Abstract:
:A series of 3-deoxy-3-N-arylated-β-d-galactoside and -guloside derivatives have been synthesized by cesium fluoride/trimetylsilylaryl triflate-mediated benzyne generation and N-arylation of 3-deoxy-3-amino-β-d-galactosides and -gulosides, respectively. Evaluation as ligands to galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9C, and 9N revealed that the galactosides selectively bound galectin-9C, whereas the gulosides selectively bound galectin-9N. Hence, the N-aryl group induces galectin-9 selectivity and the ligand 3C-configuration acts as an epimeric selectivity switch between the two domains of galectin-9. Furthermore, MD simulations revealed that galacto derivatives in galectin-9C and gulo derivatives in galectin-9N find stable poses with specific interactions, which proposes a possible explanation to the gal/gulo 9C/9N selectivity.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Mahanti M,Pal KB,Sundin AP,Leffler H,Nilsson UJdoi
10.1021/acsmedchemlett.9b00396subject
Has Abstractpub_date
2019-12-04 00:00:00pages
34-39issue
1issn
1948-5875journal_volume
11pub_type
杂志文章abstract::Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we repor...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00609
更新日期:2020-02-18 00:00:00
abstract::Inhibition of Itk potentially constitutes a novel, nonsteroidal treatment for asthma and other T-cell mediated diseases. In-house kinase cross-screening resulted in the identification of an aminopyrazole-based series of Itk inhibitors. Initial work on this series highlighted selectivity issues with several other kinas...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400206q
更新日期:2013-08-12 00:00:00
abstract::A series of novel antifungal carboline derivatives was designed and synthesized, which showed broad-spectrum antifungal activity. Particularly, compound C38 showed comparable in vitro antifungal activity to fluconazole without toxicity to human embryonic lung cells. It also exhibited good fungicidal activity against b...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400492t
更新日期:2014-02-13 00:00:00
abstract::The renal outer medullary potassium channel (ROMK or Kir1.1) is a putative drug target for a novel class of diuretics that could be used for the treatment of hypertension and edematous states such as heart failure. An internal high-throughput screening campaign identified 1,4-bis(4-nitrophenethyl)piperazine (5) as a p...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml3000066
更新日期:2012-03-28 00:00:00
abstract::This report describes the investigation of a series of 5,7-disubstituted imidazo[5,1-f][1,2,4]triazine inhibitors of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR). Structure-activity relationship exploration and optimization leading to the identification, characterization, and pharmacologica...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100178g
更新日期:2010-08-30 00:00:00
abstract::Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Comp...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500142b
更新日期:2014-06-30 00:00:00
abstract::We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in v...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200199c
更新日期:2011-10-05 00:00:00
abstract::CREB (cAMP response element binding protein) has been shown to play an important role in tumor initiation, progression, and metastasis. We discovered that naphthol AS-E, a cell-permeable CREB inhibitor, presented antiproliferative activity in a broad panel of cancer cell lines in vitro. However, it has limited aqueous...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500330n
更新日期:2014-08-22 00:00:00
abstract::The receptor for the neuropeptide relaxin 3, relaxin family peptide 3 (RXFP3) receptor, is an attractive pharmacological target for the control of eating, addictive, and psychiatric behaviors. Several structure-activity relationship studies on both human relaxin 3 (containing 3 disulfide bonds) and its analogue A2 (tw...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00456
更新日期:2020-10-22 00:00:00
abstract::Tuning the bioavailability of lidocaine was explored by its incorporation into the ionic liquid lidocainium docusate ([Lid][Doc]) and the deep eutectic Lidocaine·Ibuprofen (Lid·Ibu) and comparing the transdermal absorption of these with the crystalline salt lidocainium chloride ([Lid]Cl). Each form of lidocaine was di...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00504
更新日期:2017-04-12 00:00:00
abstract::Herein, we report the structure-activity relationships within a series of mGlu7 PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (Kps > 1 and Kp,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00317
更新日期:2017-09-01 00:00:00
abstract::Ataluren was reported to suppress nonsense mutations by promoting the readthrough of premature stop codons, although its mechanism of action (MOA) is still debated. The likely interaction of Ataluren with CFTR-mRNA has been previously studied by molecular dynamics. In this work we extended the modeling of Ataluren's M...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00558
更新日期:2019-02-07 00:00:00
abstract::C646 inhibits the lysine acetyltransferases (KATs) p300 and CBP and represents the most potent and selective small molecule KAT inhibitor identified to date. To gain insights into the cellular activity of this epigenetic probe, we applied chemoproteomics to identify covalent targets of the C646 chemotype. Modeling and...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00385
更新日期:2015-10-31 00:00:00
abstract::A series of bis(l-amino acid) ester prodrugs of tenofovir (TFV) were designed and synthesized as new anti-HBV agents in this work. Four compounds 11, 12a, 12d, and 13b displayed better anti-HBV activity (IC50: 0.71-4.22 μM) than the parent drug TFV. The most active compound 11 (IC50: 0.71 μM), a bis(l-valine) ester pr...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00184
