Abstract:
:In a search for improved multiple drug resistance (MDR) modulators, we identified a novel series of substituted pyrroloquinolines that selectively inhibits the function of P-glycoprotein (Pgp) without modulating multidrug resistance-related protein 1 (MRP1). These compounds were evaluated for their toxicity toward drug-sensitive tumor cells (i.e. MCF-7, T24) and for their ability to antagonize Pgp-mediated drug-resistant cells (i.e. NCI/ADR) and MRP1-mediated resistant cells (i.e. MCF-7/VP). Cytotoxicity and drug accumulation assays demonstrated that the dihydropyrroloquinolines inhibit Pgp to varying degrees, without any significant inhibition of MRP1. The compound termed PGP-4008 was the most effective at inhibiting Pgp in vitro and was further evaluated in vivo. PGP-4008 inhibited tumor growth in a murine syngeneic Pgp-mediated MDR solid tumor model when given in combination with doxorubicin. PGP-4008 was rapidly absorbed after intraperitoneal administration, with its plasma concentrations exceeding the in vitro effective dose for more than 2 h. PGP-4008 did not alter the plasma distribution of concomitantly administered anticancer drugs and did not cause systemic toxicity as was observed for cyclosporin A. Because of their enhanced selectivity toward Pgp, these substituted dihydropyrroloquinolines may be effective MDR modulators in a clinical setting.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Lee BD,Li Z,French KJ,Zhuang Y,Xia Z,Smith CDdoi
10.1021/jm0303204keywords:
subject
Has Abstractpub_date
2004-03-11 00:00:00pages
1413-22issue
6eissn
0022-2623issn
1520-4804journal_volume
47pub_type
杂志文章abstract::Histone deacetylase 6 (HDAC6) removes the acetyl group from lysine residues in a number of non-histone substrates and plays important roles in microtubule dynamics and chaperone activities. There is growing interest in identifying HDAC6-selective inhibitors as chemical biology tools and ultimately as new therapeutic a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm502011f
更新日期:2015-03-26 00:00:00
abstract::In an analogy to the potent catechol dopamine D1 agonists dihydrexidine (1) and dinapsoline (2), benzo rings were fused onto the structures of the dopamine D2-selective agonists quinelorane (3) and quinpirole (4). Each of the phenyl ring-substituted derivatives had significant affinity for D2 receptors, albeit somewha...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9804533
更新日期:1999-03-11 00:00:00
abstract::Prolonged drug-target occupancy has become increasingly important in lead optimization, and biophysical assays that measure residence time are in high demand. Here we report a practical label-free assay methodology that provides kinetic and affinity measurements suitable for most target classes without long preincubat...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01829
更新日期:2018-06-28 00:00:00
abstract::Three ellipticine-estradiol conjugates were synthesized in an effort to target the cytotoxicity of ellipticine to estrogen-receptor positive cells. The three conjugates were prepared with linker chains extending from the 17 alpha position of the estradiol to N-2 (compound 3), N-6 (compound 4), and C-9 (compound 5) pos...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9602930
更新日期:1996-08-16 00:00:00
abstract::The synthesis of a new class of multisubstrate adduct inhibitors of polyamine biosynthesis has been investigated. The first target compound, designed to inhibit spermidine synthase, was obtained and proved to be a very potent inhibitor of that enzyme. Two synthetic routes to effect the coupling of the polyamine spermi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00014a023
更新日期:1995-07-07 00:00:00
abstract::Autoimmune deficiency and destruction in either β-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting β-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b01624
更新日期:2020-03-26 00:00:00
abstract::The intracellular delivery of nucleic acid molecules is a complex process involving several distinct steps; among these the endosomal escape appeared to be of particular importance for an efficient protein production (or inhibition) into host cells. In the present study, a new series of ionizable vectors, derived from...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b01679
更新日期:2016-04-14 00:00:00
abstract::The enantiomers of two isosteric phosphonate analogs of the ether-linked antitumor agent 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OMe) were synthesized and evaluated for their cytotoxicity against various mouse leukemic cell lines in vitro and in vivo. The key step in the synthesis of the alkyloxy a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00029a016
