Abstract:
:In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4'-methoxy- and 4'-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these derivatives, 4'-fluorogemcitabine proved to be active against varicella zoster virus (VZV, TK+ strain) with an EC50 of 0.042 μM and produced significant cytotoxicity (CC50 = 0.11 μM). Upon derivatization of this trifluoro nucleoside as its prodrug, decreased anti-VZV activity was observed, but with a concomitantly improved selectivity index (SI = 36). When this prodrug was tested against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its antiviral activity (EC50 = 0.73 μM) was comparable to or slightly lower than its cytotoxic concentration in measurements of cell growth and cell morphology, respectively.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Zheng Z,Groaz E,Snoeck R,De Jonghe S,Herdewijn P,Andrei Gdoi
10.1021/acsmedchemlett.0c00485subject
Has Abstractpub_date
2020-12-09 00:00:00pages
88-92issue
1issn
1948-5875journal_volume
12pub_type
杂志文章abstract::With only two new classes of antibiotics developed in the last 40 years, novel antibiotics are desperately needed to combat the growing problem of multidrug-resistant and extensively drug resistant bacteria, particularly Gram-negative bacteria. Described in this letter is the synthesis and antibiotic activity of 1,2,4...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00296
更新日期:2016-11-12 00:00:00
abstract::A series of potent and selective β1-adrenoreceptor ligands were identified (IC50 range, 0.04-0.25 nM; β1/β2 selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats. Tissue distribution studies demonstrated uptake of each radiotracers from the blood poo...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml1002458
更新日期:2011-07-22 00:00:00
abstract::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 ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00597
更新日期:2020-03-12 00:00:00
abstract::Based on the potent Kv7 agonist RL-81, we prepared new lead structures with greatly improved selectivity for Kv7.2/Kv7.3 over related potassium channels, i.e., Kv7.3/Kv7.5, Kv7.4, and Kv7.4/7.5. RL-36 and RL-12 maintain an agonist EC2x of ca. 1 μM on Kv7.2/Kv7.3 in a high-throughput assay on an automated electrophysio...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00097
更新日期:2019-05-08 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::ABC transporters, including ABCG2, play a vital role in defending the human body against the vast range of xenobiotics. Even though this is beneficial for human health, these protein transporters have been implicated in the emerging resistance of cancer cells to a variety of structurally and functionally diverse antic...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00289
更新日期:2018-07-25 00:00:00
abstract::The influence of ionization states of hydroxamates and retrohydroxamates and the presence of zinc ions in the active site were investigated using the wild-type and E402Q mutant of MMP-9. The deprotonated hydroxamates showed a significantly enhanced enrichment factor in the presence of zinc ions. A pharmacophore model ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200031m
更新日期:2011-03-29 00:00:00
abstract::We describe the discovery of three structurally differentiated potent and selective MTH1 inhibitors and their subsequent use to investigate MTH1 as an oncology target, culminating in target (in)validation. Tetrahydronaphthyridine 5 was rapidly identified as a highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystalli...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00420
更新日期:2019-11-19 00:00:00
abstract::A new class of 4-aminoquinolines was synthesized and evaluated in vitro for antiplasmodial activity against both the chloroquine-sensitive (3D7) and -resistant (K1 and W2) strains. The most active compounds 3c-3e had acceptable cytotoxicity but showed strong inhibition toward a panel of cytochrome P450 enzymes in vitr...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400311r
更新日期:2013-10-01 00:00:00
abstract::A novel modulator of sodium ion currents was synthesized in 6 steps from a protected dihydroxypyrrolidine nitrone, via 1,3-dipolar cycloaddition reaction with acrylamide. Sodium ion currents in B50 cells were evaluated in comparison to saxitoxin and tetrodotoxin, and revealed an IC(50) of 15.7 muM. The new compound sh...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100035t
更新日期:2010-03-31 00:00:00
abstract::GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclizati...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml1000855
更新日期:2010-06-18 00:00:00
abstract::A protein structure-guided drug design approach was employed to develop small molecule inhibitors of the BET family of bromodomains that were distinct from the known (+)-JQ1 scaffold class. These efforts led to the identification of a series of substituted benzopiperazines with structural features that enable interact...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00191
更新日期:2017-07-14 00:00:00
abstract::This study was aimed at investigating the antitumor activity of novel 2-oxindole derivatives against a well-characterized human nonsmall cell lung cancer (NSCLC) cell line. Test compounds produced an antiproliferative activity in the low micromolar/submicromolar range of concentrations and significantly induced typica...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400162g
更新日期:2013-10-18 00:00:00
