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A New Synthesis of Temozolomide. - ResearchGate

This invention relates to a novel process for the synthesis of temozolomide, ..

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A New Synthesis of Temozolomide

The synthesis of Fmoc-protected (2-aminoethyl)glycine (PNA backbone without nucleobase) was documented by Atherton and Sheppard []. The reaction product 3 is shown in Figure and was prepared as described in [].

A New Synthesis of Temozolomide., ChemInform | …

Riboflavin is an essential vitamin for cellular metabolism, and the riboflavin carrier protein (RCP) is highly upregulated in metabolically active cells [,]. Thus, flavin mononucleotide (FMN), an endogenous RCP ligand, was used as a small molecule targeting ligand for metabolically active cancer or endothelial cells. Kiessling and co-workers synthesized FMN-coated ultrasmall superparamagnetic iron oxide nanoparticles (FLUSPIO) as MRI/optical dual probes for cancer detection []. USPIO was coated with FMN through the phosphate groups of FMN, and guanosine monophosphate was added to stabilize the colloid. The hydrodynamic radius of FLUSPIO was 97 ± 3 nm, and an intense fluorescence emission band was observed at 530 nm due to FMN. cellular uptake of FLUSPIO was investigated by MRI (3T), TEM, and fluorescence microscopy of PC3 cells and HUVEC cells. Both PC3 cells and HUVEC cells showed a significantly higher R2 relaxation rate after 1 h incubation with FLUSPIO than with nontargeted USPIO. Such an uptake was considerably reduced by competitive blocking of RCP with free FMN. A strong green fluorescence in the cells was observed after FLUSPIO incubation. The perinuclear fluorescence signal suggested endosomal localization of the nanoparticles, consistent with TEM results, suggesting that FMN could serve as a versatile building block for generating tumor-targeted imaging and therapeutic modalities.

Temozolomide and analog synthesis of


In clinical therapy for GBM patients, new combinedtreatments and drugs are currently under the Phase 1 or 2 clinictrials (,); however, TMZ as a first-linetreatment is indispensable. Wide resistance to TMZ affects itsapplication, and the mechanism of resistance remain to beelucidated (–). Therefore, elucidation of the mechanisminvolved in the resistance to TMZ is crucial for improving theeffect as an anticancer drug. Previous studies have reported thatthe cytotoxicity of TMZ was mainly mediated byO-methylguanine, and a satisfactory result of TMZtreatment required functional DNA mismatch repair (MMR) and lowMGMT levels as preconditions (,).However, recent studies have found that resistance to TMZ wasassociated with various factors. For instance, miR-128 and miR-149regulate the invasion and chemosensitivity of GBM cells to TMZ bytargeting Rap1B-mediated cytoskeletal and associated molecularalterations (). Another exampleis Galectin-1 (Gal1) which regulates resistance to TMZ by targetingthe unfolded protein response to endoplasmic reticulum stress(ERS). Moreover, the cell protective autophagy has been reported tocontribute to TMZ-induced cell death (). The production of ROS and thedisruption of AKT/mTOR signal have been demonstrated to contributeto the TMZ resistance (). Inthis study, we focused on the contribution of TMZ-inducible ROSupregulation and the maintainable cysteine pool and GSH synthesisby xCT transporting and transsulfuration pathway in the resistanceto TMZ ().

24. Pipkorn R, Waldeck W, Didinger B. . Inverse-electron-demand Diels-Alder reaction as a highly efficient chemoselective ligation procedure: Synthesis and function of a BioShuttle for temozolomide transport into prostate cancer cells. 2009;15:235-41

and an increase in protein synthesis ..

US patent 6,844,434 describes synthesis of temozolomide by cyclization of 5-amino-l- ..

In general, nanoparticles tend to aggregate through hydrophobic interactions or attractive van der Waals forces in an effort to minimize the surface energy. In the blood stream, such aggregates can trigger opsonization, the process by which a particle becomes covered with opsonin proteins, thereby making it more visible to the mononuclear phagocytic system (MPS), such as RES. The phagocytic mechanisms render nanoparticles ineffective as theranostic devices by removing them from the bloodstream []. Therefore, evading uptake by RES and increasing the blood circulation half-life are major challenges for developing theranostic nanoparticles in clinical applications []. Several methods of camouflaging nanoparticles have been developed to yield 'stealth' nanoparticles, which are invisible to MPS. These approaches interfere with the binding of opsonin proteins to the nanoparticle surfaces in support of a long circulation half-life, thereby increasing the chance that the nanoparticles can effectively target tumor sites. In order to impart stealth properties to the nanoparticles, one of the most promising molecules is the FDA-approved PEG. Natural or synthetic polymers, small organic molecules, and core-shell structures have also been utilized for nanoparticle surface coatings. However, a high surface coverage can decrease binding to and uptake by target cancer cells. This section describes the use of several coating molecules as shielding materials. The optimal surface densities of the coating materials and the targeted ligands will be discussed.

