- HSDB 7666
- LDP 341
- MG 341
- NSC 681239
- PS 341
- PS 341 (pharmaceutical)
- Boronic acid and ester compounds display a variety of pharmaceutically useful biological activities.Shenvi et al., U.S. Pat. No. 4,499,082 (1985 ), discloses that peptide boronic acids are inhibitors of certain proteolytic enzymes.Kettner and Shenvi, U.S. Pat. No. 5,187,157 (1993 ),U.S. Pat. No. 5,242,904 (1993 ), and U.S. Pat. No. 5,250,720 (1993 ), describe a class of peptide boronic acids that inhibit trypsin-like proteases. Kleeman et al., U.S. Pat. No. 5,169,841 (1992 ), disclosesN-terminally modified peptide boronic acids that inhibit the action of renin. Kinder et al., U.S. Pat. No. 5,106,948 (1992 ), discloses that certain tripeptide boronic acid compounds inhibit the growth of cancer cells.
- More recently, boronic acid and ester compounds have displayed particular promise as inhibitors of the proteasome, a multicatalytic protease responsible for the majority of intracellular protein turnover.Ciechanover, Cell, 79: 13-21 (1994), discloses that the proteasome is the proteolytic component of the ubiquitin-proteasome pathway, in which proteins are targeted for degradation by conjugation to multiple molecules of ubiquitin. Ciechanover also discloses that the ubiquitin-proteasome pathway plays a key role in a variety of important physiological processes.
- Adams et al., U.S. Patent No. 5,780,454 (1998 ),U.S. Patent No. 6,066,730 (2000 ), U.S. Patent No. 6,083,903 (2000 ),U.S. Patent No. 6,297,217 (2001 ), U.S. Patent No. 6,548,668 , andU.S. Patent No. 6,617,317 (2003 ), hereby incorporated by reference in their entirety, describe peptide boronic ester and acid compounds useful as proteasome inhibitors. The references also describe the use of boronic ester and acid compounds to reduce the rate of muscle protein degradation, to reduce the activity of NF-κB in a cell, to reduce the rate of degradation of p53 protein in a cell, to inhibit cyclin degradation in a cell, to inhibit the growth of a cancer cell, to inhibit antigen presentation in a cell, to inhibit NF-κB dependent cell adhesion, and to inhibit HIV replication.
- Albanell and Adams, Drugs of the Future 27: 1079-1092 (2002), discloses that one such peptide boronic acid proteasome inhibitor, bortezomib (N-2-pyrazinecarbonyl-L-phenylalanine-L-leucineboronic acid), shows significant antitumor activity in human tumor xenograft models and is undergoing clinical evaluation. Richardson et al., New Engl. J. Med., 348:2609 (2003), reports the results of a Phase 2 study of bortezomib, showing its effectiveness in treating relapsed and refractory multiple myeloma.
- Studies of boronic acid protease inhibitors have been greatly advanced by the development of chemistry for the preparation of functionalized boronic acid compounds, particularly alpha-halo- and alpha-aminoboronic acids. Matteson and Majumdar, J. Am. Chem. Soc., 102:7590 (1980), discloses a method for preparing alpha-chloroboronic esters by homologation of boronic esters, and Matteson and Ray, J. Am. Chem. Soc., 102:7591 (1980), reports that chiral control of the homologation reaction can be achieved by the use of pinanediol boronic esters. The preparation of alpha-aminoboronic acid and ester compounds from the corresponding alpha-chloroboronic esters has also been reported (Matteson et al., J. Am. Chem. Soc., 103:5241 (1981);Shenvi, U.S. Patent No. 4,537,773 (1985 )).
- Matteson and Sadhu, U.S. Patent No. 4,525,309 (1985 ), describes an improved procedure for the homologation of boronic esters by rearrangement of the intermediate boron "ate" complex in the presence of a Lewis acid catalyst. The Lewis acid is reported to promote the rearrangement reaction and to minimize epimerization at the alpha-carbon atom. Rigorous exclusion of water and careful control of Lewis acid stoichiometry are required for optimum results, however. These features render the reaction difficult to perform successfully on a production scale, and limit the availability of pharmaceutically important boronic ester and acid compounds, such as bortezomib
- A) fractional crystallisation, or
- B) a reslurry/hydrolysis, or
- C) chromatography,
- D) or combinations of any of the above three techniques
These are exemplified in the following 3 examples.
enantiomeric resolution coupling reagent
or a boronic acid anhydride thereof. The process comprises the steps:
- (a) providing a boron "ate" complex of formula ( XV ):wherein:
- is a nucleofugic group;
- is a nucleofugic group; and
- is an alkali metal;
- (b) contacting the boron "ate" complex of formula ( XV ) with a Lewis acid under conditions that afford a boronic ester compound of formula ( XVI ):said contacting step being conducted in a reaction mixture comprising:
- (i) a coordinating ether solvent that has low miscibility with water; or
- (ii) an ether solvent that has low miscibility with water and a coordinating co-solvent;
- (c) treating the boronic ester compound of formula ( XVI ) with a reagent of formula M1-N(G)2, where M1 is an alkali metal and each G individually or together is an amino group protecting group, to form a compound of formula ( XVII ):
- (d) removing the G groups to form a compound of formula ( XVIII ):or an acid addition salt thereof;
- (e) coupling the compound of formula ( XVIII ) with a compound of formula ( XIX );wherein:
to form a compound of formula ( XX ):wherein P1 is as defined above;
- P1 is a cleavable amino group protecting moiety; and
- X is OH or a leaving group;
- (f) removing the protecting group P1 to form a compound of formula ( XXI ):or an acid addition salt thereof;
- (g) coupling the compound of formula ( XXI ) with a reagent of formula ( XXII )wherein X is a OH or a leaving group, to form a compound of formula ( XXIII ):and
- (h) deprotecting the boronic acid moiety to form the compound of formula ( XIV ) or a boronic acid anhydride thereof.
