688009-09-8

Basic information

• Product Name: DTBS-GEMCITABINE
• Synonyms: DTBS-GEMCITABINE;3',5'-Bis-O-tert-butyldimethylsilyl-2'-deoxy-2',2'-difluorocytidine
• CAS NO: 688009-09-8
• Molecular Formula: C₂₁H₃₉F₂N₃O₄Si₂
• Molecular Weight: 491.72
• Mol File: 688009-09-8.mol

Chemical Properties

• Appearance: /
• CAS DataBase Reference: DTBS-GEMCITABINE(CAS DataBase Reference)
• NIST Chemistry Reference: DTBS-GEMCITABINE(688009-09-8)
• EPA Substance Registry System: DTBS-GEMCITABINE(688009-09-8)

Safety Data

• Hazardous Substances Data: 688009-09-8(Hazardous Substances Data)

Upstream product

• 18162-48-6 tert-butyldimethylsilyl chloride 
• 122111-03-9 gemcitabine hydrochloride 
• 95058-81-4 gemcitabine 
• 69739-34-0 t-butyldimethylsiyl triflate 

Relevant articles and documents

Enhancing efficacy of gemcitabine in pancreatic patient-derived xenograft mouse models

Gemcitabine (Gem), a nucleoside analog, is a preferred choice of treatment for pancreatic cancer (PCa) and often used in combination therapy against wide range of solid tumors. It is known to be rapidly inactivated in blood by cytidine deaminase. The objective of the study was to improve the systemic stability and anticancer activity of modified Gem termed 4-N-stearoylGem (4NSG) In this study, the IC50 values of 4NSG treated MiaPaCa-2 and primary pancreatic cancer (PPCL-46) cultures were significantly lower when compared with gemcitabine hydrochloride (GemHCl) treated cultures. In acute toxicity study, liver enzyme level of aspartate aminotransferase (AST) of the control mice was not significantly different from AST levels of 4NSG and GemHCl treated mice. However, alanine aminotransferase (ALT) level of control mice (67 ± 5 mUnits/mL) was significantly lower compared with ALT levels of GemHCl (232 ± 28 mUnits/mL) and that of 4NSG (172 ± 22 mUnits/mL) (p a remarkable tumor growth inhibition and revealed significant antiangiogenic activity in 4GSN treated pancreatic PDX tumor.

Gemcitabine Lipid Prodrugs: The Key Role of the Lipid Moiety on the Self-Assembly into Nanoparticles

A small library of amphiphilic prodrugs has been synthesized by conjugation of gemcitabine (Gem) (a hydrophilic nucleoside analogue) to a series of lipid moieties and investigated for their capacity to spontaneously self-assemble into nanosized objects by simple nanoprecipitation. Four of these conjugates formed stable nanoparticles (NPs), while with the others, immediate aggregation occurred, whatever the tested experimental conditions. Whether such capacity could have been predicted based on the prodrug physicochemical features was a matter of question. Among various parameters, the hydrophilic-lipophilic balance (HLB) value seemed to hold a predictive character. Indeed, we identified a threshold value which well correlated with the tendency (or not) of the synthesized prodrugs to form stable nanoparticles. Such a hypothesis was further confirmed by broadening the analysis to Gem and other nucleoside prodrugs already described in the literature. We also observed that, in the case of Gem prodrugs, the lipid moiety affected not only the colloidal properties but also the in vitro anticancer efficacy of the resulting nanoparticles. Overall, this study provides a useful demonstration of the predictive potential of the HLB value for lipid prodrug NP formulation and highlights the need of their opportune in vitro screening, as optimal drug loading does not always translate in an efficient biological activity.

Enhanced anti-tumor efficiency of gemcitabine prodrug by FAPα-mediated activation

Gemcitabine (Gem) as an anti-cancer agent has been limited by its short circulation time and rapid metabolism that reflects in low tumor uptake and low therapeutic efficiency. To improve its anti-tumor activity, a novel FAPα enzyme-activated prodrug of Z-

Integrin-Targeting Knottin Peptide–Drug Conjugates Are Potent Inhibitors of Tumor Cell Proliferation

Antibody–drug conjugates (ADCs) offer increased efficacy and reduced toxicity compared to systemic chemotherapy. Less attention has been paid to peptide–drug delivery, which has the potential for increased tumor penetration and facile synthesis. We report a knottin peptide–drug conjugate (KDC) and demonstrate that it can selectively deliver gemcitabine to malignant cells expressing tumor-associated integrins. This KDC binds to tumor cells with low-nanomolar affinity, is internalized by an integrin-mediated process, releases its payload intracellularly, and is a highly potent inhibitor of brain, breast, ovarian, and pancreatic cancer cell lines. Notably, these features enable this KDC to bypass a gemcitabine-resistance mechanism found in pancreatic cancer cells. This work expands the therapeutic relevance of knottin peptides to include targeted drug delivery, and further motivates efforts to expand the drug-conjugate toolkit to include non-antibody protein scaffolds.

