51248-35-2

Usage

Preparation

A solution of phosgene(12.5% in toluene, 25 mL, 31.6 mmol) was added to a suspension of l-leucine (1.31 g, 10 mmol) in dioxane (30 mL) and ethyl acetate (25 mL) at 40 ℃ under a static atmosphere of nitrogen. After 4 h, the leucine had dissolved and then the excess phosgene was removed in a stream of nitrogen. The solvent was removed at 40 ℃ in vacuo and the residue was recrystallized from diethyl ether/light petroleum (bp 40–60 ℃) to yield colorless needles of 4-(2-methylpropyl)oxazolidine-2,5-dione (1.01 g, 69%).

Upstream product

• 75-44-5 phosgene 
• 328-38-1 (R)-leucine 
• 114488-94-7 H-D-Leu-OH 
• 328-39-2 LEUCINE 
• 117919-56-9 methoxycarbonyl-dl-leucine 
• 2018-66-8 N-carbobenzyloxy leucine 
• 61-90-5 L-leucine 
• 42534-05-4 N-carbamoyl-DL-leucine 
• 32315-10-9 bis(trichloromethyl) carbonate 
• 61-90-5 L-leucine 
• 15984-97-1 leucine 
• 503-38-8 trichloromethyl chloroformate 

Downstream Products

• 61-90-5 L-leucine 
• 686-50-0 L-leucyl-glycine 
• 462-60-2 N-carbamoylglycine 
• 3063-05-6 Leu-Phe-OH 
• 7298-84-2 Leu-Ala 
• 13079-20-4 2-Amino-4-methyl-pentanoic acid amide 
• 54745-19-6 4-isobutyl-3-(2-nitro-phenylsulfanyl)-oxazolidine-2,5-dione 

Relevant academic research and scientific papers

PEG-polyaminoacid based micelles for controlled release of doxorubicin: Rational design, safety and efficacy study

A library of amphiphilic monomethoxypolyethylene glycol (mPEG) terminating polyaminoacid co-polymers able to self-assemble into colloidal systems was screened for the delivery and controlled release of doxorubicin (Doxo). mPEG-Glu/Leu random co-polymers were generated by Ring Opening Polymerization from 5 kDa mPEG-NH2 macroinitiator using 16:0:1, 8:8:1, 6:10:1, 4:12:1 γ-benzyl glutamic acid carboxy anhydride monomer/leucine N-carboxy anhydride monomer/PEG molar ratios. Glutamic acid was selected for chemical conjugation of Doxo, while leucine units were introduced in the composition of the polyaminoacid block as spacer between adjacent glutamic repeating units to minimize the steric hindrance that could impede the Doxo conjugation and to promote the polymer self-assembly by virtue of the aminoacid hydrophobicity. The benzyl ester protecting the γ-carboxyl group of glutamic acid was quantitatively displaced with hydrazine to yield mPEG5kDa-b-(hydGlum-r-Leun). Doxo was conjugated to the diblock co-polymers through pH-sensitive hydrazone bond. The Doxo derivatized co-polymers obtained with a 16:0:1, 8:8:1, 6:10:1 Glu/Leu/PEG ratios self-assembled into 30–40 nm spherical nanoparticles with neutral zeta-potential and CMC in the range of 4-7 μM. At pH 5.5, mimicking endosome environment, the carriers containing leucine showed a faster Doxo release than at pH 7.4, mimicking the blood conditions. Doxo-loaded colloidal formulations showed a dose dependent cytotoxicity on two cancer cell lines, CT26 murine colorectal carcinoma and 4T1 murine mammary carcinoma with IC50 slightly higher than those of free Doxo. The carrier assembled with the polymer containing 6:10:1 hydGlu/Leu/PEG molar ratio {mPEG5kDa-b-[(Doxo-hydGlu)6-r-Leu10]} was selected for subsequent in vitro and in vivo investigations. Confocal imaging on CT26 cell line showed that intracellular fate of the carrier involves a lysosomal trafficking pathway. The intratumor or intravenous injection to CT26 and 4T1 subcutaneous tumor bearing mice yielded higher antitumor activity compared to free Doxo. Furthermore, mPEG5kDa-b-[(Doxo-hydGlu)6-r-Leu10] displayed a better safety profile when compared to commercially available Caelyx.

Polyamino acid carrier with acid-sensitive connecting arm in middle as well as preparation method and application of polyamino acid carrier

The invention discloses a polyamino acid carrier with an acid-sensitive connecting arm in the middle as well as a preparation method and application of the polyamino acid carrier. The polyamino acid carrier contains a hydrophilic part, a hydrophobic part and a responsive connecting arm; a specific disulfide bond is introduced into the carrier design, the disulfide bond can be controllably broken into sulfydryl in vitro, the small molecule with the sulfydryl fragment or the gene with sulfydryl inherent on the surface is bonded with the protein drug again, and a covalent disulfide bond is formedto complete chemical bonding delivery of the drug. The polyamino acid carrier and the drug are bonded in a covalent bond manner, so that the drug can be stably transported in systemic circulation. When the carrier reaches high-metabolism and high-reducibility parts such as tumors or inflammations, disulfide bonds are broken again under the condition of high glutathione (GSH), and the activity ofthe drug is released and recovered. Therefore, the purposes of firstly masking the drug activity, then stably delivering the drug in vivo and recovering accurate regulation and control of the drug activity after the drug reaches a target position are achieved.