Kandil S, Brennan L and McBean GJ:Glutathione depletion causes a JNK and p38MAPK-mediated increase inexpression of cystathionine-gamma-lyase and upregulation of thetranssulfuration pathway in C6 glioma cells. Neurochem Int.56:611–619. 2010. : :

Alkylation of the anion of nor-temozolomide with methyl iodide gave a new route to temozolomide …
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    The present invention relates to a method for the synthesis of temozolomide which uses water and moderate amounts of ..

  • Info Publication number JP4358510B2


  • Authority JP Grant status Grant Patent type

    Synthesis of Paclitaxel

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Synthesis of the ABC Ring of Paclitaxel by SmI2 ..

A) Shows the chemical structure of 4, the cRGD-peptide derivatized with tetra-[(2-aminoethyl)glycine] N-functionalized Reppe Anhydride. B) Synthetic route for the preparation of 4. The solid phase support is depicted by the grey circle. (a) condensation of the first amino acid; (b) stepwise elongation on 2-chlorotrityl resin; (c) cyclization steps: 1. Pd(PPh3)4, morpholine; 2. PyCLOCK, DIPEA; (d) conjugation to Reppe Anhydride derivative: 1. Hydrazine monohydrate; 2. Stepwise elongation, 3. Acetylation; (e) cleavage from resin and deprotection: TFA, TIS, water. C) The upper panel shows the HPLC chromatogram of the purified peptide 4. The solvent gradient was raised from 5 % to 100 % acetonitrile in 5 min (starting immediately) at a flow rate of 6 ml/min. The aqueous phase consisted of water containing 0.1 % TFA. The lower panel shows the MALDI-TOF spectrum of the purified peptide 4.


The glutamate/cystine antiporter systemx is an obligate sodium-independent aminoacid antiporter, comprising 12-pass transmembrane transporterprotein xCT (SLC7A11) which is connected to the 4F2 cell surfaceantigen 4F2hc (CD98/SLC3A2) by a disulfide bridge (,).System x transports extracellular cystineinto cells in exchange for intracellular glutamate at a ratio of1:1, and maintaining intracellular cysteine pools is important(). Cysteine is a crucialmaterial in glutathione (GSH) synthesis, which is indispensable formaintaining intracellular redox balance and drug metabolism(,). xCT expression is mediated by theoxidative stress-response transcription factor NF-E2 related tofactor 2 (Nrf2) and activation of transcription factor 4 (ATF4)(). xCT is expressed in manytypes of malignancies and is associated with tumor growth andmetastasis. It is also associated with resistance to chemotherapyand poor survival (–). Accordingly, xCT has been consideredas a potential therapeutic target (,,,).Sulfasalazine (SASP) is a sulfa drug used for inflammatory boweldiseases and rheumatoid arthritis treatment and is a widelyrecognized xCT-specific inhibitor (). Although it has been suggested thatthe inhibitory effect of SASP on xCT can suppress GBM cell growth,the combination of SASP combined with TMZ for GBM treatment in theclinic has yielded controversial results (,).Erastin (ERA) is a voltage-dependent anion channels (VDAC)-bindingsmall molecule that is selectively lethal to some cancer cells(). Compared to SASP, ERA exertsa stronger inhibitory effect on xCT (). In addition, ERA is able to inhibitthe activity of certain GSH-related enzymes, such as glutathioneperoxidase 4 (GPx4), resulting in more lethal oxidative damage tocells (). ERA can cause a uniqueform of cell death on iron-dependent tumor cells as compared toconventional apoptosis, necrosis and autophagy ().

Prodrug - an overview | ScienceDirect Topics

A. Partially schematized structural formula and the chemical reaction step of the complete 3-mercapto-propionic-cyclohexenyl-Cy7-bis-TMZ-bromide-CPP 12. This fluorescent peptide conjugate 12 mainly consists of the amino acid sequence of the CPP connected via the thioether of the 3-mercapto-propionic-cyclohexenyl-Cy7-bis-norbornenyl-bromide. The norbornenes act as dienophilic reaction partners in the DARinv. According to the protocols of Saracoglu [] and Hansell [] we coupled 11 with 10. Using we synthesized the final reaction product 12. B. Quantitative analysis in HPLC and MS spectrograph of the reaction product 12. The peak of the retention time was measured at 16.33 min. The relative amount of the peak area was 78.5%. The MS spectrograph shows the m/e 690.67/833.69 representing the sixfold/fivefold cation of the calculated isotope pattern and demonstrates the identity of the reaction product 12.

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