Single Diastereomers of the Clinical Anticancer ProTide Agents NUC-1031 and NUC-3373 Preferentially Target Cancer Stem CellsIn Vitro

A 3′-protected route toward the synthesis of the diastereomers of clinically active ProTides, NUC-1031 and NUC-3373, is described. Thein vitrocytotoxic activities of the individual diastereomers were found to be similar to their diastereomeric mixtures. In the KG1a cell line, NUC-1031 and NUC-3373 have preferential cytotoxic effects on leukemic stem cells (LSCs). These effects were not diastereomer-specific and were not observed with the parental nucleoside analogues gemcitabine and FUDR, respectively. In addition, NUC-1031 preferentially targeted LSCs in primary AML samples and cancer stem cells in the prostate cancer cell line, LNCaP. Although the mechanism for this remains incompletely resolved, NUC-1031-treated cells showed increased levels of triphosphate in both LSC and bulk tumor fractions. As ProTides are not dependent on nucleoside transporters, it seems possible that the LSC targeting observed with ProTides may be caused, at least in part, by preferential accumulation of metabolized nucleos(t)ide analogues.

A self-assembling prodrug nanosystem to enhance metabolic stability and anticancer activity of gemcitabine

Self-assembly is a powerful approach in molecular engineering for biomedical applications, in particular for creating self-assembling prodrugs. Here, we report a self-assembling prodrug of the anticancer drug gemcitabine (Gem) based on amphiphilic dendrimer approach. The prodrug reported in this study demonstrates high drug loading (40%) and robust ability to self-assemble into small nanomicelles, which increase the metabolic stability of Gem and enable entry into cells via endocytosis, hence bypassing transport-mediated uptake. In addition, this prodrug nanosystem exhibited an effective pH- and enzyme-responsive release of Gem, resulting in enhanced anticancer activity and reduced toxicity. Harboring advantageous features of both prodrug- and nanotechnology-based drug delivery, this self-assembling Gem prodrug nanosystem constitutes a promising anticancer candidate. This study also offers new perspectives of the amphiphilic dendrimer nanoplatforms for the development of self-assembling prodrugs.

Prodrug based on gemcitabine structure as well as preparation method and application of prodrug

The invention discloses a prodrug based on a gemcitabine structure. The prodrug has a structure of general formula I. The prodrug has certain inhibitory activity on tumors. The invention further discloses a preparation method of the prodrug. According to the preparation method, lipid solubility of the prodrug is improved by modifying N4 site of the gemcitabine structure, and membrane permeabilityof the compound is improved. The invention further discloses application of the prodrug in antitumor drugs. The fat-soluble prodrug can enter tumors through passive diffusion and active transport, thereby inhibiting tumor growth, overcoming tumor drug resistance, and improving tumor targeting of gemcitabine. The invention further discloses a pharmaceutical composition containing the prodrug. The pharmaceutical composition is administrated in an oral administration mode, and after the prodrug is absorbed, the prodrug can be rapidly broken into gemcitabine in vivo, thereby exerting a therapeuticeffect in time and increasing oral bioavailability of gemcitabine.

A PRODRUG PLATFORM USEFUL TO DELIVER AMINES, AMIDES AND PHENOLS

Provided herein is a prodrug platform useful to deliver pharmaceutically active amines, amides and phenols and their use in the diagnosis, prevention and/or treatment of various diseases. Compared with the parent drug (e.g., Gemcitabine), the prodrugs show a significant overall safety improvement (therapeutic index (TI) improvement), especially in liver.

SONODYNAMIC THERAPY

The invention provides a method of preparing a microbubble covalently attached to at least one therapeutic agent which comprises: (i) providing a lipid (e.g. a phospholipid) capable of forming a microbubble; covalently linking at least one therapeutic agent to said lipid to produce a functionalised lipid; and preparing a microbubble from said functionalised lipid. Microbubble-therapeutic agent complexes which comprise a microbubble shell formed from a plurality of lipids (e.g. phospholipids) in which at least a proportion of the lipids are covalently linked to at least one therapeutic agent are also provided. Examples of therapeutic agents which may be attached to the microbubble include chemotherapeutic agents and sonosensitising agents. The complexes find use in methods of sonodynamic therapy and, in particular, in methods of combined sonodynamic therapy and chemotherapy.

LIVER SPECIFIC DELIVERY-BASED GEMCITABINE PRODRUG NUCLEOSIDE CYCLIC PHOSPHATE COMPOUND, AND APPLICATION THEREOF

Provided are a liver specific delivery (LSD)-based anticancer prodrug nucleoside cyclic phosphate compound and an application thereof, and in particular, a compound represented by formula (I) as well as isomers, pharmaceutically acceptable salts, hydrates, and solvates thereof, and corresponding pharmaceutical compositions. Also provided is an application of the compound alone or in combination with other anticancer drugs in anticancer area, particularly the treatment of hepatocellular carcinoma (HHC).