- Acetylene functionalized BODIPY dyes and their application in the synthesis of activity based proteasome probes
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The synthesis of three acetylene functionalized BODIPY dyes is described. These dyes are used to fluorescently modify an azido functionalized epoxomicin analogue employing the Huisgen 1,3-dipolar cycloaddition, resulting in a panel of fluorescent epoxomic
- Verdoes, Martijn,Hillaert, Ulrik,Florea, Bogdan I.,Sae-Heng, Myra,Risseeuw, Martijn D.P.,Filippov, Dmitri V.,van der Marel, Gijsbert A.,Overkleeft, Herman S.
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Read Online
- Preparation method of carfilzomib intermediate
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The invention relates to a preparation method of a carfilzomib intermediate F, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps: by taking t-butyloxycarbonyl-L-leucine as a starting material, carrying out condensation, Grignard reaction, reduction, epoxidation, oxidation and salt forming reaction to obtain a carfilzomib key intermediate F. The method has the advantages of mild reaction conditions, high yield, good selectivity and less generated three wastes, and is suitable for industrial amplification production.
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- Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer's Disease
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Previously, we reported that immunoproteasome (iP)-targeting linear peptide epoxyketones improve cognitive function in mouse models of Alzheimer's disease (AD) in a manner independent of amyloid β. However, these compounds' clinical prospect for AD is limited due to potential issues, such as poor brain penetration and metabolic instability. Here, we report the development of iP-selective macrocyclic peptide epoxyketones prepared by a ring-closing metathesis reaction between two terminal alkenes attached at the P2 and P3/P4 positions of linear counterparts. We show that a lead macrocyclic compound DB-60 (20) effectively inhibits the catalytic activity of iP in ABCB1-overexpressing cells (IC50: 105 nM) and has metabolic stability superior to its linear counterpart. DB-60 (20) also lowered the serum levels of IL-1α and ameliorated cognitive deficits in Tg2576 mice. The results collectively suggest that macrocyclic peptide epoxyketones have improved CNS drug properties than their linear counterparts and offer promising potential as an AD drug candidate.
- Lee, Min Jae,Bhattarai, Deepak,Jang, Hyeryung,Baek, Ahreum,Yeo, In Jun,Lee, Seongsoo,Miller, Zachary,Lee, Sukyeong,Hong, Jin Tae,Kim, Dong-Eun,Lee, Wooin,Kim, Kyung Bo
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p. 10934 - 10950
(2021/08/20)
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- Discovery of novel tripeptide propylene oxide proteasome inhibitors for the treatment of multiple myeloma
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The ubiquitin proteasome pathway (UPP) plays a critical role in the maintenance of cell homeostasis and the development of diseases, such as cancer and neurodegenerative disease. A series of novel tripeptide propylene oxide compounds as proteasome inhibitors were designed, synthesized and biologically investigated in this manuscript. The enzymatic activities of final compounds against 20S human proteasome were investigated and structure-activity relationship (SAR) was summarized. Some potent compounds were further evaluated to inhibit the proliferation of multiple myeloma (MM) cancer cell lines RPMI8226 and U266B. The results showed that some compounds were active against MM cancer cell lines with IC50 values of less than 50 nM. The microsomal metabolic stabilities in human, rat and mice species were carried out and the results showed that compounds 30 and 31 were stable enough to be in vivo investigated. The in vivo pharmacokinetic results showed that compounds 30 and 31 had acceptable biological parameters for both ig and iv administrations. In vivo antitumor activities of compounds 30 and 31 with the doses of 100 mg/kg and 50 mg/kg BIW were performed by using RPMI8226 xenograft nude mouse model. Toxicities of compounds 30 and 31 were not observed during the experiment and dose dependent effect was obvious and the tumor volume was greatly inhibited.
