167479-01-8Relevant academic research and scientific papers
RAS PROTEIN DEGRADERS, PHARMACEUTICAL COMPOSITIONS THEREOF, AND THEIR THERAPEUTIC APPLICATIONS
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Paragraph 0263, (2021/03/19)
Provided herein are RAS protein degraders, e.g., a compound of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a RAS-mediated disorder, disease, or condition.
Novel BQCA- and TBPB-Derived M1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism
Schramm, Simon,Agnetta, Luca,Bermudez, Marcel,Gerwe, Hubert,Irmen, Matthias,Holze, Janine,Littmann, Timo,Wolber, Gerhard,Tr?nkle, Christian,Decker, Michael
supporting information, p. 1349 - 1358 (2019/07/12)
Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein-coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1-(1′-(2-tolyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one] as M1-selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M1 positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy.
Evaluation of Nitrosamide Formation in the Cytochrome P450-Mediated Metabolism of Tobacco-Specific Nitrosamines
Carlson, Erik S.,Upadhyaya, Pramod,Hecht, Stephen S.
, p. 2194 - 2205 (2016/12/26)
N′-Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are carcinogenic tobacco-specific nitrosamines believed to play a vital role in the initiation of tobacco-related cancers. For their carcinogenicities to be exhibited, both NNN and NNK must be metabolically activated by cytochrome P450s, specifically P450 2A6 and P450 2A13, respectively. Prior research has focused on α-hydroxylation, which leads to the formation of several DNA adducts that have been identified and quantified in vivo. However, some studies indicate that P450s can retain substrates within their active sites and perform processive oxidation. For nitrosamines, this would oxidize the highly unstable α-hydroxynitrosamines to potentially more stable nitrosamides, which could also alkylate DNA. Thus, we hypothesized that both NNN and NNK are processively oxidized in vitro to nitrosamides by P450 2A6 and P450 2A13, respectively. To test this hypothesis, we synthesized the NNN- and NNK-derived nitrosamides, determined their half-lives at pH 7.4 and 37 °C, and monitored for nitrosamide formation in an in vitro P450 system with product analysis by LC/NSI+-HRMS/MS. Half-lives of the nitrosamides were determined by HPLC-UV and ranged from 7-35 min, which is more than 40 times longer than the corresponding α-hydroxynitrosamines. Incubation of NNN in the P450 2A6 system resulted in the formation of the nitrosamide N′-nitrosonorcotinine (NNC) at low levels. Similarly, the nitrosamide 4-(methylnitrosamino)-1-(3-pyridyl)-1,4-butanedione (CH2-oxo-NNK) was detected in low amounts in the incubation of NNK with the P450 2A13 system. The other possible NNK-derived nitrosamide, 4-(nitrosoformamido)-1-(3-pyridyl)-1-butanone (CH3-oxo-NNK), was not observed in the P450 2A13 reactions. CH2-oxo-NNK readily formed O6meGua in reactions with dGuo and calf thymus DNA. These results demonstrate that NNC and CH2-oxo-NNK are novel metabolites of NNN and NNK, respectively. Though low-forming, their increased stability may allow for mutagenic DNA damage in vivo. More broadly, this study provides the first account of a cytochrome P450-mediated conversion of nitrosamines to nitrosamides, which warrants further studies to determine how general this phenomenon is in nitrosamine metabolism.
Synthesis of fluorescent molecular probes based on cis-cinnamic acid and molecular imaging of lettuce roots
Fukuda, Hiroshi,Nishikawa, Keisuke,Fukunaga, Yukihiro,Okuda, Katsuhiro,Kodama, Kozue,Matsumoto, Kenji,Kano, Arihiro,Shindo, Mitsuru
supporting information, p. 6492 - 6498 (2016/09/23)
We synthesized azo dye- and fluorescence-labeled cis-cinnamic acid analogues possessing inhibitory activity against lettuce root growth and a trans-isomer without bioactivity as a control probe. The radicles incubated with the azo dye-labeled analogue were stained red, with their tips especially deeply dyed. The fluorescent images of the radicles incubated with each of these molecular probes depicted that the root cap was fluorescence-stained. However, images of the control radicles prepared by staining with the trans-isomer fluorescent probe did not show emission at the root cap. These contrasts suggest specific localization of the cis-cinnamate analogue at the columella cells.
