungi vs. piperacillin and mycostatine antibiotics as standard antibacterial and antifungal agents, respectively. The voltammetric behavior of two newly spirothiazolidinone steroids (2a & 5a) was critically studied. Compound 5a physically immobilized polyurethane foam solid sorbent was successfully used for removal and/or separation of bismuth(III) from water.

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“…In the last decade, the “three fluorine atoms for biochemical screening (3-FABS)” has emerged as a useful biochemical tool with heightened signal sensitivity by labeling a substrate with a CF 3 moiety and using 19 F NMR spectroscopy for the analysis of enzymatic processes [18–20]. Our laboratory has been exploring “fluorine-probes” for structural analysis of paclitaxel and taxoids in the absence and presence of microtubules by 19 F NMR in solution and solid state, as well as in combination with computational analysis [21–26]. As Figure 1 shows, we also applied time-resolved 19 F NMR spectroscopy to demonstrate a proof of concept for the mechanism-based drug release through thiol-triggered cleavage of a self-immolative disulfide linker and subsequent thiolactonization, using a model system [27].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and application of fluorine-labeled taxoids as 19F NMR probes for the metabolic stability assessment of tumor-targeted drug delivery systems

Seitz

Vineberg

Wei

et al. 2015

Journal of Fluorine Chemistry

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Novel tumor-targeting drug conjugates, BLT-F2 (1) and BLT-S-F6 (2), bearing a fluorotaxoid as the warhead, a mechanism-based self-immolative disulfide linker, and biotin as the tumor-targeting module, were designed and synthesized as 19F NMR probes. Fluorine atoms and CF3 groups were strategically incorporated into the conjugates to investigate the mechanism of linker cleavage and factors that influence their plasma and metabolic stability by real-time monitoring with 19F NMR. Time-resolved 19F NMR study on probe 1 disclosed a stepwise mechanism for release of a fluorotaxoid, which might not have been detected by other analytical methods. Probe 2 was designed to bear two CF3 groups in the taxoid moiety as “3-FAB” reporters for enhanced sensitivity and a polyethylene glycol oligomer insert to improve solubility. The clean analysis of the linker stability and reactivity of drug conjugates in blood plasma or cell culture media by HPLC and 1H NMR is troublesome, due to the overlap of key signals/peaks with background arising from highly complex ingredients in biological systems. Accordingly, the use of 19F NMR would provide a practical solution to this problem. In fact, our “3-FAB” probe 2 was proven to be highly useful to investigate the stability and reactivity of the self-immolative disulfide linker system in human blood plasma by 19F NMR. It has also been revealed that the use of polysorbate 80 as excipient for the formulation of probe 2 dramatically increases the stability of the disulfide linker system. This finding further indicates that the tumor-targeting drug conjugates with polysorbate 80/EtOH/saline formulation for in vivo studies would have high stability in blood plasma, while the drug release in cancer cells proceeds smoothly.

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Exploration of Fluorine Chemistry at the Multidisciplinary Interface of Chemistry and Biology

Cited by 174 publications

References 174 publications

Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies

Strategic incorporation of fluorine into taxoid anticancer agents for medicinal chemistry and chemical biology studies

Synthesis, Voltammetric and Analytical Applications of Some Fluorine Substituted Spirosteroidalthiazolidin‐4‐one Derivatives of Sulfa Drugs

Design, synthesis and application of fluorine-labeled taxoids as 19F NMR probes for the metabolic stability assessment of tumor-targeted drug delivery systems

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