Bortezomib CAS 179324-69-7
Introduction：Basic information about Bortezomib CAS 179324-69-7, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Bortezomib Basic informationDescription Drug for Cancer treatment Background
| Product Name: | Bortezomib |
| Synonyms: | Boronic acid, B-[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(2-pyrazinylcarbonyl)aMino]propyl]aMino]bu;MG-341 PS-341;BortezoMib Base;BortezoMib-D8;bortezoMib(other);MLM341;BortezoMib R;VELCADE(BORTEZOMIB) |
| CAS: | 179324-69-7 |
| MF: | C19H25BN4O4 |
| MW: | 384.24 |
| EINECS: | 605-854-3 |
| Product Categories: | peptides;Inhibitor;Pepetides;Apis;Final material;API;Boron Derivatives;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;ProteasomeInhibitors;179324-69-7 |
| Mol File: | 179324-69-7.mol |
Bortezomib Chemical Properties
| Melting point | 122-124°C |
| density | 1.214 |
| RTECS | ED7771666 |
| storage temp. | Inert atmosphere,Store in freezer, under -20°C |
| solubility | Soluble in chloroform, dimethyl sulfoxide, ethanol and methanol. |
| pka | 9.66±0.43(Predicted) |
| form | solid |
| color | White |
| Optical Rotation | Consistent with structure |
| Stability: | Hygroscopic and Moisture Sensitive |
| InChIKey | GXJABQQUPOEUTA-RDJZCZTQSA-N |
| SMILES | B([C@@H](NC(=O)[C@@H](NC(C1=NC=CN=C1)=O)CC1=CC=CC=C1)CC(C)C)(O)O |
| CAS DataBase Reference | 179324-69-7(CAS DataBase Reference) |
Safety Information
| Risk Statements | 23/24/25-48/23/24/25 |
| Safety Statements | 9-27-36/37-45-60 |
| WGK Germany | WGK 3 |
| HazardClass | 6.1 |
| HS Code | 29339900 |
| Storage Class | 11 - Combustible Solids |
| Hazardous Substances Data | 179324-69-7(Hazardous Substances Data) |
| Description | Bortezomib, a modified dipeptidyl boronic acid, is a therapeutic proteasome inhibitors used for the treatment of cancers. It is indicated for the treatment of relapsed multiple myeloma and mantle cell lymphoma. It is capable of inhibiting the mammalian 26S proteasome, which is important in regulating the intracellular concentration of specific proteins to maintain homeostasis within cells. The disruption of 26S proteasome function disrupts normal cellular homeostasis, leading to cytotoxic effect on various kinds of cancer cells. |
| Drug for Cancer treatment | Bortezomib is a drug for treatment of hematopoietic malignancies with the appearance being white or white-like crystalline powder. It is easily soluble in dimethyl sulfoxide, ethanol, but insoluble in aqueous solution. This product is the reversible inhibitor of the mammal cell 26S proteasome chymotrypsin-like activity. 26S proteasome is a large protein complex which can degrade ubiquitin. Ubiquitin proteasome pathway plays an important role in regulation of the intracellular concentration of specific proteins in order to maintain the stability of the intracellular environment. Proteolytic affects intracellular multi-level signalling cascade. The disruption of the normal intracellular environment can lead to cell death while the inhibition of the 26S proteasome can prevent the hydrolysis of specific proteins. In vitro tests have proved bortezomib exhibits cytotoxicity to multiple types of cancer cells. The in vivo models of preclinical tumor have proved that bortezomib is capable of delaying the tumor growth of multiple myeloma which is suitable for the treatment of multiple myeloma. The above information is edited by the Chemicalbook of Dai Xiongfeng. |
