87694-50-6Relevant academic research and scientific papers
A Flavin-Dependent Decarboxylase-Dehydrogenase-Monooxygenase Assembles the Warhead of α,β-Epoxyketone Proteasome Inhibitors
Zabala, Daniel,Cartwright, Joshua W.,Roberts, Douglas M.,Law, Brian J. C.,Song, Lijiang,Samborskyy, Markiyan,Leadlay, Peter F.,Micklefield, Jason,Challis, Gregory L.
, p. 4342 - 4345 (2016)
The α,β-epoxyketone proteasome inhibitor TMC-86A was discovered as a previously unreported metabolite of Streptomyces chromofuscus ATCC49982, and the gene cluster responsible for its biosynthesis was identified via genome sequencing. Incorporation experiments with [13C-methyl]l-methionine implicated an α-dimethyl-β-keto acid intermediate in the biosynthesis of TMC-86A. Incubation of the chemically synthesized α-dimethyl-β-keto acid with a purified recombinant flavin-dependent enzyme that is conserved in all known pathways for epoxyketone biosynthesis resulted in formation of the corresponding α-methyl-α,β-epoxyketone. This transformation appears to proceed via an unprecedented decarboxylation-dehydrogenation-monooxygenation cascade. The biosynthesis of the TMC-86A warhead is completed by cytochrome P450-mediated hydroxylation of the α-methyl-α,β-epoxyketone.
Structure–activity relationship study of hydroxyethylamine isostere and P1′ site structure of peptide mimetic BACE1 inhibitors
Kobayashi, Kazuya,Otani, Takuya,Ijiri, Saki,Kawasaki, Yuki,Matsubara, Hiroki,Miyagi, Takahiro,Kitajima, Taishi,Iseki, Risa,Ishizawa, Katsuyasu,Shindo, Naoka,Okawa, Kouta,Ueda, Kouta,Ando, Syun,Kawakita, Momoka,Hattori, Yasunao,Akaji, Kenichi
, (2021/10/27)
An aromatic substituent has been introduced into a known hydroxyethylamine (HEA)-type BACE1 inhibitor containing the superior substrate sequence to enhance inhibitory activity. The HEA-type isosteres bearing different hydroxyl group and methyl group confi
Synthesis and Structure-Activity Relationship of Xenocoumacin 1 and Analogues as Inhibitors of Ribosomal Protein Synthesis
Zumbrunn, Cornelia,Krüsi, Daniela,Stamm, Christina,Caspers, Patrick,Ritz, Daniel,Rueedi, Georg
supporting information, p. 891 - 897 (2020/12/15)
Ribosomal protein synthesis is an important target in antibacterial drug discovery. Numerous natural products have served as starting points for the development of antibiotics. We report here the total synthesis of xenocoumacin 1, a natural product that binds to 16S ribosomal RNA at a highly conserved region, as well as analogues thereof. Preliminary structure–activity relationship studies were aimed at understanding and modulating the selectivity between eukaryotic and prokaryotic ribosomes. Modifications were mainly tolerated in the aromatic region. Whole-cell activity against Gram-negative bacteria is limited by efflux and penetration, as demonstrated in genetically modified strains of E. coli. Analogues with high selectivity for eukaryotic ribosomes were identified, but it was not possible to obtain inhibitors selective for bacterial protein synthesis. Achieving high selectivity (albeit not the desired one) was thus possible despite the high homology between eukaryotic and prokaryotic ribosomes in the binding region.
Preparation method of carfilzomib intermediate
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Paragraph 0095-0097, (2021/08/06)
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.
Probing α-Amino Aldehydes as Weakly Acidic Pronucleophiles: Direct Access to Quaternary α-Amino Aldehydes by an Enantioselective Michael Addition Catalyzed by Br?nsted Bases
García-Urricelqui, Ane,de Cózar, Abel,Mielgo, Antonia,Palomo, Claudio
supporting information, p. 2483 - 2492 (2020/12/25)
The high tendency of α-amino aldehydes to undergo 1,2-additions and their relatively low stability under basic conditions have largely prevented their use as pronucleophiles in the realm of asymmetric catalysis, particularly for the production of quaternary α-amino aldehydes. Herein, it is demonstrated that the chemistry of α-amino aldehydes may be expanded beyond these limits by documenting the first direct α-alkylation of α-branched α-amino aldehydes with nitroolefins. The reaction produces densely functionalized products bearing up to two, quaternary and tertiary, vicinal stereocenters with high diastereo- and enantioselectivity. DFT modeling leads to the proposal that intramolecular hydrogen bonding between the NH group and the carbonyl oxygen atom in the starting α-amino aldehyde is key for reaction stereocontrol.
Macrocyclic Immunoproteasome Inhibitors as a Potential Therapy for Alzheimer's Disease
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
, p. 10934 - 10950 (2021/08/20)
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.
Discovery of novel tripeptide propylene oxide proteasome inhibitors for the treatment of multiple myeloma
Zhang, Wen,Wang, Xueyuan,Zhang, Haoyang,Wen, Tiantian,Yang, Lin,Miao, Hang,Wang, Jia,Liu, Hailong,Yang, Xu,Lei, Meng,Zhu, Yongqiang
supporting information, (2021/05/13)
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.
Continuous Process Improvement in the Manufacture of Carfilzomib, Part 1: Process Understanding and Improvements in the Commercial Route to Prepare the Epoxyketone Warhead
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.
, p. 481 - 489 (2020/04/10)
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).
LMP2 Inhibitors as a Potential Treatment for Alzheimer's Disease
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
, p. 3763 - 3783 (2020/04/30)
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.
Structurally Diverse Acyl Bicyclobutanes: Valuable Strained Electrophiles
Attard, Riley H.,Gardiner, Michael G.,Malins, Lara R.,Schwartz, Brett D.,Zhang, Meng Yao
supporting information, p. 2808 - 2812 (2020/03/04)
Bicyclo[1.1.0]butanes (BCBs) are highly strained carbocycles that have emerged as versatile synthetic tools, particularly for the construction of functionalized small molecules. This work reports two efficient pathways for the rapid preparation of over 20 structurally diverse BCB ketones, encompassing simple alkyl and aryl derivatives, as well as unprecedented amino acid, dipeptide, bioisostere, and bifunctional linchpin reagents currently inaccessible using literature methods. Analogues are readily forged in two steps and in high yields from simple carboxylic acids or through unsymmetrical ketone synthesis beginning with a convenient carbonyl dication equivalent. The utility of this novel toolbox of strained electrophiles for the selective modification of proteinogenic nucleophiles is highlighted.