更新日期:1994-02-04 00:00:00
abstract::The syntheses of 1,7,12-trimethyl- and 2,7,12-trimethylbenz[a]anthracenes are described. The lack of carcinogenic activity of these compounds is discussed in relationship to the carcinogenic activity of other substituted benz[a]anthracenes. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00211a043
更新日期:1977-01-01 00:00:00
abstract::We previously reported that (+/-)-6-(4-(benzylamino)-7-quinazolinyl)-4,5- dihydro-5-methyl-3(2H)-pyridazinone (+/-)-1, KF15232) showed potent cardiotonic activity with a strong myofibrillar Ca(2+)-sensitizing effect. As an extension of our work, we attempted to synthesize optically active 1. (+/-)-4-(4-(Benzylamino)-7...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm950197j
更新日期:1996-01-05 00:00:00
abstract::Polymeric nanoparticles (PNPs) may efficiently deliver in vivo therapeutics to tumors when conjugated to specific targeting agents. Gint4.T aptamer specifically recognizes platelet-derived growth factor receptor β and can cross the blood-brain barrier (BBB). We synthesized Gint4.T-conjugated PNPs able of high uptake i...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00527
更新日期:2017-05-25 00:00:00
abstract::The synthesis of various chiral derivatives of (+)-erythro-9-(2-hydroxy-3-nonyl)adenine, (+)-EHNA, from (2S,3R)-3-amino-1,2-O-isopropylidene-1,2-nonanediol by condensation with 5-amino-4,6-dichloropyrimidine is described. The compounds synthesized were C1'- and nor-C1'-(+)-EHNA derivatives. When tested with calf splee...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00100a025
更新日期:1992-10-30 00:00:00
abstract::HCV infection affects more than 170 million people worldwide and many of those patients will reach the end stage complications of the disease which include hepatocarcinoma and liver failure. The success rate for treatment of patients infected with genotype-1 is about 40%. Therefore, novel treatments are needed to comb...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9016027
更新日期:2010-04-22 00:00:00
abstract::Probucol (1) and probucol analogues with the substitutions at the disulfide-linked carbon (2, 3) and an additional substitution at a tert-butyl of each phenolic ring (4) were tested for their ability to lower total serum cholesterol and prevent aortic atherosclerosis in modified Watanabe heritable hyperlipidemic (WHHL...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00105a046
更新日期:1991-01-01 00:00:00
abstract::A number of 6-sulfenamide, 6-sulfinamide, and 6-sulfonamide derivatives of 2-aminopurine and certain related purine ribonucleosides have been synthesized and evaluated for antileukemic activity in mice. Amination of 6-mercaptopurine ribonucleoside (7a) and 6-thioguanosine (7b) with chloramine solution gave 9-beta-D-ri...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00163a020
更新日期:1990-01-01 00:00:00
abstract::The constitution of chlorpromazine has been studied in the context of its phototoxicity. Electron transfer from the side chain to the aromatic nucleus of the drug contributes to its instability to light. Even without the side chain, however, chlorophenothiazines appear to be very photolabile, so that it is unlikely th...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00188a016
更新日期:1979-02-01 00:00:00
abstract::Development of orally available phosphodiesterase 4 (PDE4) inhibitors as anti-inflammatory drugs has been going on for decades. However, only roflumilast has received FDA approval. One key challenge has been the low therapeutic window observed in the clinic for PDE4 inhibitors, primarily due to PDE4 mediated side effe...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/jm500378a
更新日期:2014-07-24 00:00:00
abstract::A series of cis- and trans-6,6a,7,8,9,10,10a,11-octahydro-11- oxodibenzo[b,e]thiepinacetic acids (6-9) and -oxepinacetic acids (10-13) were prepared and their antiinflammatory activity was examined in the rat carrageenan hind paw edema test. The antiinflammatory activity of these compounds depended on their stereochem...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00164a006
更新日期:1990-02-01 00:00:00
abstract::Prostate-specific membrane antigen (PSMA) is an excellent biomarker for the early diagnosis of prostate cancer progression and metastasis. The most promising PSMA-targeted agents in the clinical phase are based on the Lys-urea-Glu motif, in which Lys and Glu are α-(l)-amino acids. In this study, we aimed to determine ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.9b02022