| Description | Bortezomib, a potent ubiquitin proteasome (26S) inhibitor (Ki=0.6 nM), was launchedin the US as a treatment for multiple myeloma. This proteasome is required for the proteolytic degradation of the majority of cellular proteins and is present in all cells.It is required for the control of inflammatory processes, cell cycle regulation and geneexpression and is a novel target in cancer treatment. Bortezomib is a N-acyl-pseudodipeptidylboronic acid and formulated as a mannitol ester. Aldehyde containingpeptides are also proteasome inhibitors, but lack chiral stability (racemization) andselectivity against other proteases including cysteine proteases. Replacement of thealdehyde moiety by a boronic acid avoids these shortcomings and provides somemeasure of selective proteasome inhibition relative to many other serine proteases. It isprepared by coupling the pinanediol ester of leucine boronic acid with N-tert-Bocphenylalanineutilizing O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) as the coupling agent. The tert-Boc protecting group is thencleaved from the dipeptide and pyrazinecarboxylic acid is coupled to form the terminalamide. Hydrolysis of the boronate ester is accomplished via a two-phase transesterificationprocedure using isobutyl boronic acid and aqueous extraction. In a study ofpatients who had received at least two prior therapies and demonstrated diseaseprogression on their most recent therapy, about twenty eight percent showed a responseto bortezomib. The response lasted a median time of one year. Another trial in 54patients with relapsed multiple myeloma showed similar responses. It is dosedintravenously at an exposure of 1.3 mg/m2/dose twice weekly for two weeks followedby a 10-day drug-holiday. At therapeutic doses, the plasma drug levels were reported todrop to near detection limits within minutes of intravenous dosing. Based upon an exvivo proteasome activity assay using blood cells, the pharmacodynamic half-life rangedfrom 9 to 15 h in patients with advanced malignancies. |
| Chemical Properties | Yellow Solid |
| Originator | Millenium(LeukoSite, Proscript) (US) |
| Uses | Bortezomib is the first proteasome inhibitor to be approved b the US FDA for multiple myeloma, a blood cancer. A reversible inhibitor of the 26S proteasome-a barrel-shaped multiprotein particle found in the nucleus and cytosol of all eukaryotic cells. T |
| Uses | A potent, highly selective and reversible inhibitor of the 20S proteasome, Bortezomib is used as an antineoplastic agent, which controls the growth of cancer cells. It is also useful in the treatment of multiple myeloma. |
| Definition | ChEBI: Bortezomib is l-Phenylalaninamide substituted at the amide nitrogen by a 1-(dihydroxyboranyl)-3-methylbutyl group and at N(alpha) by a pyrazin-2-ylcarbonyl group. It is a dipeptidyl boronic acid that reversibly inhibits the 26S proteasome. It has a role as an antineoplastic agent, a proteasome inhibitor, a protease inhibitor and an antiprotozoal drug. It is an amino acid amide, a member of pyrazines and a L-phenylalanine derivative. It is functionally related to a boronic acid. |
| Brand name | Velcade(Millennium). |
| General Description | Proteasomes normally function to degrade proteins that areno longer needed by the cell. Such proteins are normallymarked by the addition of ubiquitin, a 76 amino acid proteinthat is added to the -amino group of lysine residues onthe target proteins. The marked proteins are then hydrolyzedby the large barrel-shaped proteasomes to givepeptides of 7 to 8 residues that may be further hydrolyzedand reutilized by the cell. This process serves to regulateprotein levels within the cell, remove defective proteins,and becomes important in maintaining normal signal transduction.Inhibition of the proteasomes results in the buildup of ubiquitylated proteins, which disrupts cell-signalingprocesses and cell growth. The signaling bytranscription factor NF-B (nuclear factor B) appears tobe especially sensitive to bortezomib. NF-B is associatedwith the transcription of antiapoptotic and proliferativegenes but is under the control of IB (inhibitor of NF-B).IB can itself be phosphorylated by IKK (IB kinase),which marks IB for ubiquitylation and destruction allowingNF-B to mediate its antiapoptotic and proliferative effects effects.In the presence of the competitive inhibitor bortezomib(IC50＝0.6 nM), the 26S proteasome is inhibitedand the ubiquitylated IkB is still capable of inhibiting NF-kB, preventing its effects. |
