Design, Synthesis, and Biological Evaluation of Theranostic Vitamin–Linker–Taxoid Conjugates

Vineberg, Jacob G.; Wang, Tao; Zuniga, Edison S.; Ojima, Iwao

doi:10.1021/jm5019115

Cited by 34 publications

(37 citation statements)

References 38 publications

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“…Next, they adopted this strategy to report two tumor-targeting theranostic conjugates 61a and 61b. 200 The cytotoxic drug taxoid 3 was conjugated with a fluorine-labeled prosthetic (61a) or a fluorophore fluorescein (61b) via a disulfide bond. Once internalized into tumor cells, the disulfide bond was cleaved by endogenous biothiols and .…”

Section: Therapeutics With Disulfide Bonds and Targeting Ligands Thementioning

confidence: 99%

Fluorescent chemical probes for accurate tumor diagnosis and targeting therapy

et al. 2017

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Surgical resection of solid tumors is currently the gold standard and preferred therapeutic strategy for cancer. Chemotherapy drugs also make a significant contribution by inhibiting the rapid growth of tumor cells and these two approaches are often combined to enhance treatment efficacy. However, surgery and chemotherapy inevitably lead to severe side effects and high systemic toxicity, which in turn results in poor prognosis. Precision medicine has promoted the development of treatment modalities that are developed to specifically target and kill tumor cells. Advances in in vivo medical imaging for visualizing tumor lesions can aid diagnosis, facilitate surgical resection, investigate therapeutic efficacy, and improve prognosis. In particular, the modality of fluorescence imaging has high specificity and sensitivity and has been utilized for medical imaging. Therefore, there are great opportunities for chemists and physicians to conceive, synthesize, and exploit new chemical probes that can image tumors and release chemotherapy drugs in vivo. This review focuses on small molecular ligand-targeted fluorescent imaging probes and fluorescent theranostics, including their design strategies and applications in clinical tumor treatment. The progress in chemical probes described here suggests that fluorescence imaging is a vital and rapidly developing field for interventional surgical imaging, as well as tumor diagnosis and therapy.

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Section: Therapeutics With Disulfide Bonds and Targeting Ligands Thementioning

confidence: 99%

Fluorescent chemical probes for accurate tumor diagnosis and targeting therapy

et al. 2017

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“…97,111−115 In this regard, we have developed novel self-immolative disulfide linkers that can release unmodified cytotoxic drugs (Figure 20). 105,114−119 …”

Section: Tumor-targeted Drug Delivery Of Next-generation Taxoid Anticmentioning

confidence: 99%

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

et al. 2018

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Paclitaxel and docetaxel are among the most widely used chemotherapeutic drugs against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop next-generation taxoid anticancer agents with better pharmacological properties and improved activity especially against drug-resistant and metastatic cancers. The SAR studies by the authors have led to the development of numerous highly potent novel second- and third-generation taxoids with systematic modifications at the C-2, C-10, and C-3′ positions. The third-generation taxoids showed virtually no difference in potency against drug-resistant and drug-sensitive cell lines. Some of the next-generation taxoids also exhibited excellent potency against cancer stem cells. This account summarizes concisely investigations into taxoids over 25 years based on a strong quest for the discovery and development of efficacious next-generation taxoids. Discussed herein are SAR studies on different types of taxoids, a common pharmacophore proposal for microtubule-stabilizing anticancer agents and its interesting history, the identification of the paclitaxel binding site and its bioactive conformation, characteristics of the next-generation taxoids in cancer cell biology, including new aspects of their mechanism of action, and the highly efficacious tumor-targeted drug delivery of potent next-generation taxoids.

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“…Because of the critical importance of linker dynamics for TTDD efficacy, various smart linker systems have been developed in the last two decades, in particular for antibody–drug conjugates (ADCs) [9, 12, 53–57] and small-molecule drug conjugates (SMDCs) [9, 17, 58–60]. In this regard, we have developed novel self-immolative disulfide linkers that can release unmodified cytotoxic drugs via glutathione-triggered linker cleavage, involving thiolactonization [15–17, 61–63]. …”

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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Design, Synthesis, and Biological Evaluation of Theranostic Vitamin–Linker–Taxoid Conjugates

Cited by 34 publications

References 38 publications

Fluorescent chemical probes for accurate tumor diagnosis and targeting therapy

Fluorescent chemical probes for accurate tumor diagnosis and targeting therapy

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

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

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