更新日期:2020-03-26 00:00:00
abstract::A series of cephalosporins has been prepared in which the 3'-position was linked to the nitrogen of the antibacterial quinolone ciprofloxacin through a carbamate function. Like the ester-linked and quaternary-linked dual-action cephalosporins reported earlier, these carbamate-linked compounds exhibited a broad antibac...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00113a026
更新日期:1991-09-01 00:00:00
abstract::We recently described a number of inhibitors of P450(17 alpha), the key enzyme of androgen biosynthesis. Here, we report the synthesis and activity of novel 17-imidazolyl, pyrazolyl, and isoxazolyl androstene derivatives as potential agents for the treatment of prostatic cancer. A number of 17-(4'-Imidazolyl) derivati...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970337k
更新日期:1997-09-26 00:00:00
abstract::Prodrug-mediated utilization of the cytochrome P450 (CYP) 1A1 to obtain the selective release of potent anticancer products within cancer tissues is a promising approach in chemotherapy. We herein report the rationale, preparation, biological evaluation, and mechanism of action of phenyl 4-(2-oxo-3-alkylimidazolidin-1...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00343
更新日期:2017-06-22 00:00:00
abstract::Three analogs of luteinizing hormone-releasing hormone (LH-RH) of the structure less than Glu-His-Trp-Ser-Tyr-Gly-Gly-Leu-Arg-Pro-Gly-NH2, involving substitutions inpositions 1, 3, and 8 with nonprotein amino acids, have been synthesized by the solid-phase method. They are [pyro-L-alpha-(1-aminoadipic)]-LH-RH, [3-(2-n...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00226a008
更新日期:1976-04-01 00:00:00
abstract::We have synthesized several 7alpha-fluoro (F) and 7alpha-iodo (I) analogues of 5alpha-dihydrotestosterone (5alpha-DHT) and 19-nor-5alpha-dihydrotestosterone (5alpha-NDHT) and tested them for binding to the androgen receptor and for their biological activity in an in vitro assay with cells that have been engineered to ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm990064o
更新日期:1999-06-03 00:00:00
abstract::Serotonin N-acetyltransferase, also called the melatonin rhythm enzyme, is thought to play an important regulatory role in circadian rhythm in animals and people. A series of analogues were synthesized in which indole and coenzyme A were linked via ketone tethers as designed inhibitors of this enzyme. These compounds ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010049v
更新日期:2001-07-19 00:00:00
abstract::A series of 7 alpha-methoxy-7 beta-amido-3-chloro-3-cephem-4-carboxylic acids was prepared and evaluated for biological activity. When compared with the parent 7-non-methoxy analogues, these new 7 alpha-methoxy-3-chloro cephalosporins displayed diminished antimicrobial activity. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00118a024
更新日期:1988-10-01 00:00:00
abstract::Series of N-alkylated derivatives of 2-amino-4,6-dihydroxyindan 3 and 6-amino-1,3-dihydroxybenzocycloheptene 2 were prepared for pharmacological testing as congeners of 2-amino-5,7-dihydroxytetralin, which elicits dopaminergic effects in a variety of assays. All of the subject compounds demonstrated a lower order of d...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00368a014
更新日期:1984-02-01 00:00:00
abstract::MTH1 is a member of the nudix phosphohydrolase superfamily of enzymes, and it is involved in nucleotide pool homeostasis. The protein exerts its scavenging action by hydrolyzing oxidized nucleotides, thus avoiding their misincorporation into replicating DNA. Recent reports have validated its inhibition as a potential ...
journal_title:Journal of medicinal chemistry
pub_type: 评论,杂志文章
doi:10.1021/acs.jmedchem.6b00283
更新日期:2016-03-24 00:00:00
abstract::A series of phenylenebis(oxy)bis[2,2-dimethylpentanoic acid]s have been synthesized and evaluated as potential hypolipidemic agents. Compound 18 (CI-924) was found to be the most potent compound in this series. In rats, compound 18 not only reduced low-density lipoprotein cholesterol but also increased high-density li...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00361a015
更新日期:1983-07-01 00:00:00
abstract::A new approach to rapidly score protein-ligand interactions is tested on several protein-ligand systems. Results using this approach - the OWFEG free energy grid - are quite promising and are generally in better agreement with experiment (in some cases much better) than those obtained employing scoring techniques curr...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm000375v
更新日期:2001-02-15 00:00:00