Tosh DK, Salmaso V, Rao H
… +5 more, Campbell R, Bitant A, Gao ZG, Auchampach JA, Jacobson KA
ACS Med Chem Lett
· 2020 Oct · PMID 33062176
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A side-by-side pharmacological comparison of ribose and (N)-methanocarba (bicyclo[3.1.0]hexane) nucleosides as AAR agonists indicated that the bicyclic pseudoribose ring constraint provided higher affinity/selectivity at...A side-by-side pharmacological comparison of ribose and (N)-methanocarba (bicyclo[3.1.0]hexane) nucleosides as AAR agonists indicated that the bicyclic pseudoribose ring constraint provided higher affinity/selectivity at human and mouse AAR. The mean affinity enhancement for 5 pairs of 5'-methylamides was 11-fold at hAAR and 42-fold at mAAR. Novel C2-(5-fluorothien-2-ylethynyl) substitution enhanced affinity in the methanocarba but not ribose series, with highly hAAR-selective (MRS7334) displaying K 280 pM and favorable pharmacokinetics and off-target activity profile. Molecular dynamics comparison of and its corresponding riboside suggested a qualitative entropic advantage of in hAAR binding. The 5-F substitution tended to increase hAAR affinity (cf. 5-Cl) for methanocarba but not ribose derivatives. A representative methanocarba agonist was shown to interact potently exclusively with AAR, among 240 GPCRs and 466 kinases. Thus, despite added synthetic difficulty, the (N)-methanocarba modification has distinct advantages for AAR agonists, which have translational potential for chronic disease treatment.
Gao H, Wu Y, Sun Y
… +3 more, Yang Y, Zhou G, Rao Y
ACS Med Chem Lett
· 2020 Oct · PMID 33062164
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Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, exerts kinase-dependent enzymatic functions and kinase-independent scaffolding functions, both of which are crucial in cancer development, early embryon...Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase, exerts kinase-dependent enzymatic functions and kinase-independent scaffolding functions, both of which are crucial in cancer development, early embryonic development, and reproduction. However, previous efforts for FAK blocking mainly focus on kinase inhibitors. Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that allow direct post-translational knockdown of proteins via ubiquitination of a target protein by E3 ubiquitin ligase and subsequent proteasomal degradation. Here, we designed and synthesized a FAK PROTAC library with FAK inhibitor (PF562271 or VS6063) and CRBN E3 ligand. A novel FAK-targeting PROTAC, FC-11, showed a rapid and reversible FAK degradation with a picomolar of DC in various cell lines in vitro, which imply that FAK-PROTACs could be useful as expand tools for studying functions of FAK in biological system and as potential therapeutic agents.
Mufti F, Jung YH, Giancotti LA
… +5 more, Yu J, Chen Z, Phung NB, Jacobson KA, Salvemini D
ACS Med Chem Lett
· 2020 Jun · PMID 32551012
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Eight P2YR antagonists, including three newly synthesized analogues, containing a naphthalene or phenyl-triazolyl scaffold were compared in a mouse model of chronic neuropathic pain (sciatic constriction). P2YR antagonis...Eight P2YR antagonists, including three newly synthesized analogues, containing a naphthalene or phenyl-triazolyl scaffold were compared in a mouse model of chronic neuropathic pain (sciatic constriction). P2YR antagonists rapidly (≤30 min) reversed mechano-allodynia, with maximal effects typically within 1 h after injection. Two analogues (4-[4-(4-piperidinyl)phenyl]-7-[4-(trifluoromethyl)phenyl]-2-naphthalenecarboxylic acid and -acetyl analogue , 10 μmol/kg, i.p.) achieved complete pain reversal (100%) at 1 to 2 h, with relief evident up to 5 h for (41%). A reversed triazole analogue reached 87% maximal protection. Receptor affinity was determined using a fluorescent antagonist binding assay, indicating similar mouse and human P2YR affinity. The mP2YR affinity was only partially predictive of efficacy, suggesting the influence of pharmacokinetic factors. Thus P2YR is a potential therapeutic target for treating chronic pain.