- A solution of (1S,2S,3R,5S)-Pinanediol N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronate (25.2 g) in 207 mL of MeOH and 190 mL of hexane was cooled to 15 °C, and 109.4 mL of 1N HCl were added in portions, keeping the temperature between 15 and 25 °C. 2-Methylpropaneboronic acid (8.67 g) was then added under vigorous stirring, and the stirring of the biphasic mixture was continued over night. After separation of the two phases, the lower layer was extracted once with 75 mL of hexane. The lower layer was then concentrated in vacuo until it became cloudy, followed by the addition of 109.4 mL of 2N NaOH and 100 mL of Et2O. The two phases were separated the lower layer was extracted with Et2O (4 · 100 mL each), and then brought to pH 6.0 by the addition of 109 mL of 1N HCl. After extraction with 100 mL of ethyl acetate, the lower layer was adjusted to pH 6.0 with 1N HCl and extracted one more time with 75 mL of ethyl acetate. The combined ethyl acetate layers were washed with semi-saturated brine (2 · 25 mL) and brine (2 · 25 mL), dried over Na2SO4, filtered, and concentrated to afford 15.3 g (81.8 %) of crude N-(2-Pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic anhydride as a foam. The crude material was dissolved in 150 mL of ethyl acetate and concentrated in vacuo to a suspension, followed by the addition of 150 mL of MTBE. The suspension was stored between 2 and 8 °C over night, filtered, washed twice with MTBE, and dried under high vacuum, yielding 10.69 g (57.2 %) of N-(2-pyrazinecarbonyl)-L-phenylalanine-L-leucine boronic anhydride as a white solid.
- Takimoto CH, Calvo E. "Principles of Oncologic Pharmacotherapy" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
- Adams J, Kauffman M (2004). "Development of the Proteasome Inhibitor Velcade (Bortezomib)". Cancer Invest 22 (2): 304–11. doi:10.1081/CNV-120030218.PMID 15199612.
- Stephen R.Byrn et al (2011). "Analysis of two commercially available bortezomib products: differences in assay of active agent and impurity profile". AAPS PharmSciTech (April 1).
- Bonvini P, Zorzi E, Basso G, Rosolen A (2007). "Bortezomib-mediated 26S proteasome inhibition causes cell-cycle arrest and induces apoptosis in CD-30+ anaplastic large cell lymphoma". Leukemia 21 (4): 838–42. doi:10.1038/sj.leu.2404528. PMID 17268529.
- Gelman JS, Sironi J, Berezniuk I, Dasgupta S, Castro LM, Gozzo FC, Ferro ES, Fricker LD (2013). "Alterations of the intracellular peptidome in response to the proteasome inhibitor bortezomib". In Gartel, Andrei L. PLoS One 8 (8): e53263.doi:10.1371/journal.pone.0053263. PMC 3538785. PMID 23308178.
- Voorhees PM, Dees EC, O'Neil B, Orlowski RZ (2003). "The proteasome as a target for cancer therapy". Clin Cancer Res 9 (17): 6316–25. PMID 14695130.
- "NHS watchdog rejects cancer drug". BBC News UK. 20 October 2006. Retrieved 2009-08-14.
- "Summary of VELCADE Response Scheme". Retrieved 2009-08-14.
- "More Velcade-Style Risk-Sharing In The UK?". Euro Pharma Today. 21 January 2009. Retrieved 2009-08-14.
- Oakervee HE, Popat R, Curry N, et al. (2005). "PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma". Br J Haematol 129 (6): 755–62. doi:10.1111/j.1365-2141.2005.05519.x. PMID 15953001.
- Pour L., Adam Z., Buresova L., et al. (2009). "Varicella-zoster virus prophylaxis with low-dose acyclovir in patients with multiple myeloma treated with bortezomib". Clinical Lymphoma & Myeloma 9 (2): 151–3. doi:10.3816/CLM.2009.n.036. PMID 19406726.
- Highlights Of Prescribing Information
- "Cancer drug benefits could be negated by healthy tea treatment". Belfast Telegraph. 3 February 2009. Retrieved 2009-08-14.
- "Green tea may counteract anticancer effects of cancer therapy, bortezomib (Velcade)". Retrieved 15 July 2013.
- "Green tea clash with bortezomib suggested". Retrieved 26 July 2013.
- Golden EB, et al.; Lam, P. Y.; Kardosh, A.; Gaffney, K. J.; Cadenas, E.; Louie, S. G.; Petasis, N. A.; Chen, T. C.; Schonthal, A. H. (2009). "Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors". Blood 113 (23): 5927–37.doi:10.1182/blood-2008-07-171389. PMID 19190249.
- Curran M, McKeage K. (2009). "Bortezomib: A Review of its Use in Patients with Multiple Myeloma". Drugs 69 (7): 859–888. doi:10.2165/00003495-200969070-00006.PMID 19441872. doi:10.2165/00003495-200969070-00006.
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- WO2009/36281 A2, ANDUS2013/85277 A1,
- Myeloma patients campaigning for access to a life prolonging cancer drug
- Millennium Pharmaceuticals website on Velcade
- Multiple Myeloma Research Foundation article on Velcade
- International Myeloma Foundation article on Velcade
- U.S. Food and Drugs Administration on Velcade
- Dedicated website for European audience
- Presentation at 2006 ASCO of the PINNACLE Study on MCL by Dr. Goy, with video/slides
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