- Bioinspired manganese complexes catalyzed epoxidation for the synthesis of the epoxyketone fragment of carfilzomib
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We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone (tert-butyl ((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermediate of carfilzomib. A series of bioinspired manganese complexes bearing N4 ligands are carefully investigated in the epoxidation of enone precursor with H2O2 as oxidant in the presence of carboxylic acid (e.g., acetic acid).
- Qiu, Bin,Xia, Chungu,Sun, Wei
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Read Online
- Continuous Process Improvement in the Manufacture of Carfilzomib, Part 2: An Improved Process for Synthesis of the Epoxyketone Warhead
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The development and kilogram-scale demonstration of an improved process for the synthesis of the epoxyketone warhead of carfilzomib is described. Critical to the success of this process was: (1) development of a scalable asymmetric epoxidation protocol; (2) identification of a crystalline intermediate with improved physical properties for isolation; (3) discovery and optimization of epimerization conditions to set the target stereochemistry; and (4) introduction of a seeded-bed coaddition crystallization to facilitate isolation of the final low-melting target. The results of kilogram-scale demonstration runs are shared, including details of a continuous process for the safe execution of an exothermic Barbier-type Grignard process.
- Beaver, Matthew G.,Shi, Xianqing,Riedel, Jan,Patel, Parth,Zeng, Alicia,Corbett, Michael T.,Robinson, Jo Anna,Parsons, Andrew T.,Cui, Sheng,Baucom, Kyle,Lovette, Michael A.,I?ten, El?in,Brown, Derek B.,Allian, Ayman,Flick, Tawnya G.,Chen, Wendy,Yang, Ning,Walker, Shawn D.
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Read Online
- 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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- Asymmetric Epoxidation of Olefins Catalyzed by Substituted Aminobenzimidazole Manganese Complexes Derived from L-Proline
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A family of manganese complexes [Mn(Rpeb)(OTf)2] (peb=1-(1-ethyl-1H-benzo[d]imidazol-2-yl)-N-((1-((1-ethyl-1H-benzo[d]imidazol-2-yl)methyl) pyrrolidin-2-yl)methyl)-N-methylmethanamine)) derived from L-proline has been synthesized and characterized, where R refers to the group at the diamine backbone. X-ray crystallographic analyses indicate that all the manganese complexes [Mn(Rpeb)(OTf)2] exhibit cis-α topology. These types of complexes are shown to catalyze the asymmetric epoxidation of olefins employing H2O2 as a terminal oxidant with up to 96% ee. Obviously, the R group of the diamine backbone can influence the catalytic activity and enantioselectivity in the asymmetric epoxidation of olefins. In particular, Mn(i-Prpeb)(OTf)2 bearing an isopropyl arm, cannot catalyze the epoxidation reaction with H2O2 as the oxidant. However, when PhI(OAc)2 is used as the oxidant instead, all the manganese complexes including Mn(i-Prpeb)(OTf)2 can promote the epoxidation reactions efficiently. Taken together, these results indicate that isopropyl substitution on the Rpeb ligand inhibits the formation of active Mn(V)-oxo species in the H2O2/carboxylic acid system via an acid-assisted pathway.
- Lin, Jin,Sun, Wei,Tian, Jing,Xia, Chungu,Zhang, Jisheng
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supporting information
(2021/11/16)
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- Continuous Process Improvement in the Manufacture of Carfilzomib, Part 1: Process Understanding and Improvements in the Commercial Route to Prepare the Epoxyketone Warhead
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Epoxyketone 4 is an isolated intermediate in the manufacturing route to the commercial proteasome inhibitor carfilzomib (Kyprolis). Commercial process development and optimization efforts toward the preparation of epoxyketone 4 highlighted several opportunities for process improvement. In this article, three case studies are presented that demonstrate how a detailed understanding of the reaction mechanism led to improvements that increased the overall robustness of the process. In the first case study, the mechanism of racemization of an α-chiral enone was investigated, resulting in the development of an improved aqueous workup procedure. Next, the stability of a bleach/pyridine mixture used for the step 3 epoxidation reaction was studied, leading to the identification of pyridine as a key raw material and improved reaction conditions and control strategy to meet the conversion target. Finally, oxidized butylated hydroxytoluene (oBHT) was identified as an impurity arising from the use of BHT-stabilized tetrahydrofuran in steps preceding the oxidation. The process understanding obtained from these investigations led to the implementation of process improvements that improved the robustness of the process. The development of a second-generation route to 4 is the subject of part 2 in this series (DOI: 10.1021/acs.oprd.0c00052).