abstract::Based on hit-likeness and chemical diversity, a number of chalcones and chalcone-mimetic compounds were selected as putative Notch inhibitors. The evaluation of the antiproliferative effect combined with the inhibition of Notch1 expression in KOPTK1 cell line identified compound 18, featuring a tetrahydronaphthalene-b...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00608
更新日期:2019-02-26 00:00:00
abstract::mPTPB is a virulent phosphatase from Mycobacterium tuberculosis and a promising therapeutic target for tuberculosis. To facilitate mPTPB-based drug discovery, we identified α-sulfophenylacetic amide (SPAA) from cefsulodin, a third generation β-lactam cephalosporin antibiotic, as a novel pTyr pharmacophore for mPTPB. S...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00373
更新日期:2015-11-03 00:00:00
abstract::Minibodies show rapider blood clearance than IgGs due to smaller size that improves target-to-background ratio (TBR) in in vivo imaging. Additionally, the ability to activate an optical probe after binding to the target greatly improves the TBR. An optical imaging probe based on a minibody against prostate-specific me...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400533y
更新日期:2014-01-17 00:00:00
abstract::Replication Protein A is the primary eukaryotic ssDNA binding protein that has a central role in initiating the cellular response to DNA damage. RPA recruits multiple proteins to sites of DNA damage via the N-terminal domain of the 70 kDa subunit (RPA70N). Here we describe the optimization of a diphenylpyrazole carbox...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml5003629
更新日期:2014-11-11 00:00:00
abstract::A series of N-(3-ethynyl-2,4-difluorophenyl)sulfonamides were identified as new selective Raf inhibitors. The compounds potently inhibit B-Raf(V600E) with low nanomolar IC50 values and exhibit excellent target specificity in a selectivity profiling investigation against 468 kinases. They strongly suppress proliferatio...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00039
更新日期:2015-03-18 00:00:00
abstract::Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquired resistance by secondary EGFR mutations or by amplification of ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml4003309
更新日期:2014-01-30 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::A series of alkylpyrimidine-4,6-diol derivatives were designed and synthesized as novel GRP84 agonists based on a high-throughput screening (HTS) hit 1. 6-Nonylpyridine-2,4-diol was identified as the most potent agonist of GPR84 reported so far, with an EC50 of 0.189 nM. These novel GPR84 agonists will provide valuabl...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.6b00025
更新日期:2016-03-30 00:00:00
abstract::A medicinal chemistry effort focused on identifying a structurally diverse candidate for phosphoinositide 3-kinase delta (PI3Kδ) led to the discovery of clinical candidate INCB050465 (20, parsaclisib). The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in o...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00334
更新日期:2019-10-17 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::Nonsense mutations introduce a premature termination codon (PTC) and are the underlying cause of multiple rare genetic diseases and cancers. Although certain aminoglycosides bind to eukaryotic ribosomes enabling incorporation of an amino acid at the PTC and formation of full-length protein, they are inefficient and to...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00610
更新日期:2019-04-09 00:00:00
abstract::Protein kinases are key regulators that govern complex cellular processes. Dysregulation of kinase signaling is associated in many human diseases, particularly cancers and developmental and metabolic disorders. Tyrosine kinase inhibitors have achieved great success in molecular targeted therapies for cancer and now is...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml500091p
更新日期:2014-03-06 00:00:00
abstract::Acetylcholinesterase is a critical enzyme that regulates neurotransmission by degrading the neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for both therapeutic drugs that treat Alzheimer's disease and chemical warfare agents that cripple the nervous system and cause death t...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400304w
更新日期:2013-09-23 00:00:00
abstract::Primary open angle glaucoma is the second most common cause of blindness worldwide. Nitric oxide has recently received particular attention as a potential antiglaucoma agent. In this work, gem-dinitroalkyl benzenes are evaluated for their capability to act as a new class of IOP lowering agents. These derivatives have ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00264
更新日期:2017-09-13 00:00:00
abstract::The identification of Pim-1/2 kinase overexpression in B-cell malignancies suggests that Pim kinase inhibitors will have utility in the treatment of lymphoma, leukemia, and multiple myeloma. Starting from a moderately potent quinoxaline-dihydropyrrolopiperidinone lead, we recognized the potential for macrocyclization ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.5b00403
更新日期:2016-02-12 00:00:00
abstract::The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cel...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00002
更新日期:2018-02-27 00:00:00
abstract::In this paper, we describe the discovery and optimization of a series of noncovalent reversible epidermal growth factor receptor inhibitors of EGFRL858R/T790M/C797S. One of the most promising compounds, 25g, inhibited the enzymatic activity of EGFRL858R/T790M/C797S with an IC50 value of 2.2 nM. Cell proliferation assa...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.8b00564
更新日期:2019-05-22 00:00:00