- Zhang, Wen,Wang, Xueyuan,Zhang, Haoyang,Wen, Tiantian,Yang, Lin,Miao, Hang,Wang, Jia,Liu, Hailong,Yang, Xu,Lei, Meng,Zhu, Yongqiang
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- Exploration of the carmaphycins as payloads in antibody drug conjugate anticancer agents
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Antibody–drug conjugates (ADCs) represent a new dimension of anticancer chemotherapeutics, with warheads to date generally involving either antitubulin or DNA-directed agents to achieve low-to sub-nanomolar potency. However, other potent cytotoxins working by different pharmacological mechanisms are under investigation, such as α,β-epoxyketone based proteasome inhibitors. These proteasome active agents are an emerging class of anticancer drug that possesses ultra-potent cytotoxicity to some cancer cell lines. The carmaphycins are representatives of this latter class that we isolated and characterized from a marine cyanobacterium, and these as well as several synthetic analogues exhibit this level of potency. In the current work, we investigated the use of these highly potent cytotoxic compounds as warheads in the design of novel ADCs. We designed and synthesized a library of carmaphycin B analogues that contain amine handles, enabling their attachment to an antibody linker. The basicity of these incorporated amine handles was shown to strongly affect their cytotoxic properties. Linear amines resulted in the greatest reduction in cytotoxicity whereas less basic aromatic amines retained potent activity as demonstrated by a 4-sulfonylaniline derivative. These investigations resulted in identifying the P2 residue in the carmaphycins as the most suitable site for linker attachment point, and hence, we synthesized a highly potent analogue of carmaphycin B that contained a 4-sulfonylaniline handle as an attachment point for the linker antibody.
- Almaliti, Jehad,Miller, Bailey,Pietraszkiewicz, Halina,Glukhov, Evgenia,Naman, C. Benjamin,Kline, Toni,Hanson, Jeffrey,Li, Xiaofan,Zhou, Sihong,Valeriote, Frederick A.,Gerwick, William H.
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p. 416 - 432
(2018/10/31)
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- Preparation and biological evaluation of soluble tetrapeptide epoxyketone proteasome inhibitors
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A series of novel tetrapeptidyl epoxyketone inhibitors of 20S proteasome was designed and synthesized. To fully understand the SAR, various groups at R1, R2, R3, R4 and R5 positions, including aromatic and aliphatic substituents were designed, synthesized and biologically assayed. Based on the enzymatic results, seven compounds were selected to evaluate their cellular activities and soluble compound 36 showed strong potency against human multiple myeloma (MM) cell lines. Microsomal stability results indicated that compound 36 was more stable in mice, rat and human microsomes than marketed carfilzomib. The in vivo activities of this compound were evaluated with the xenograft mice models of MM cell lines ARH77 and RPMI-8226 with luciferase expression and the T/C value of the two models were 49.5% and 37.6%, respectively. To evaluate the potential cardiovascular toxicity, inhibition of hERG ion channel in HEK293 cells by compound 36 and carfilzomib was carried out. The results indicated that 36 had no binding affinity for the hERG ion channel while carfilzomib could bind it with IC50 of 92.1 μM.
- Lei, Meng,Zhang, Haoyang,Miao, Hang,Du, Xiao,Zhou, Hui,Wang, Jia,Wang, Xueyuan,Feng, Huayun,Shi, Jingmiao,Liu, Zhaogang,Shen, Jian,Zhu, Yongqiang
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p. 4151 - 4162
(2019/08/07)
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- SYNTHESIS OF (S)-2-AMINO-4-METHYL-1-((R)-2-METHYLOXIRANE-2-YL)-PENTAN-1-ONE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention provides new methods for preparing compound (5), and pharmaceutically acceptable salts thereof, of structure. Compound (5), or a pharmaceutically acceptable salt thereof, is an important intermediate in the synthesis of carfilzomib. The invention further provides methods of making a useful manganese catalyst that may be used in the epoxidation step of the present invention.
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- PROCESS FOR THE PREPARATION OF AN INTERMEDIATE FOR THE SYNTHESIS OF CARFILZOMIB
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The present invention provides a compound which is the trichloroacetic acid salt of a compound of Formula (II) wherein R is selected from the group consisting of H, CH3-, (CH3)2CH-, (CH3)2CHCH2-, CH3CH2CH(CH3)-, and PhCH2-, and a process for its preparation. Formula (II) Also provided is a process for its preparation based on the stereoselective epoxidation of the corresponding olefin precursor and a process for the preparation of several pharmaceutically active ingredients comprising the preparation of the compound of formula (II).