- Dornan, Peter K.,Anthoine, Travis,Beaver, Matthew G.,Cheng, Guilong Charles,Cohen, Dawn E.,Cui, Sheng,Lake, William E.,Langille, Neil F.,Lucas, Susan P.,Patel, Jenil,Powazinik, William,Roberts, Scott W.,Scardino, Chris,Tucker, John L.,Spada, Simone,Zeng, Alicia,Walker, Shawn D.
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p. 481 - 489
(2020/04/10)
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- LMP2 Inhibitors as a Potential Treatment for Alzheimer's Disease
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The immunoproteasome (iP), an inducible proteasome variant harboring three immunosubunits, low molecular mass polypeptide-2 (LMP2), multicatalytic endopeptidase complex subunit-1, and low molecular mass polypeptide-7 (LMP7), is involved in multiple facets of inflammatory responses. We recently reported that YU102, a dual inhibitor of the iP subunit LMP2 and the constitutive proteasome catalytic subunit β1, ameliorates cognitive impairments in mouse models of Alzheimer's disease (AD) independently of amyloid deposits. To investigate whether inhibition of LMP2 is sufficient to improve the cognitive functions of AD mice, here we prepared 37 YU102 analogues and identified a potent LMP2 inhibitor DB-310 (28) (IC50: 80.6 nM) with improved selectivity and permeability in cells overexpressing ABCB1 transporters. We show that DB-310 induces suppression of IL-1α production in microglia cells and improves cognitive functions in the Tg2576 transgenic mouse model of AD. This study supports that inhibition of LMP2 is a promising therapeutic strategy for treatment of AD.
- Bhattarai, Deepak,Lee, Min Jae,Baek, Ahruem,Yeo, In Jun,Miller, Zachary,Baek, Yu Mi,Lee, Sukyeong,Kim, Dong-Eun,Hong, Jin Tae,Kim, Kyung Bo
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p. 3763 - 3783
(2020/04/30)
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- Preparation method of carfilzomib
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The invention relates to a preparation method of carfilzomib, which comprises the following steps of: by using a compound represented by a formula I as an intermediate, carrying out deprotection, andreacting with a compound represented by a formula IV to prepare carfilzomib. The preparation method of the compound shown in the formula I comprises the following steps of: taking hydrogen peroxide asan oxidizing agent, and preparing a carfilzomib intermediate, namely the compound shown in the formula I, through selective epoxidation of a chiral organic catalyst. The preparation method disclosedby the invention is simple in reaction condition, simple and convenient to operate, good in asymmetric selectivity, good in yield, high in purity and suitable for industrial production.
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Paragraph 0019-0046
(2020/09/21)
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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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- Tripeptide analogues of MG132 as protease inhibitors
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The 26S proteasome and calpain are linked to a number of important human diseases. Here, we report a series of analogues of the prototypical tripeptide aldehyde inhibitor MG132 that show a unique combination of high activity and selectivity for calpains over proteasome. Tripeptide aldehydes (1–3) with an aromatic P3 substituent show enhanced activity and selectivity against ovine calpain 2 relative to chymotrypsin-like activity of proteasome. Docking studies reveal the key contacts between inhibitors and calpain to confirm the importance of the S3 pocket with respect to selectivity between calpains 1 and 2 and the proteasome.
- Pehere, Ashok D.,Nguyen, Steven,Garlick, Sarah K.,Wilson, Danny W.,Hudson, Irene,Sykes, Matthew J.,Morton, James D.,Abell, Andrew D.