ACS Med Chem Lett
· 2020 Mar · PMID 32184950
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PROTACs-induced targeted protein degradation has emerged as a novel therapeutic strategy in drug development and attracted the favor of academic institutions, large pharmaceutical enterprises (e.g., AstraZeneca, Bayer, N...PROTACs-induced targeted protein degradation has emerged as a novel therapeutic strategy in drug development and attracted the favor of academic institutions, large pharmaceutical enterprises (e.g., AstraZeneca, Bayer, Novartis, Amgen, Pfizer, GlaxoSmithKline, Merck, and Boehringer Ingelheim, etc.), and biotechnology companies. PROTACs opened a new chapter for novel drug development. However, any new technology will face many new problems and challenges. Perspectives on the potential opportunities and challenges of PROTACs will contribute to the research and development of new protein degradation drugs and degrader tools.
Zhang Y, Tangadanchu VKR, Cheng Y
… +3 more, Yang RG, Lin JM, Zhou CH
ACS Med Chem Lett
· 2018 Mar · PMID 29541368
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A series of isopropanol-bridged carbazole azoles as potential antimicrobial agents were designed and synthesized from commercial carbazoles. Bioassay revealed that 3,6-dichlorocarbazolyl triazole could effectively inhib...A series of isopropanol-bridged carbazole azoles as potential antimicrobial agents were designed and synthesized from commercial carbazoles. Bioassay revealed that 3,6-dichlorocarbazolyl triazole could effectively inhibit the growth of with minimal inhibitory concentration of 2 μg/mL. The active molecule showed lower propensity to trigger the development of resistance in bacteria than norfloxacin and exerted rapidly bactericidal ability. Compound also exhibited low cytotoxicity to normal mammalian RAW264.7 cells. Further mechanism exploration indicated that conjugate was membrane active against and could form -DNA complex by intercalating into DNA of resistant , which might be responsible for its antimicrobial action. Molecular docking showed an efficient binding of triazole derivative with DNA gyrase enzyme through noncovalent interactions.
Chen YY, Gopala L, Bheemanaboina RRY
… +4 more, Liu HB, Cheng Y, Geng RX, Zhou CH
ACS Med Chem Lett
· 2017 Dec · PMID 29259757
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A series of novel naphthalimide aminothiazoles were developed for the first time and evaluated for their antimicrobial activity. Some prepared compounds possessed good inhibitory activity against the tested bacteria and...A series of novel naphthalimide aminothiazoles were developed for the first time and evaluated for their antimicrobial activity. Some prepared compounds possessed good inhibitory activity against the tested bacteria and fungi. Noticeably, the piperazine derivative displayed superior antibacterial activity against MRSA and with MIC values of 4 and 8 μg/mL, respectively, to reference drugs. The most active compound showed low toxicity against mammalian cells with no obvious triggering of the development of bacterial resistance, and it also possessed rapid bactericidal efficacy and efficient membrane permeability. Preliminarily investigations revealed that compound could not only bind with gyrase-DNA complex through hydrogen bonds but could effectively intercalate into MRSA DNA to form -DNA supramolecular complex, which might be responsible for the powerful bioactivity. Further transportation behavior evaluation indicated that molecule could be effectively stored and carried by human serum albumin, and the hydrophobic interactions and hydrogen bonds played important roles in the binding process.
Janssens J, Decruy T, Venken K
… +6 more, Seki T, Krols S, Van der Eycken J, Tsuji M, Elewaut D, Van Calenbergh S
ACS Med Chem Lett
· 2017 Jun · PMID 28626526
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A synthesis strategy for the swift generation of 4″-modified α-galactosylceramide (α-GalCer) analogues is described, establishing a chemical platform to comprehensively investigate the structure-activity relationships (S...A synthesis strategy for the swift generation of 4″-modified α-galactosylceramide (α-GalCer) analogues is described, establishing a chemical platform to comprehensively investigate the structure-activity relationships (SAR) of this understudied glycolipid part. The strategy relies on a late-stage reductive ring-opening of a -methoxybenzylidene (PMP) acetal to regioselectively liberate the 4″-OH position. The expediency of this methodology is demonstrated by the synthesis of a small yet diverse set of analogues, which were tested for their ability to stimulate invariant natural killer T-cells (NKT) and . The introduction of a -chlorobenzyl ether yielded an analogue with promising immunostimulating properties, paving the way for further SAR studies.