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- AN IMPROVED PROCESSES FOR THE PREPARATION OF CARFILZOMIB OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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The present invention relates to an improved process for the preparation of carfilzomib or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the preparation of amorphous form of carfilzomib.
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- Preparation method of carfilzomib intermediate and intermediate chemical compounds of carfilzomib
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The invention discloses a novel preparation method of a carfilzomib key intermediate. L-leucine is taken as an original raw material, two reactive hydrogen on an amino group are protected, a chemical compound V is prepared and subjected to Weinreb amidation, a chemical compound IV is prepared, IV and 2-allyl magnesium bromide have a reaction, a chemical compound III is prepared and has an epoxidation reaction, a chemical compound II is prepared and subjected to deamination protection, and a chemical compound I is prepared. The invention further discloses intermediate chemical compounds II, III, IV and V of carfilzomib. The preparation method is simple to operate, the total yield is high, the cost is low, the selectivity is high, and the preparation method is suitable for industrial production.
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- CRYSTALLINE PEPTIDE EPOXY KETONE PROTEASE INHIBITORS AND THE SYNTHESIS OF AMINO ACID KETO-EPOXIDES
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The invention relates to crystalline peptide keto epoxide compounds, methods of their preparation, and related pharmaceutical compositions. This invention also relates to methods for the preparation of amino acid keto-epoxides. Specifically, allylic ketones are stereoselectively converted to the desired keto epoxides.
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- Systematic Analyses of Substrate Preferences of 20S Proteasomes Using Peptidic Epoxyketone Inhibitors
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Cleavage analyses of 20S proteasomes with natural or synthetic substrates allowed to infer the substrate specificities of the active sites and paved the way for the rational design of high-affinity proteasome inhibitors. However, details of cleavage prefe
- Huber, Eva M.,De Bruin, Gerjan,Heinemeyer, Wolfgang,Soriano, Guillem Paniagua,Overkleeft, Herman S.,Groll, Michael
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supporting information
p. 7835 - 7842
(2015/07/02)
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- PEPTIDE EPOXYKETONE COMPOUNDS
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The present disclosure relates to novel compounds and pharmaceutical compositions thereof which are useful as inhibitors of proteasomes. The compounds provided herein are capable of inhibiting all three of CT-L, T-L, and PGPH activities of proteasomes, and are useful in treating various conditions or diseases associated with proteasomes.
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- Exploring dual electrophiles in peptide-based proteasome inhibitors: Carbonyls and epoxides
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Peptide epoxyketones are potent and selective proteasome inhibitors. Selectivity is governed by the epoxyketone dual electrophilic warhead, which reacts with the N-terminal threonine 1,2-amino alcohol uniquely present in proteasome active sites. We studied a series of C-terminally modified oligopeptides featuring adjacent electrophiles based on the epoxyketone warhead. We found that the carbonyl moiety in the natural warhead is essential, but that the adjacent epoxide can be replaced by a carbonyl, though with considerable loss of activity. the Partner Organisations 2014.
- Xin, Bo-Tao,De Bruin, Gerjan,Verdoes, Martijn,Filippov, Dmitri V.,Van Der Marel, Gijs A.,Overkleeft, Herman S.