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p. 436 - 441
(2019/01/04)
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- Covalent docking modelling-based discovery of tripeptidyl epoxyketone proteasome inhibitors composed of aliphatic-heterocycles
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The potential of specific proteasome inhibitors to act as anti-cancer agents has attracted intensive investigations. The proteasome can be covalently inhibited by epoxyketone derivatives via a two-step reaction. Several computational approaches have been developed to mimic the covalent binding event. Compound 1 composed of a six-membered heterocyclic ring was designed by using covalent docking. With a possible different binding mode from the clinical compound Carfilzomib, it occupied the S5 pocket of 20S proteasome and showed favorable inhibitory activity. Subsequently optimization and evaluation were taken place. Among these compounds, 11h demonstrated extraordinary in vitro inhibitory activity and selectivity, and good in vivo proteasome inhibitory activity, a favorable pharmacokinetic profile and xenograft tumor inhibition. The possible binding pattern of compound 11h against proteasome was further fully explored via calculations, providing a theoretical basis for finding potent proteasome inhibitors.
- Dong, Xiao-Wu,Zhang, Jian-Kang,Xu, Lei,Che, Jin-Xin,Cheng, Gang,Hu, Xiao-Bei,Sheng, Li,Gao, An-Hui,Li, Jia,Liu, Tao,Hu, Yong-Zhou,Zhou, Yu-Bo
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p. 602 - 614
(2019/01/11)
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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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Page/Page column 18; 19
(2018/06/22)
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- Method for synthesizing carfilzomib intermediates
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The invention discloses a method for synthesizing carfilzomib intermediates. The method includes carrying out epoxidation reaction on compounds II or salt and acid of the compounds II and oxidizing agents in solvents under the condition of the presence of catalysts so as to generate compounds I or salt of the compounds I. The structures of the compounds I and the compounds II are shown as formulas, and an R in the formulas represents amino protecting groups. Compared with the prior art, the method for synthesizing the carfilzomib intermediates has the advantages that the reaction selectivity can be obviously improved, the yield can be obviously increased, and the method is economical and environmentally friendly and is high in efficiency.
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Page/Page column 6-9; 10; 11; 12; 13
(2018/09/12)
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- The card must assists the rice key intermediate and its derivatives
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The invention belongs to the technical field of compound preparation, and more specifically relates to a carfilzomib key intermediate [(1S)-3-methyl-1-[[(2R)-2-methyloxiranyl]carbonyl]butyl]-carbamate and a preparation method of its derivative. The method takes a compound E as a raw material, the compound E is dissolved by a solvent and is reacted with diisopropylethylaine and pyridine, after complete reaction, a reaction product is purified to obtain a product F; the concrete reaction processes are shown in a following specification: wherein, R1 is selected from C1-6 alkyl or C6-10 aryl C1-6 alkyl; R2 is tertbutyloxycarbonyl (Boc) or benzyloxycarbonyl (Cbz). According to the invention, operation condition for all the steps is mild, the used reagents are conventional reagents which have the advantages of low cost, high yield, and little environmental pollution, and the key intermediate is adapted to large scale industrial production.
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- A [(1S) - 3 - methyl - 1 - [[ (2R) - 2 - methyl epoxy ethyl] carbonyl] butyl] carbamic acid tert-butyl preparation method
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The invention relates to a preparation method of a carfilzomib intermediate: [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate. The preparation method comprises the following step: adding triphenylphosphine and tert-butyl alcohol hydroperoxide to a compound (III) to carry out catalytic reaction in the presence of an asymmetric chiral catalyst (R)-La-BINOL. The compound (III) is shown in a formula in the specification. The carfilzomib intermediate (I) can be synthesized with a starting material (III) by adopting the preparation method. The preparation method is accessible in used raw materials and simple in reaction conditions, is simple and convenient to operate, is simple in aftertreatment, has good selectivity, is good in yield and is suitable for industrial production.
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Paragraph 0024; 0025; 0027-0043
(2017/11/01)
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- A [(1S) - 3 - methyl - 1 - [[ (2R) - 2 - methyl epoxy ethyl] carbonyl] butyl] carbamic acid tert-butyl chiral preparation method
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The invention relates to a chiral preparation method of a carfilzomib intermediate: [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate. The preparation method comprises the step that a compound (III) carries out catalytic reaction with a phase transfer catalyst (PTC) and hydrogen peroxide under alkaline conditions. The compound (III) is shown in a formula in the specification. The carfilzomib intermediate (I) can be synthesized with a starting material (III) by adopting the preparation method. The preparation method is available in used raw materials and simple in reaction conditions, is simple and convenient to operate, is simple in aftertreatment, has good selectivity, is good in yield and is suitable for industrial production.