| Pharmaceutical Applications | Bortezomib belong to the class of drugs called proteasome inhibitors and is licensed in the United States andthe United Kingdom for the treatment of multiple myeloma. The drug has been licensed for patients in whomthe myeloma has progressed despite prior treatment or where a bone marrow transplant is not possible or wasnot successful. It is marketed under the name Velcade? or Cytomib?. Velcade is administered via injectionand is sold as powder for reconstitution. Bortezomib was the first drug approved in the new drug class of proteasome inhibitors and boron seems tobe its active element. For the mode of action, it is believed that the boron atom binds with high affinity andspecificity to the catalytic site of 26S proteasome and inhibits its action. Therapy with Bortezomib can leadto a variety of adverse reactions, including peripheral neuropathy, myelosuppression, renal impairment andgastrointestinal (GI) disturbances together with changes in taste. Nevertheless, the side effects are in mostcases less severe than with alternative treatment options such as bone marrow transplantation. |
| Biochem/physiol Actions | Cell permeable: yes |
| Clinical Use | Proteasome inhibitor: Treatment of multiple myeloma for people who have already tried at least 1 prior therapy and have disease progression |
| Synthesis | Although the synthesis of dipeptidyl boronic acidshave appeared on several reports, the syntheticdetails for bortezomib were not revealed. The synthetic routefor the preparation of bortezomib is depicted in the scheme.The pinanediol ester of leucine boronic acid (56)wascoupled with N-Boc phenylalanine (57) in the presence ofTBTU followed by deprotection of the Boc group to provide58. N-Acylation of 58 then furnished the dipeptide boronateester 60. Deprotection of the boronic ester functionality wasachieved by bi-phase transfer esterification with isobutylboronic acid. Bortezomib (VI) was isolated by extractiveworkup. |
| target | 20S proteasome |
| Drug interactions | Potentially hazardous interactions with other drugs Antibacterials: potential reduced efficacy with rifampicin resulting in increased monoclonal IgG λ – avoid. Antipsychotics: avoid with clozapine, increased risk of agranulocytosis. |
| Metabolism | In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolised via cytochrome P450 enzymes, 3A4, 2C19, and 1A2. The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors. |
| storage | +4°C |
| Background | Bortezomib, a boronic acid dipeptide, is a specific, potent, and reversable proteasome inhibitor that has also been shown to have a stabilizing effect on proteins that inhibit cell survival and cell cycle progression, such as p53. Researchers have demostrated that bortezomib inhibits activation and nuclear translocation of NF-κB, subsequently decreasing early tumor survival. The increase in bortezomib-stablilized, misfolded, and ubiquitinated proteins that interfere with cell survival and other important pathways further support its anti-tumor effects. |
| References | [1] J ADAMS. Proteasome inhibitors: a novel class of potent and effective antitumor agents.[J]. Cancer research, 1999, 59 11: 2615-2622. [2] SIMON WILLIAMS. Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts.[J]. Molecular Cancer Therapeutics, 2003, 2 9: 835-843. [3] PAUL G RICHARDSON Kenneth C A Teru Hideshima. Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers.[J]. Cancer Control, 2003, 10 5: 361-369. DOI:10.1177/107327480301000502 [4] MYLÈNE HERVÉ El C I. Proteasome inhibitors to alleviate aberrant IKBKAP mRNA splicing and low IKAP/hELP1 synthesis in familial dysautonomia[J]. Neurobiology of Disease, 2017, 103: Pages 113-122. DOI:10.1016/j.nbd.2017.04.009 |
Bortezomib Preparation Products And Raw materials
| Raw materials | BORTEZOMIB-PINANEDIOL-->Hydrochloric acid |
| Preparation Products | N-((S)-1-(((R)-1-Hydroxy-3-Methylbutyl)aMino)-1-oxo-3-phenylpropan-2-yl)pyrazine-2-carboxaMide |