Amin H, Wani NA, Farooq S
… +7 more, Nayak D, Chakraborty S, Shankar S, Rasool RU, Koul S, Goswami A, Rai R
ACS Med Chem Lett
· 2015 Oct · PMID 26487914
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The present work describes the anti-invasive effect of conjugate BC06, a novel conjugate of EPA, (2E,4E)-4-(benzo[d][1,3]dioxol-5-ylmethylene) hex-2-enoic acid with β,β-disubstituted-β-amino acid, β(3,3)-Pip-OH (2-(4-ami...The present work describes the anti-invasive effect of conjugate BC06, a novel conjugate of EPA, (2E,4E)-4-(benzo[d][1,3]dioxol-5-ylmethylene) hex-2-enoic acid with β,β-disubstituted-β-amino acid, β(3,3)-Pip-OH (2-(4-aminopiperidin-4-yl)acetic acid), in human pancreatic carcinoma. The conjugate BC06 inhibited invasion and migration of PANC-1 cells in wound healing, matrigel invasion, and gelatin degradation assays. Apart from suppressing PI3K/Akt/NF-kB signaling, which is involved in the up-regulation of matrix metalloproteinases, our study also demonstrated that dose-dependent treatment of BC06 results in the upregulation of TIMP-1 and E-cadherin expression. Further, BC06 was found to be inhibiting the metastatic ability of PANC-1 cells by reducing MMP-2 and MMP-9 expression. These findings suggest that EPA conjugate with β(3,3)-Pip-OH, BC06, may be used as an anti-invasive agent against human pancreatic carcinoma.
Tosh DK, Crane S, Chen Z
… +6 more, Paoletta S, Gao ZG, Gizewski E, Auchampach JA, Salvemini D, Jacobson KA
ACS Med Chem Lett
· 2015 Jul · PMID 26191370
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Substitution of rigidified A3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic...Substitution of rigidified A3 adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in place of ribose, which adopts a receptor-preferred conformation. N (6)-Small alkyl derivatives were newly optimized for A3AR affinity and the effects of a 1-deaza-adenine modification probed. 1-Deaza-N (6)-ethyl alkyne 20 (MRS7144, K i 1.7 nM) and 1-aza N (6)-propyl alkyne 12 (MRS7154, K i 1.1 nM) were highly efficacious in vivo. Thus, the presence of N1 is not required for nanomolar binding affinity or potent, long-lasting functional activity. Docking of 1-deaza compounds to a receptor homology model confirmed a similar binding mode as previously reported 1-aza derivatives. This is the first demonstration in nonribose adenosine analogues that the 1-deaza modification can maintain high A3AR affinity, selectivity, and efficacy.
Dix AV, Conroy JL, George Rosenker KM
… +2 more, Sibley DR, Appella DH
ACS Med Chem Lett
· 2015 Apr · PMID 25893044
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Peptide nucleic acid scaffolds represent a promising tool to interrogate the multivalent effects of ligand binding to a membrane receptor. Dopamine D2 receptors (D2R) are a class of G-protein coupled receptors (GPCRs), a...Peptide nucleic acid scaffolds represent a promising tool to interrogate the multivalent effects of ligand binding to a membrane receptor. Dopamine D2 receptors (D2R) are a class of G-protein coupled receptors (GPCRs), and the formation of higher-ordered structures of these receptors has been associated with the progression of several neurological diseases. In this Letter, we describe the synthesis of a library of ligand-modified PNAs bearing a known D2R agonist, (±)-PPHT. The D2R activity for each construct was assessed, and the multivalent effects were evaluated.
Macegoniuk K, Dziełak A, Mucha A
… +1 more, Berlicki Ł
ACS Med Chem Lett
· 2015 Feb · PMID 25699141
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Inhibitors of bacterial ureases are considered to be promising compounds in the treatment of infections caused by Helicobacter pylori in the gastric tract and/or by urealytic bacteria (e.g., Proteus species) in the urina...Inhibitors of bacterial ureases are considered to be promising compounds in the treatment of infections caused by Helicobacter pylori in the gastric tract and/or by urealytic bacteria (e.g., Proteus species) in the urinary tract. A new, extended transition state scaffold, bis(aminomethyl)phosphinic acid, was successfully explored for the construction of effective enzyme inhibitors. A reliable methodology for the synthesis of phosphinate analogues in a three-component Mannich-type reaction was elaborated. The obtained molecules were assayed against ureases purified from Sporosarcina pasteurii and Proteus mirabilis, and aminomethyl(N-n-hexylaminomethyl)phosphinic acid was found to be the most potent inhibitor, with a K i = 108 nM against the S. pasteurii enzyme.