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Paragraph 0010; 0031-0034; 0036-0041; 0052-0057; 0070-0073
(2017/04/07)
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- An efficient preparation of novel epoxyketone intermediates for the synthesis of carfilzomib and its derivatives
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A novel and efficient preparation of epoxyketone intermediates for the synthesis of carfilzomib and its derivatives has been developed. Compared to reported methods, this highly stereoselective, environmentally friendly, low-cost method can be used in scaling up the synthesis of carfilzomib and its derivatives.
- Du, Xiao,Zhang, Hao-Yang,Lei, Meng,Li, Zi-Yuan,Zhu, Yong-Qiang
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- PROCESS FOR THE PREPARATION OF (2S)-N-((S)-1-((S)-4-METHYL-1-((R)-2-METHYL OXIRAN-2-YL)-1-OXOPENTAN-2-YLCARBAMOYL)-2-PHENYLETHYL)-2-((S)-2-(2-MORPHOLINO ACETAMIDO)-4-PHENYLBUTANAMIDO)-4-METHYLPENTANAMIDE
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The present invention relates to process for the preparation of (2S)-N-((S)-l -((S)-4-methyl-1 -((R)-2-methyloxiran-2-yl)-1-oxopentan-2-ylcarbamoyl)-2-phenylethyl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-4 -methylpentanamide represented by the following structural formula-1.
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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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- 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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Paragraph 0533; 0534
(2016/10/27)
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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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- 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 22-27
(2014/01/17)
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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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- Design, synthesis and biological evaluation of novel tripeptidyl epoxyketone derivatives constructed from β-amino acid as proteasome inhibitors
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A series of novel tripeptidyl epoxyketone derivatives constructed from β-amino acid were designed, synthesized and evaluated as proteasome inhibitors. All target compounds were tested for their proteasome inhibitory activities and selected compounds were tested for their anti-proliferation activities against two multiple myeloma (MM) cell lines RPMI 8226 and NCI-H929. Among them, eleven compounds exhibited proteasome inhibitory rates of more than 50% at the concentration of 1 μg/mL and nine compounds showed anti-proliferation activities with IC50 values at low micromolar level. Compound 20h displayed the most potent proteasome inhibitory activities (IC50: 0.11 ± 0.01 μM) and anti-proliferation activities with IC50 values at 0.23 ± 0.01 and 0.17 ± 0.02 μM against two tested cell lines. Additionally, the poly-ubiquitin accumulation in the western blot analysis supported that proteasome inhibition in a cellular system was induced by compound 20h. All these experimental results confirmed that β-amino acid can be introduced as a building block for the development of proteasome inhibitors.
- Zhang, Jiankang,Cao, Jiayi,Xu, Lei,Zhou, Yubo,Liu, Tao,Li, Jia,Hu, Yongzhou
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p. 2955 - 2965
(2014/05/20)
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- Enzyme inhibition by hydroamination: Design and mechanism of a hybrid carmaphycin-syringolin enone proteasome inhibitor
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Hydroamination reactions involving the addition of an amine to an inactivated alkene are entropically prohibited and require strong chemical catalysts. While this synthetic process is efficient at generating substituted amines, there is no equivalent in small molecule-mediated enzyme inhibition. We report an unusual mechanism of proteasome inhibition that involves a hydroamination reaction of alkene derivatives of the epoxyketone natural product carmaphycin. We show that the carmaphycin enone first forms a hemiketal intermediate with the catalytic Thr1 residue of the proteasome before cyclization by an unanticipated intramolecular alkene hydroamination reaction, resulting in a stable six-membered morpholine ring. The carmaphycin enone electrophile, which does not undergo a 1,4-Michael addition as previously observed with vinyl sulfone and α,β-unsaturated amide-based inhibitors, is partially reversible and gives insight into the design of proteasome inhibitors for cancer chemotherapy.
