Abstract:
:We have developed a novel albumin-binding prodrug of doxorubicin that incorporates p-aminobenzyloxycarbonyl (PABC) as a 1,6 self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, as a substrate for the prostate-specific antigen (PSA) that is overexpressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. The prodrug exhibited good water solubility and was bound rapidly to the cysteine-34 position of human serum albumin. Incubation studies with PSA demonstrated that the albumin-bound form of the prodrug was cleaved rapidly at the P1-P1' scissile bond, releasing H-Ser-Leu-PABC-DOXO, which was further degraded to release doxorubicin as a final cleavage product within a few hours in prostate tumor tissue homogenates as well as in PSA-positive LNCaP LN cell lysates. Moreover, our prodrug exhibited antiproliferative activity in a low micromolar range against a PSA-expressing prostate cancer cell line (LNCaP).
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Elsadek B,Graeser R,Warnecke A,Unger C,Saleem T,El-Melegy N,Madkor H,Kratz Fdoi
10.1021/ml100060msubject
Has Abstractpub_date
2010-05-26 00:00:00pages
234-8issue
5issn
1948-5875journal_volume
1pub_type
杂志文章abstract::We describe the synthesis and SAR studies of divin-a small molecule that blocks bacterial division by perturbing the assembly of proteins at the site of cell septation. The bacteriostatic mechanism of action of divin is distinct from other reported inhibitors of bacterial cell division and provides an opportunity for ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400234x
更新日期:2013-09-12 00:00:00
abstract::Visible light-mediated photocatalysis, which relies on the ability of photocatalysts to absorb low-energy visible light and engage in single-electron transfer (SET) or energy transfer (ET) processes with organic substrates, has emerged as one of the fastest growing fields in organic synthesis. This catalytic platform ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00436
更新日期:2020-09-21 00:00:00
abstract::Pursuing our effort for developing effective inhibitors of the cancer-related hCA IX isoform, here we describe the synthesis of novel benzofuran-based carboxylic acid derivatives, featuring the benzoic (9a-f) or hippuric (11a,b) acid moieties linked to 2-methylbenzofuran or 5-bromobenzofuran tails via an ureido linker...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00094
更新日期:2020-03-18 00:00:00
abstract::By employing a phenotypic screen, a set of compounds, exemplified by 1, were identified which potentiate the ability of histone deacetylase inhibitor vorinostat to reverse HIV latency. Proteome enrichment followed by quantitative mass spectrometric analysis employing a modified analogue of 1 as affinity bait identifie...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00551
更新日期:2020-12-23 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::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::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 recently reported a series of 2,6-dipeptidyl-anthraquinone conjugates (AQs) as Trans-Activation Response element (TAR) RNA-binding agents able to inhibit in vitro the HIV-1 nucleocapsid (NC) protein-mediated processes. Because NC is a highly adaptable nucleic acid chaperone assisting several crucial steps along rev...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00682
更新日期:2020-03-23 00:00:00
abstract::Retinoid X receptor-alpha (RXRα) is implicated in the regulation of many biological processes and also represents a unique intracellular target for pharmacologic interventions. Efforts on discovery of small molecules targeting RXRα have been primarily focused on the molecules that bind to its classical ligand-binding ...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml5000405
更新日期:2014-05-14 00:00:00
abstract::Stable isotope-mass spectrometry (MS)-based metabolomic profiling is a powerful technique for following changes in specific metabolite pool sizes and metabolic flux under various experimental conditions in a test organism or cell type. Here, we use a metabolomics approach to interrogate the mechanism of antibiotic act...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400349n
更新日期:2013-12-12 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::Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in e.g. malaria. Yet only few nonphosphorus inhibitors have been reported so far. Here, we explore an isoxazole fragment hit, leading to the discovery of...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00537
更新日期:2020-02-17 00:00:00
abstract::SMARTCyp is an in silico method that predicts the sites of cytochrome P450-mediated metabolism of druglike molecules. The method is foremost a reactivity model, and as such, it shows a preference for predicting sites that are metabolized by the cytochrome P450 3A4 isoform. SMARTCyp predicts the site of metabolism dire...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml100016x
更新日期:2010-03-15 00:00:00
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::EPAC proteins are therapeutic targets for the potential treatment of cardiac hypertrophy and cancer metastasis. Several laboratories use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1 in various disease states. Here, we report SAR studies with tetrahydroquinoline analogs that explore various functio...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.7b00358
更新日期:2017-10-02 00:00:00
abstract::Measuring innovation in the pharmaceutical industry is challenging. Counts of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) are commonly used, but this measure only gauges quantity not innovativeness. A new indicator of innovation for small molecule and peptide drugs based on structu...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00319
更新日期:2020-09-10 00:00:00
abstract::Medicinal chemists have increasing opportunities to transition from the pharmaceutical industry to academic medical centers interested in translational research. This Viewpoint highlights some of the differences between these two cultures and strategies to succeed in academic drug discovery. ...