Calosso M, Tambutet G, Charpentier D
… +6 more, St-Pierre G, Vaillancourt M, Bencheqroun M, Gratton JP, Prévost M, Guindon Y
ACS Med Chem Lett
· 2014 Sep · PMID 25221666
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We report on the design and synthesis of molecules having E- and P-selectins blocking activity both in vitro and in vivo. The GlcNAc component of the selectin ligand sialyl Lewis(X) was replaced by an acyclic tether that...We report on the design and synthesis of molecules having E- and P-selectins blocking activity both in vitro and in vivo. The GlcNAc component of the selectin ligand sialyl Lewis(X) was replaced by an acyclic tether that links two saccharide units. The minimization of intramolecular dipole-dipole interactions and the gauche effect would be at the origin of the conformational bias imposed by this acyclic tether. The stereoselective synthesis of these molecules, their biochemical and biological evaluations using surface plasmon resonance spectroscopy (SPR), and in vivo assays are described. Because the structure of our analogues differs from the most potent E-selectin antagonists reported, our acyclic analogues offer new opportunities for chemical diversity.
Moss SM, Jayasekara PS, Paoletta S
… +2 more, Gao ZG, Jacobson KA
ACS Med Chem Lett
· 2014 Sep · PMID 25221664
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Adenosine receptors (ARs) are members of the G protein-coupled receptor (GPCR) superfamily and have shown much promise as therapeutic targets. We have used an agonist-bound A2AAR X-ray crystallographic structure to desig...Adenosine receptors (ARs) are members of the G protein-coupled receptor (GPCR) superfamily and have shown much promise as therapeutic targets. We have used an agonist-bound A2AAR X-ray crystallographic structure to design a chemically reactive agonist for site-specific chemical modification of the receptor. To further explore and chemically engineer its binding cavity, a 2-nitrophenyl active ester was attached through an elongated chain at adenine C2 position. This general structure was designed for irreversible transfer of a terminal acyl group to a nucleophilic amino group on the A2AAR. Preincubation with several O-acyl derivatives prevented radioligand binding that was not regenerated upon extensive washing. In silico receptor docking suggested two lysine residues (second extracellular loop) as potential target sites for an O-acetyl derivative (MRS5854, 3a), and site-directed mutagenesis indicated that K153 but not K150 is essential. Similarly, a butyl azide for click reaction was incorporated in the active ester moiety (3b). These promising results indicate a stable, covalent modification of the receptor by several reactive adenosine derivatives, which could be chemical tools for future imaging, structural probing, and drug discovery. Thus, structure-based ligand design has guided the site-specific modification of a GPCR.
Calosso M, Charpentier D, Vaillancourt M
… +4 more, Bencheqroun M, St-Pierre G, Wilkes BC, Guindon Y
ACS Med Chem Lett
· 2012 Dec · PMID 24900426
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The discovery of molecules that interfere with the binding of a ligand to a receptor remains a topic of great interest in medicinal chemistry. Herein, we report that a monosaccharide unit of a polysaccharide ligand can b...The discovery of molecules that interfere with the binding of a ligand to a receptor remains a topic of great interest in medicinal chemistry. Herein, we report that a monosaccharide unit of a polysaccharide ligand can be replaced advantageously by a conformationally locked acyclic molecular entity. A cyclic component of the selectin ligand Sialyl Lewis(x), GlcNAc, is replaced by an acyclic tether, tartaric esters, which link two saccharide units. The conformational bias of this acyclic tether originates from the minimization of intramolecular dipole-dipole interaction and the gauche effect. The evaluation of the binding of these derivatives to P-selectin was measured by surface plasmon resonance spectroscopy. The results obtained in our pilot study suggest that the discovery of tunable tethers could facilitate the exploration of the carbohydrate recognition domain of various receptors.