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p. 5710 - 5718
(2014/07/22)
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- Systematic comparison of peptidic proteasome inhibitors highlights the α-ketoamide electrophile as an auspicious reversible lead motif
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The ubiquitin-proteasome system (UPS) has been successfully targeted by both academia and the pharmaceutical industry for oncological and immunological applications. Typical proteasome inhibitors are based on a peptidic backbone endowed with an electrophi
- Stein, Martin L.,Cui, Haissi,Beck, Philipp,Dubiella, Christian,Voss, Constantin,Krueger, Achim,Schmidt, Boris,Groll, Michael
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p. 1679 - 1683
(2014/03/21)
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- METHOD FOR PRODUCING STEREOSELECTIVE EPOXYKETONE COMPOUND
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A novel method for producing a stereoselective epoxyketone compound is provided. A method for producing an epoxyketone compound represented by the formula (1), as represented by the following scheme, whereby it is possible to obtain an epoxyketone derivative in good yield and at high selectivity and to provide an industrially useful production method and an intermediate thereof. wherein R1 is a hydrogen atom, a linear, branched or cyclic alkyl group, an aromatic group which may have a substituent, or a heterocyclic group which may have a substituent, and R2 is a protective group for an amino group. R is a hydrogen atom or a C1-10 alkyl group, and R's may be the same or different, provided that at least one R is a C1-10 alkyl group.
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Page/Page column 22
(2014/01/17)
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- HIV protease-mediated activation of sterically capped proteasome inhibitors and substrates
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Strategies for selectively killing HIV-infected cells present an appealing alternative to traditional antiretroviral drugs. We show here the first example of an inactive "Trojan horse" molecule that releases a cytotoxic, smallmolecule proteasome inhibitor upon cleavage by HIV-1 protease. As a proof-of-concept strategy, the protein avidin was used to block entry of the compound into the proteasome in the absence of HIV-1 protease. We demonstrate that this strategy is also feasible without requiring an exogenous protein; a polylysine dendrimer-containing molecule is unable to enter the proteasome until cleaved by HIV-1 protease. These results demonstrate that conditional proteasome inhibitors could prove useful in the development of new tools for chemical biology and future therapeutics.
- Buckley, Dennis L.,Corson, Timothy W.,Aberle, Nicholas,Crews, Craig M.
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p. 698 - 700
(2011/04/15)
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- A panel of subunit-selective activity-based proteasome probes
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Mammals express seven different catalytically active proteasome subunits. In order to determine the roles of the different proteolytically active subunits in antigen presentation and other cellular processes, highly specific inhibitors and activity-based probes that selectively target specific active sites are needed. In this work we present the development of fluorescent activity-based probes that selectively target the β1 and β5 sites of the constitutive proteasome.
- Verdoes, Martijn,Willems, Lianne I.,Van Der Linden, Wouter A.,Duivenvoorden, Boudewijn A.,Van Der Marel, Gijsbert A.,Florea, Bogdan I.,Kisselev, Alexei F.,Overkleeft, Herman S.
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experimental part
p. 2719 - 2727
(2010/08/22)
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- Sugar amino acid based peptide epoxyketones as potential proteasome inhibitors
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This paper describes the synthesis and biological evaluation of nine epoxomicin-derived sugar amino acid containing peptide epoxyketones. The title compounds are assembled from six sugar amino acid dipeptide isosteres and are synthesized using solution-phase peptide synthesis protocols. Although neither of the compounds displays inhibitory activity towards any of the proteasome active sites, our approach holds promise towards the development of structurally new proteasome inhibitors. It is likely that the central sugar amino acid dipeptide isoster needs to be designed such that it closely resemble dipeptides at position P2 and P3 in proteasome substrates inhibitors, such as the Thr-Ile dipeptide present in the lead compound, epoxomicin.
- Risseeuw, Martijn D.P.,Florea, Bogdan I.,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.,Overhand, Mark
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experimental part
p. 202 - 209
(2010/09/14)
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- O-GlcNAc peptide epoxyketones are recognized by mammalian proteasomes
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(Chemical Equation Presented) Cytosolic and nuclear proteins may be subject to both O-GlcNAcylation and proteasomal degradation. By means of activity-based profiling, we demonstrate that O-GlcNAc serinecontaining peptide epoxyketones bind to the proteasome catalytic active sites and thus provide the first clear evidence that proteasomes recognize peptides post-translationally modified with a GlcNAc moiety.
- Witte, Martin D.,Florea, Bogdan I.,Verdoes, Martijn,Adeyanju, Oloruntosin,Van Der Marel, Gijs A.,Overkleeft, Herman S.
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supporting information; experimental part
p. 12064 - 12065
(2010/01/30)
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