Abstract：
:Previously reported 2-(hydroxymethyl)indoloquinones, prepared as their acetates or carbamates, were less active than 2-methyl analogues in bacterial cultures and they had no activity in mice, despite functionality appropriate for DNA cross-linking. On the basis of the hypothesis that these compounds might have been too reactive chemically for selective alkylation of DNA, we prepared new analogues with substituents that could give variation in the reduction potential of the quinone ring, which might control their rate of bioactivation. The 5-methoxyindoloquinones were much more potent cytotoxics than mitomycin C against human tumor cell lines, but they were inactive against P388 leukemia in mice. Two 5-aziridinylindoloquinones were also more potent than mitomycin C against the cell lines and one of them was active in the P388 model upon in vivo assay. The corresponding 5-amino analogues were less potent than mitomycin C against both the cell lines and murine P388 leukemia. A 2-(1-hydroxyethyl)carbamate was prepared by a 20-step synthesis. It was about one-fourth as potent as mitomycin C against two cell lines.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Iyengar BS,Remers WA,Catino JJdoi
10.1021/jm00128a030subject
Has Abstractpub_date
1989-08-01 00:00:00pages
1866-72issue
8eissn
0022-2623issn
1520-4804journal_volume
32pub_type
杂志文章abstract：:A series of novel benzoheterocyclic [(methoxyphenyl)amino]oxoalkanoic acid esters has been prepared. These compounds were tested as inhibitors of rat polymorphonuclear leukocyte 5-lipoxgenase (LO) in vitro and as inhibitors of leukotriene D4 (LTD4) and ovalbumin (OA) induced bronchospasm in the guinea pig (GP) in vivo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00385a024
更新日期：1987-02-01 00:00:00
abstract：:Mechanism-based inhibitors of human cytomegalovirus (HCMV) protease have been designed based on the pyrrolidine-5,5-trans-lactam ring system. New routes to the beta-methyl-, desmethyl-, and alpha-methyl-pyrrolidine-5,5-trans-lactam templates have been developed from 2,4-diaminobutyric acid. ESI/MS studies have shown t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm000078q
更新日期：2000-11-16 00:00:00
abstract：:The leukotrienes, metabolites of arachidonic acid produced through the action of the enzyme 5-lipoxygenase, are important mediators of immediate hypersensitivity and inflammation. Among the variety of diseases in which the leukotrienes may play a symptomatic or causative role is the dermatological condition psoriasis,...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00165a005
更新日期：1990-03-01 00:00:00
abstract：:The ortho hydroxy/methyl, hydroxy/hydroxymethyl, hydroxy/formyl, and hydroxy/carboxy substitution patterns, some of which confer dopaminergic agonist effects upon 2-aminotetralin ring systems, have been incorporated into beta-phenethylamine, 2-aminoindan, and trans-octahydrobenzo[f]quinoline rings. Certain of the 2-am...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00160a036
更新日期：1986-10-01 00:00:00
abstract：:Attempts to develop new (aryloxy)acetic acids with a better profile of diuretic and uricosuric activities as well as with fewer side effects have produced a series of compounds in which the ring system has been varied. Diuretic screening of these analogues in rats indicated that the great difference in the activity be...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00113a006
更新日期：1991-09-01 00:00:00
abstract：:Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9014845
更新日期：2010-02-11 00:00:00
abstract：:A series of dithiocarbamates were prepared by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of four human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX, and XII, involved in pathologies such as gl...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300031j
更新日期：2012-02-23 00:00:00
abstract：:A series of 3-(4-phenoxyphenyl)-1H-pyrazoles were synthesized and characterized as potent state-dependent sodium channel blockers. A limited SAR study was carried out to delineate the chemical requirements for potency. The results indicate that the distal phenyl group is critical for activity but will tolerate lipophi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030498q
更新日期：2004-03-11 00:00:00