journal_title:ACS medicinal chemistry letters
pub_type: 社论
doi:10.1021/acsmedchemlett.9b00107
更新日期:2019-04-15 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::Human mitogen-activated protein kinases (MAPK)-interacting kinases 1 and 2 (Mnk1/2) are promising anticancer targets. Mnks possess special insertions and a DFD-motif that are distinct from other kinases. Crystallographic studies of Mnk1/2 have revealed that the DFD-motif adopts the DFG/D-out conformation in which resi...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400145x
更新日期:2013-06-24 00:00:00
abstract::[This corrects the article DOI: 10.1021/acsmedchemlett.9b00612.]. ...
journal_title:ACS medicinal chemistry letters
pub_type: 已发布勘误
doi:10.1021/acsmedchemlett.0c00336
更新日期:2020-06-24 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::The 5-HT(2C) receptor is an attractive drug target in the quest for new therapeutics to treat a variety of human disorders. We have previously undertaken a structural optimization campaign that has led to some potent and moderately selective 5-HT(2C) receptor agonists. After expanding our structure-function library, w...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml200206z
更新日期:2011-12-08 00:00:00
abstract::The Hu family of RNA-binding proteins plays a crucial role in post-transcriptional processes; indeed, Hu-RNA complexes are involved in various dysfunctions (i.e., inflammation, neurodegeneration, and cancer) and have been recently proposed as promising therapeutic targets. Intrigued by this concept, our research effor...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.9b00659
更新日期:2020-01-28 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::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::Mitragyna speciosa, also known as kratom, has the potential meet the need for pain medications that lack the addictiveness and overdose risk of classical opioid analgesics, such as morphine. This need is urgent because opioid addiction and overdose deaths have risen throughout diverse segments of U.S. society. Some op...
journal_title:ACS medicinal chemistry letters
pub_type: 社论
doi:10.1021/acsmedchemlett.7b00298
更新日期:2017-08-08 00:00:00
abstract::Antibiotic-resistant bacteria are emerging at an alarming rate in both hospital and community settings. Motivated by this issue, we have prepared desmethyl (i.e., replacing methyl groups with hydrogens) analogues of third-generation macrolide drugs telithromycin (TEL, 2) and cethromycin (CET, 6), both of which are sem...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml400337t
更新日期:2013-11-14 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::A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure-activity relationships (SAR) in conjunction with X-ray crysta...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/ml300237v
更新日期:2012-10-24 00:00:00
abstract::B-cell lymphoma 6 (BCL6) is a transcriptional repressor frequently deregulated in lymphoid malignancies. BCL6 engages with number of corepressors, and these protein-protein interactions are being explored as a strategy for drug development. Here, we report the development of an irreversible BCL6 inhibitor TMX-2164 tha...
journal_title:ACS medicinal chemistry letters
pub_type: 杂志文章
doi:10.1021/acsmedchemlett.0c00111
更新日期:2020-04-03 00:00:00