更新日期:2019-05-16 00:00:00
abstract::Structure-activity relationship translation offers an expeditious means for discovery of new active series. This approach was applied to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule disruptors. The two A-ring elements of a three-point steroidal pharmacophore were incorporated into a THIQ-ba...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200232c
更新日期:2012-01-12 00:00:00
abstract::Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00533
更新日期:2020-12-13 00:00:00
abstract::IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and p...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00291
更新日期:2018-10-30 00:00:00
abstract::A series of N-acylbenzenesulfonamide dihydro-1,3,4-oxadiazole hybrids (EMAC8000a-m) was designed and synthesized with the aim to target tumor associated carbonic anhydrase (hCA) isoforms IX and XII. Most of the compounds were selective inhibitors of the tumor associated hCA XII. Moreover, resolution of EMAC8000d racem...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00205
更新日期:2017-06-21 00:00:00
abstract::All eight of the major active metabolites of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221, compound 1), an inhibitor of 11β-hydroxysteroid dehydrogenase type 1 that has entered the clinic for the treatment of type 2 diabetes, were synthetically prepared and confirmed...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml2001467
更新日期:2011-09-13 00:00:00
abstract::In light of the biomedical significance of metallo-β-lactamases (MβLs), ten new mercaptoacetic acid thioester amino acid derivatives were synthesized and characterized. Biological activity assays indicated that all these synthesized compounds are very potent inhibitors of L1, exhibiting an IC50 value range of 0.018-2....
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00098
更新日期:2015-04-23 00:00:00
abstract::APD334 was discovered as part of our internal effort to identify potent, centrally available, functional antagonists of the S1P1 receptor for use as next generation therapeutics for treating multiple sclerosis (MS) and other autoimmune diseases. APD334 is a potent functional antagonist of S1P1 and has a favorable PK/P...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500389m
更新日期:2014-11-04 00:00:00
abstract::A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, includ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400183q
更新日期:2013-09-05 00:00:00
abstract::[(11)C]N-Methyl lansoprazole ([(11)C]NML, 3) was synthesized and evaluated as a radiopharmaceutical for quantifying tau neurofibrillary tangle (NFT) burden using positron emission tomography (PET) imaging. [(11)C]NML was synthesized from commercially available lansoprazole in 4.6% radiochemical yield (noncorrected RCY...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300216t
更新日期:2012-09-25 00:00:00
abstract::A series of TRPA1 antagonists is described which has as its core structure an indazole moiety. The physical properties and in vitro DMPK profiles are discussed. Good in vivo exposure was obtained with several analogs, allowing efficacy to be assessed in rodent models of inflammatory pain. Two compounds showed signific...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00140
更新日期:2017-05-18 00:00:00
abstract::Novel sources of antibiotics are needed to address the serious threat of bacterial resistance. Accordingly, we have launched a structure-based drug design program featuring a desmethylation strategy wherein methyl groups have been replaced with hydrogens. Herein we report the total synthesis, molecular modeling, and b...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml5002097
更新日期:2014-07-16 00:00:00
abstract::A series of urea/thiourea substituted benzoxaboroles was investigated for the inhibition of the three carbonic anhydrases encoded by Vibrio cholerae (VchCAα, VchCAβ, and VchCAγ). In particular, benzoxaborole derivatives were here first assayed for the inhibition of a γ-class CA, extending the panel of CA classes that ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00403
更新日期:2020-09-09 00:00:00
abstract::Using the HIV-1 protease binding mode of MK-8718 and PL-100 as inspiration, a novel aspartate binding bicyclic piperazine sulfonamide core was designed and synthesized. The resulting HIV-1 protease inhibitor containing this core showed an 60-fold increase in enzyme binding affinity and a 10-fold increase in antiviral ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00386
更新日期:2017-11-13 00:00:00
abstract::We report here the total synthesis of B-973 (five steps), a recently identified α7 nAChR ago-PAM, its enantiomeric resolution, and its electrophysiological characterization in Xenopus oocytes to identify (-)-B-973B as the bioactive enantiomer. The asymmetric synthesis of B-973B was accomplished in 99% ee, and X-ray cr...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00407
更新日期:2018-10-11 00:00:00
abstract::A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-f][1,2,4]triazine connected to various sugar moieties through a C-C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold w...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00269
更新日期:2020-07-09 00:00:00
abstract::We report the synthesis of a novel heat shock protein 90 (hsp90) inhibitor conjugated to a star polymer. Using reversible addition-fragmentation chain-transfer (RAFT) polymerization, we prepared star polymers comprised of PEG attached to a predesigned functional core. The stars were cross-linked using disulfide linker...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400082b
更新日期:2013-07-25 00:00:00