179324-69-7 Usage
Description
Bortezomib, also known as Velcade, is a modified dipeptidyl boronic acid and the first proteasome inhibitor approved by the US FDA for the treatment of multiple myeloma, a blood cancer. It is a potent, highly selective, and reversible inhibitor of the 26S proteasome, a barrel-shaped multiprotein particle found in the nucleus and cytosol of all eukaryotic cells. Bortezomib is capable of inhibiting the mammalian 26S proteasome, which plays a crucial role in regulating intracellular protein concentrations to maintain cellular homeostasis. The disruption of 26S proteasome function by Bortezomib leads to the accumulation of ubiquitylated proteins, disrupting cell-signaling processes and cell growth, particularly affecting the transcription factor NF-kB.
Uses
Used in Oncology:
Bortezomib is used as an antineoplastic agent for the treatment of multiple myeloma, a cancer that arises from plasma cells. It controls the growth of cancer cells by inhibiting the 26S proteasome, which is essential for the degradation of proteins marked by ubiquitin. This inhibition disrupts normal cellular homeostasis, leading to cytotoxic effects on various kinds of cancer cells.
Used in the Treatment of Relapsed Multiple Myeloma:
Bortezomib is used as a therapeutic agent for patients with relapsed multiple myeloma who have received at least two prior therapies and demonstrated disease progression on their most recent therapy. In a study, about twenty-eight percent of these patients showed a response to Bortezomib, with the response lasting a median time of one year.
Used in the Treatment of Mantle Cell Lymphoma:
Bortezomib is also indicated for the treatment of mantle cell lymphoma, a type of non-Hodgkin lymphoma. It has shown efficacy in this application due to its ability to inhibit the 26S proteasome, which plays a role in the survival and proliferation of cancer cells.
Used in Cancer Research:
Bortezomib is used as a research tool in the study of the proteasome's role in various cellular processes, including cell cycle regulation, gene expression, and inflammatory processes. Its ability to inhibit the 26S proteasome makes it a valuable compound for investigating the mechanisms of cancer development and progression.
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 lookchem of Dai Xiongfeng.
Originator
Millenium
(LeukoSite, Proscript) (US)
Pharmaceutical Applications
Bortezomib belong to the class of drugs called proteasome inhibitors and is licensed in the United States and
the United Kingdom for the treatment of multiple myeloma. The drug has been licensed for patients in whom
the myeloma has progressed despite prior treatment or where a bone marrow transplant is not possible or was
not successful. It is marketed under the name Velcade? or Cytomib?. Velcade is administered via injection
and is sold as powder for reconstitution.
Bortezomib was the first drug approved in the new drug class of proteasome inhibitors and boron seems to
be its active element. For the mode of action, it is believed that the boron atom binds with high affinity and
specificity to the catalytic site of 26S proteasome and inhibits its action. Therapy with Bortezomib can lead
to a variety of adverse reactions, including peripheral neuropathy, myelosuppression, renal impairment and
gastrointestinal (GI) disturbances together with changes in taste. Nevertheless, the side effects are in most
cases 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 acids
have appeared on several reports, the synthetic
details for bortezomib were not revealed. The synthetic route
for the preparation of bortezomib is depicted in the scheme.The pinanediol ester of leucine boronic acid (56)was
coupled with N-Boc phenylalanine (57) in the presence of
TBTU followed by deprotection of the Boc group to provide
58. N-Acylation of 58 then furnished the dipeptide boronate
ester 60. Deprotection of the boronic ester functionality was
achieved by bi-phase transfer esterification with isobutyl
boronic acid. Bortezomib (VI) was isolated by extractive
workup.
Drug interactions
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.
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.
References
1) Adams et al. (1999), Proteasome inhibitors: a novel class of potent and effective antitumor agents; Cancer Res., 59 2615
2) Williams et al. (2003), Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts; Mol. Cancer Ther., 2 835
3) Richardson et al. (2003), Bortezomib (PS-341): a novel, first-in-class proteasome inhibitor for the treatment of multiple myeloma and other cancers; Cancer Control, 10 361
4) Herve and Ibrahim (2017), Proteasome inhibitors to alleviate aberrant IKBKAP mRNA splicing and low IKAP/hELP1 synthesis in familial dysautonomia; Neurobiol. Dis., 103 113
Check Digit Verification of cas no
The CAS Registry Mumber 179324-69-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,7,9,3,2 and 4 respectively; the second part has 2 digits, 6 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 179324-69:
(8*1)+(7*7)+(6*9)+(5*3)+(4*2)+(3*4)+(2*6)+(1*9)=167
167 % 10 = 7
So 179324-69-7 is a valid CAS Registry Number.