Tosh DK, Paoletta S, Phan K
… +2 more, Gao ZG, Jacobson KA
ACS Med Chem Lett
· 2012 Jul · PMID 23145215
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C2-Arylethynyladenosine-5'-N-methyluronamides containing a bicyclo[3.1.0]hexane ((N)-methanocarba) ring are selective A(3) adenosine receptor (AR) agonists. Similar 4'-truncated C2-arylethynyl-(N)-methanocarba nucleoside...C2-Arylethynyladenosine-5'-N-methyluronamides containing a bicyclo[3.1.0]hexane ((N)-methanocarba) ring are selective A(3) adenosine receptor (AR) agonists. Similar 4'-truncated C2-arylethynyl-(N)-methanocarba nucleosides containing alkyl or alkylaryl groups at the N(6) position were low-efficacy agonists or antagonists of the human A(3)AR with high selectivity. Higher hA(3)AR affinity was associated with N(6)-methyl and ethyl (K(i) 3-6 nM), than with N(6)-arylalkyl groups. However, combined C2-phenylethynyl and N(6)-2-phenylethyl substitutions in selective antagonist 15 provided a K(i) of 20 nM. Differences between 4'-truncated and nontruncated analogues of extended C2-p-biphenylethynyl substitution suggested a ligand reorientation in AR binding, dominated by bulky N(6) groups in analogues lacking a stabilizing 5'-uronamide moiety. Thus, 4'-truncation of C2-arylethynyl-(N)-methanocarba adenosine derivatives is compatible with general preservation of A(3)AR selectivity, especially with small N(6) groups, but reduced efficacy in A(3)AR-induced inhibition of adenylate cyclase.
ACS Med Chem Lett
· 2012 Aug · PMID 24900525
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Warfarin is an anticoagulant drug extensively used in the treatment and prevention of thrombotic disorders. Previous studies have shown that warfarin binds extensively to blood plasma proteins and that only a small fract...Warfarin is an anticoagulant drug extensively used in the treatment and prevention of thrombotic disorders. Previous studies have shown that warfarin binds extensively to blood plasma proteins and that only a small fraction of the drug is unbound and thus available for therapeutic function. Both warfarin's narrow therapeutic window and the susceptibility of anticoagulant function to patient-dependent factors necessitate regular monitoring. In this study, we have shown that the lifetimes for each of the various bound and free forms of the drug in blood plasma can be quantified in situ by time-correlated single-photon counting fluorescence spectroscopy over the clinically significant concentration range. A relationship between the blood coagulation and the distribution of fluorescence lifetimes was observed. The in situ detection of clinically relevant concentrations of warfarin in its respective bound and unbound forms could provide a prognostic tool for use in patient treatment.
Kim SH, Bok JH, Lee JH
… +13 more, Kim IH, Kwon SW, Lee GB, Kang SK, Park JS, Jung WH, Kim HY, Rhee SD, Ahn SH, Bae MA, Ha DC, Kim KY, Ahn JH
ACS Med Chem Lett
· 2012 Feb · PMID 24900439
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A new series of cyclic sulfamide derivatives were synthesized and evaluated for their ability to inhibit 11β-HSD1. Among this series, 18e showed good in vitro activity toward human 11β-HSD1, selectivity against 11β-HSD2,...A new series of cyclic sulfamide derivatives were synthesized and evaluated for their ability to inhibit 11β-HSD1. Among this series, 18e showed good in vitro activity toward human 11β-HSD1, selectivity against 11β-HSD2, microsomal stability, and pharmacokinetic and safety profiles (hERG, CYP, and acute toxicity). Additionally, 18e exhibited good in vivo efficacy in rat and monkey models.
Tosh DK, Phan K, Deflorian F
… +3 more, Wei Q, Gao ZG, Jacobson KA
ACS Med Chem Lett
· 2011 Aug · PMID 21858244
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A(1) adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A(1)AR were truncated to eliminate 5'-CH(2)OH. This modification...A(1) adenosine receptor (AR) agonists are neuroprotective, cardioprotective, and anxiolytic. (N)-Methanocarba adenine nucleosides designed to bind to human A(1)AR were truncated to eliminate 5'-CH(2)OH. This modification previously converted A(3)AR agonists into antagonists, but the comparable effect at A(1)AR is unknown. In comparison to ribosides, affinity at the A(1)AR was less well preserved than at the A(3)AR, although a few derivatives were moderately A(1)AR selective, notably full agonist 21 (N(6)-dicyclopropylmethyl, K(i) 47.9 nM). Thus, at the A(1)AR recognition elements for nucleoside binding depend more on 5'region interactions, and in their absence A(3)AR selectivity predominates. Based on the recently reported agonist-bound AR structure, this difference between subtypes likely correlates with an essential His residue in transmembrane domain 6 of A(1) but not A(3)AR. The derivatives ranged from partial to full agonists in A(1)AR-mediated adenylate cyclase inhibition. Truncated derivatives have more drug-like physical properties than other A(1)AR agonists; this approach is appealing for preclinical development.