Large-scale synthesis of α-amino acid-N-carboxyanhydrides

Hetero- and homopolymers prepared from α-amino acid-N-carboxyanhydrides (NCAs) monomers are widely useful products. The preparation of pure NCA monomers has been extensively studied in the past. Purification methods including repeated crystallizations, extraction, and flash column chromatography have been devised. However, these methods are not easily amendable to large-scale NCA preparations. This article describes the synthesis of numerous highly purified NCAs on a >100 g scale using a simple filtration step through diatomaceous earth (celite). The resulting NCAs provided polyethylene glycol (PEG)–amino acid triblock polymers devoid of low-molecular-weight by-products that were routinely observed when unfiltered batches of NCAs were used. Also disclosed is the preparation of NCAs at ambient temperature. Traditionally, NCA reactions using a phosgene source are heated. This study shows these reactions can be driven by the slight exotherm that forms upon reagent mixing. This eliminates the need for an external heating source, simplifying large-scale reactions.

COPOLYMERS FOR STABLE MICELLE FORMULATIONS

The present invention relates to the field of polymer chemistry and more particularly to multiblock copolymers and micelles comprising the same. Compositions herein are useful for drug-delivery applications.

BLOCK COPOLYMERS FOR STABLE MICELLES

The present invention relates to the field of polymer chemistry and more particularly to multiblock copolymers and micelles comprising the same. Compositions herein are useful for drug-delivery applications.

Novel shell-cross-linked micelles with detachable PEG corona for glutathione-mediated intracellular drug delivery

A series of novel disulfide-containing triblock copolymers, poly(ethylene glycol)-b-poly(l-lysine)-b-poly(rac-leucine) (PEG-SS-PLys-PLeu), were prepared. In an aqueous solution, the copolymers could self-assemble to form core-shell-corona micelles with a disulfide-linked detachable PEG corona, since the PLys middle shell with primary amine groups was linked by a disulfide-containing cross-linker. The morphology and stability of self-assembled micelles were characterized by TEM, DLS and SEM. In the intracellular environment, the micelles underwent destruction of the cross-linked shell with detachment of the PEG corona due to the cleavage of disulfide bonds, followed by the collapse of micelles. The in vitro drug release in response to GSH was further studied. Interestingly, it was found that the micelles not only exhibited reduced drug loss in extracellular environments, but also drastically accelerated drug release at the cytoplasmic GSH level, leading to enhanced growth inhibition of HeLa cells. The glutathione-responsive micelles might have great potential in intracellular drug delivery.

Sheddable micelles based on disulfide-linked hybrid PEG-polypeptide copolymer for intracellular drug delivery

A novel reduction-sensitive sheddable micelle based on disulfide-linked hybrid PEG-polypeptide mPEG-SS-Pleu was demonstrated for intracellular drug delivery. These micelles are composed of an mPEG shell and polypeptide core, characterized by FT-IR, 1H NMR, fluorescence techniques, TEM, and DLS. Interestingly, they would undergo a fast sheddable process when encounter the reduction sensitive condition, indicated by the aggregation phenomena in the presence of DTT, a reduction agent, which could cleave the disulfide bond between the micellar core and shell and consequently leading to the aggregation of hydrophobic core. Cytotoxicity study revealed that copolymers in this system have good biocompatibility and their self-assembled micelles showed a high drug loading efficiency for DOX, a hydrophobic drug model, and released DOX quantitatively in response to the intracellular level of reducing potential. Cellular uptake experiments demonstrated that the fluorescently labeled micelles could be successfully internalized into human liver carcinoma HepG2 cells, evidenced by confocal laser scanning microscopy. Above results indicate that the copolymers may have great potential in drug delivery to achieve improved cancer therapy.

Organo-Soluble Chitosan Salts and Chitosan-Derived Biomaterials Prepared Thereof

Organo-soluble chitosan salts, method for preparing organo-soluble salts, chitosan-derived materials prepared with organo-soluble chitosan salts, and methods for preparing chitosan-derived materials are disclosed.

POLYMER MICELLES CONTAINING ANTHRACYLINES FOR THE TREATMENT OF CANCER

The present invention provides micelles having an anthracycline encapsulated therein, the micelles comprising a multiblock copolymer. The invention further provides methods of preparing and using said micelles, and compositions thereof.

HYBRID BLOCK COPOLYMER MICELLES WITH MIXED STEREOCHEMISTRY FOR ENCAPSULATION OF HYDROPHOBIC AGENTS

The present invention relates to the field of polymer chemistry and more particularly to multiblock copolymers and micelles comprising the same.