InChI:InChI=1/C19H25BN4O4/c1-13(2)10-17(20(27)28)24-18(25)15(11-14-6-4-3-5-7-14)23-19(26)16-12-21-8-9-22-16/h3-9,12-13,15,17,27-28H,10-11H2,1-2H3,(H,23,26)(H,24,25)/t15-,17-/m0/s1
179324-69-7Relevant articles and documents
Discovery of Novel Peptidomimetic Boronate ClpP Inhibitors with Noncanonical Enzyme Mechanism as Potent Virulence Blockers in Vitro and in Vivo
Ju, Yuan,He, Lihui,Zhou, Yuanzheng,Yang, Tao,Sun, Ke,Song, Rao,Yang, Yang,Li, Chengwei,Sang, Zitai,Bao, Rui,Luo, Youfu
, p. 3104 - 3119 (2020/03/04)
Caseinolytic protease P (ClpP) is considered as a promising target for the treatment of Staphylococcus aureus infections. In an unbiased screen of 2632 molecules, a peptidomimetic boronate, MLN9708, was found to be a potent suppressor of SaClpP function. A time-saving and cost-efficient strategy integrating in silico position scanning, multistep miniaturized synthesis, and bioactivity testing was deployed for optimization of this hit compound and led to fast exploration of structure-activity relationships. Five of 150 compounds from the miniaturized synthesis exhibited improved inhibitory activity. Compound 43Hf was the most active inhibitor and showed reversible covalent binding to SaClpP while did not destabilize the tetradecameric structure of SaClpP. The crystal structure of 43Hf-SaClpP complex provided mechanistic insight into the covalent binding mode of peptidomimetic boronate and SaClpP. Furthermore, 43Hf could bind endogenous ClpP in S. aureus cells and exhibited significant efficacy in attenuating S. aureus virulence in vitro and in vivo.
Asymmetric Synthesis of α-Aminoboronates via Rhodium-Catalyzed Enantioselective C(sp3)-H Borylation
Reyes, Ronald L.,Sato, Miyu,Iwai, Tomohiro,Sawamura, Masaya
supporting information, p. 589 - 597 (2020/01/22)
α-Aminoboronic acids, isostructural boron analogues of α-amino acids, have received much attention because of the important biomedical applications implicated for compounds containing this structure. Additionally, the inherent versatility of α-aminoboronic acids as synthetic intermediates through diverse carbon-boron bond transformations makes the efficient synthesis of these compounds highly desirable. Here, we present a Rh-monophosphite chiral catalytic system that enables a highly efficient enantioselective borylation of N-adjacent C(sp3)-H bonds for a range of substrate classes including 2-(N-alkylamino)heteroaryls and N-alkanoyl- or aroyl-based secondary or tertiary amides, some of which are pharmaceutical agents or related compounds. Various stereospecific transformations of the enantioenriched α-aminoboronates, including Suzuki-Miyaura coupling with aryl halides and the Rh-catalyzed reaction with an isocyanate derivative of α-amino acid, affording a new peptide chain elongation method, have been demonstrated. As a highlight of this work, the borylation protocol was successfully applied to the catalyst-controlled site-selective and stereoselective C(sp3)-H borylation of an unprotected dipeptidic compound, allowing remarkably streamlined synthesis of the anti-cancer drug molecule bortezomib and offering a straightforward route for the synthesis of privileged molecular architectures.
Virtues of Volatility: A Facile Transesterification Approach to Boronic Acids
Hinkes, Stefan P.A.,Klein, Christian D.P.
supporting information, p. 3048 - 3052 (2019/05/10)
Boronic acids are an increasingly important compound class for many applications, including C-C bond formation reactions, medicinal chemistry, and diagnostics. The deprotection of boronic ester intermediates is frequently a problematic and inefficient step in boronic acid syntheses. We describe an approach that highly facilitates this transformation by leveraging the volatility of methylboronic acid and its diol esters. The method is performed under mild conditions, provides high yields, and eliminates cumbersome and problematic purification steps.