- Trivella, Daniela B.B.,Pereira, Alban R.,Stein, Martin L.,Kasai, Yusuke,Byrum, Tara,Valeriote, Frederick A.,Tantillo, Dean J.,Groll, Michael,Gerwick, William H.,Moore, Bradley S.
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p. 782 - 791
(2014/07/07)
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- METHODS OF PROMOTING NEURON GROWTH
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The present invention provides methods to treat, prevent, reverse and/or ameliorate a neurodegenerative disease or condition by partially or completely inhibiting a chymotrypsin-like protease or a proteasome activity.
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- The Carmaphycins: New Proteasome Inhibitors Exhibiting an α,β-Epoxyketone Warhead from a Marine Cyanobacterium
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Two new peptidic proteasome inhibitors were isolated as trace components from a Curacao collection of the marine cyanobacterium Symploca sp. Carmaphycin A (1) and carmaphycin B (2) feature a leucine-derived α,β-epoxyketone warhead directly connected to either methionine sulfoxide or methionine sulfone. Their structures were elucidated on the basis of extensive NMR and MS analyses and confirmed by total synthesis, which in turn provided more material for further biological evaluations. Pure carmaphycins A and B were found to inhibit the β5 subunit (chymotrypsin-like activity) of the S. cerevisiae 20S proteasome in the low nanomolar range. Additionally, they exhibited strong cytotoxicity to lung and colon cancer cell lines, as well as exquisite antiproliferative effects in the NCI60 cell-line panel. These assay results as well as initial structural biology studies suggest a distinctive binding mode for these new inhibitors.
- Pereira, Alban R.,Kale, Andrew J.,Fenley, Andrew T.,Byrum, Tara,Debonsi, Hosana M.,Gilson, Michael K.,Valeriote, Frederick A.,Moore, Bradley S.,Gerwick, William H.
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p. 810 - 817
(2012/07/28)
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- Manganese catalysts with C1-symmetric N4 ligand for enantioselective epoxidation of olefins
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Bioinspired manganese complexes based on N4 ligands, with a more rigid, chiral diamine derived from proline and two benzimidazoles, were synthesized and applied to epoxidize olefins with hydrogen peroxide as a clean oxidant. Notably, 60-99 % isolated yields and excellent ee values (up to 95 %) were obtained by using low catalyst loadings (0.01-0.2 mol %; see scheme; F green, S yellow). Copyright
- Wang, Bin,Miao, Chengxia,Wang, Shoufeng,Xia, Chungu,Sun, Wei
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supporting information; experimental part
p. 6750 - 6753
(2012/07/03)
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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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- Enzyme inhibition
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Peptide-based compounds including heteroatom-containing, three-membered rings efficiently and selectively inhibit specific activities of N-terminal nucleophile (Ntn) hydrolases. The activities of those Ntn having multiple activities can be differentially inhibited by the compounds described. For example, the chymotrypsin-like and PGPH activities of the 20S proteasome can be selectively inhibited with the inventive compounds. The peptide-based compounds include an electron withdrawing group adjacent to the ring functionality, and the peptide include at least three peptide units. Among other therapeutic utilities, the peptide-based compounds exhibit anti-inflammatory and inhibition of cell proliferation, involving therapeutic applications for these compounds.
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Page column 14, 16
(2008/06/13)
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- Total synthesis of the potent proteasome inhibitor epoxomicin: A useful tool for understanding proteasome biology
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Epoxomicin (1), a peptide α',β'-epoxyketone isolated from the actinomycete strain No. Q996-17, possesses potent in vivo anti-tumor and anti-inflammatory activities. In this paper, we report the first syntheses of epoxomicin, [3H]-epoxomicin, and a biotinylated epoxomicin analog as well as the absolute configuration of the epoxide stereocenter. The natural product and derivatives have permitted the first identification of the proteasome as the specific cellular target of epoxomicin.
- Sin, Ny,Kyung, Bo Kim,Elofsson, Mikael,Meng, Lihao,Auth, Hak,Kwok, Benjamin H. B.,Crews, Craig M.
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p. 2283 - 2288
(2007/10/03)
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