Light-mediated deoxygenation of alcohols with a dimeric gold catalyst
McCallum, Terry,Slavko, Ekaterina,Morin, Mathieu,Barriault, Louis
supporting information, p. 81 - 85 (2015/02/18)
A new protocol for the reductive deoxygenation of primary alcohols was explored. This photo-mediated method combines a novel approach to bromination of alcohols merged with the powerful reducing capability of [Au2(dppm)2]Cl2 [dppm = 1,1-bis(diphenylphosphino)methane] as a photoredox catalyst. The highly efficient methods discussed are marked by the use of UVA light-emitting diodes, which have significantly reduced reaction times and lowered setup cost.
Toward encoding reactivity using double-stranded DNA. Sequence-dependent native chemical ligation of DNA binding polyamides
Jiménez-Balsa, Adrian,Dodero, Verónica I.,Mascare?as, José L.
supporting information, p. 7847 - 7853 (2013/08/23)
The coupling reaction between distamycin-related polyamides equipped with cysteine and thioester groups can be accelerated in the presence of double-stranded (ds) oligonucleotides with selected sequences. While the coupling reaction of reactive partners containing three pyrrole units is accelerated by dsDNAs containing ATTTTA or ATGTTA sites, the heterodimeric coupling between a tripyrrole and a polyamide equipped with two pyrroles and one imidazole, is accelerated by the latter DNA, but not by the other containing the A/T rich tract. These differences can be exploited for selecting preferred coupling pairs from a mixture of reactive monomers; therefore the reaction outcome depends on the instructions provided by the dsDNA sequence.
Cascade formation of isoxazoles: Facile base-mediated rearrangement of substituted oxetanes
Burkhard, Johannes A.,Tchitchanov, Boris H.,Carreira, Erick M.
supporting information; experimental part, p. 5379 - 5382 (2011/07/08)
Give me five! Nitro compounds and oxetan-3-one react through an intriguing cascade sequence to give isoxazole-4-carbaldehydes using inexpensive reagents in a one-pot procedure (see scheme; Ms=methanesulfonyl). A variety of 3-substituted isoxazole-4-carbaldehydes were obtained in high overall yields.
Targeting multiple chorismate-utilizing enzymes with a single inhibitor: Validation of a three-stage design
Ziebart, Kristin T.,Dixon, Seth M.,Avila, Belem,El-Badri, Mohamed H.,Guggenheim, Kathryn G.,Kurth, Mark J.,Toney, Michael D.
scheme or table, p. 3718 - 3729 (2010/07/16)
Chorismate-utilizing enzymes are attractive antimicrobial drug targets due to their absence in humans and their central role in bacterial survival and virulence. The structural and mechanistic homology of a group of these inspired the goal of discovering inhibitors that target multiple enzymes. Previously, we discovered seven inhibitors of 4-amino-4-deoxychorismate synthase (ADCS) in an on-bead, fluorescent-based screen of a 2304-member one-bead-one-compound combinatorial library. The inhibitors comprise PAYLOAD and COMBI stages, which interact with active site and surface residues, respectively, and are linked by a SPACER stage. These seven compounds, and six derivatives thereof, also inhibit two other enzymes in this family, isochorismate synthase (IS) and anthranilate synthase (AS). The best binding compound inhibits ADCS, IS, and AS with K i values of 720, 56, and 80 μM, respectively. Inhibitors with varying SPACER lengths show the original choice of lysine to be optimal. Lastly, inhibition data confirm the PAYLOAD stage directs the inhibitors to the ADCS active site.
Thiomaleic anhydride: A convenient building block for the synthesis of α-substituted γ- and δ-lactones through free-radical addition, nucleophilic ring opening, and subsequent thiocarboxylate manipulation
Crich, David,Rahaman, Md. Yeajur
supporting information; experimental part, p. 6792 - 6796 (2009/12/31)
(Chemical Equation Presented) Iodoalkyl tert-butyl carbonates and carbamates undergo clean free-radical addition to thiomaleic anhydride to give substituted thiosuccinic anhydrides in high yield on treatment with tris-(trimethylsilyl)silane and a radical initiator. After removal of the tert-butyloxycarbonyl group, cyclization then affords lactones or lactams substituted in the α-position by a thiocarboxylic acid residue. This group is converted to amides through reaction with electron-deficient sulfonamides or to aldehydes and/or ketones by the reaction of derived thioesters with either thiophenol, an electron-deficient allyl phenyl sulfide, or phenylboronic acid.
Selective conversion of alcohols into alkyl iodides using a thioiminium salt
Ellwood, Adam R.,Porter, Michael J.
supporting information; experimental part, p. 7982 - 7985 (2010/02/28)
(Chemical Equation Presented) Treatment of a range of primary and secondary alcohols with MeSCH=NMe2+ I- affords the corresponding alkyl iodides in excellent yield with straightforward purification. Selective formation of a primary iodide in the presence of a secondary alcohol can be achieved.