abstract：:We report herein further insight into the biological activities displayed by a series of 2-hydroxyisoquinoline-1,3(2H,4H)-diones (HIDs). Substitution of the N-hydroxyimide two-metal binding pharmacophore at position 4 by carboxamido side chains was previously shown by us to be fruitful for this scaffold, since strong ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500109z
更新日期：2014-06-12 00:00:00
abstract：:Major urinary metabolites of carbidopa have been identified. Estimates were made based on the recovery or radio activity or by glc analysis of pooled urine of the amounts of the urinary metabolites II (2-methyl-3'-methoxy-4'-hydroxyphenylpropionic acid), III (2-methyl-3,4-dihydroxyphenylpropionic acid), IV (3,4-dihydr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00236a004
更新日期：1975-02-01 00:00:00
abstract：:Nonpeptidic chiral macrocycles were designed on the basis of an analogue of suberoylanilide hydroxamic acid (2) (SAHA, vorinostat) and evaluated against 11 histone deacetylase (HDAC) isoforms. The identification of critical amino acid residues highly conserved in the cap region of HDACs guided the design of the subero...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101092u
更新日期：2010-12-09 00:00:00
abstract：:Dideoxy- and trideoxynucleosides of 5-fluorouracil have been synthesized for antitumor evaluation. 2',5'-Dideoxy-5-fluorouridine (3) was prepared from 2'-deoxy-5-fluorouridine (1) by iodination using methyltriphenoxyphosponium iodide, followed by catalytic reduction. 1-(2',5'-Dideoxy-beta-D-threo-pentofuranosyl)5-fluo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00182a008
更新日期：1980-08-01 00:00:00
abstract：:In this article we introduce a molecular docking algorithm called MolDock. MolDock is based on a new heuristic search algorithm that combines differential evolution with a cavity prediction algorithm. The docking scoring function of MolDock is an extension of the piecewise linear potential (PLP) including new hydrogen...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm051197e
更新日期：2006-06-01 00:00:00
abstract：:A fragment-based docking procedure followed by substructure search were used to identify active-site beta-secretase inhibitors from a composite set of about 300 000 and a library of nearly 180 000 small molecules, respectively. EC(50) values less than 10 microM were measured in at least one of two different mammalian ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050499d
更新日期：2005-08-11 00:00:00
abstract：:Spiropyrimidinetriones are a novel class of antibacterial agents that target the bacterial type II topoisomerase via a new mode of action. Compound ETX0914 is thus far the only drug from this class that is being evaluated in clinical trials. To improve the antibacterial activity and pharmacokinetic properties of ETX09...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01750
更新日期：2019-03-28 00:00:00
abstract：:Among the small peptides 2-31, (H)Gly-Gly-Phe-Leu(OMe) (30) reduced prostaglandin production of COX-2 with an IC50 of 60 nM relative to 6000 nM for COX-1. The 5 mg kg(-1) dose of compound 30 rescued albino mice by 80% from capsaicin-induced paw licking and recovered it by 60% from carrageenan-induced inflammation. The...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b00134
更新日期：2016-04-28 00:00:00
abstract：:Cathepsin B (CTB) is a cysteine protease believed to be an important therapeutic target or biomarker for several diseases including aggressive cancer, arthritis, and parasitic infections. The development of probes capable of assessing CTB activity in cell lysates, living cells, and animal models of disease are needed ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500544p
更新日期：2014-07-24 00:00:00
abstract：:A new high-affinity thyroid hormone antagonist 6 with druglike properties was designed and synthesized. The compound behaved as an antagonist in a cell transactivation assay, and in a first in vivo experiment in rats. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060521i
更新日期：2006-11-16 00:00:00
abstract：:Dimethylallylguanidine, also known as galegine, isolated from Galega officinalis, has been shown to have weight reducing properties in vivo. Substitution of the guanidine group with an N-cyano group and replacement of guanidine with amidine, pyrimidine, pyridine, or the imidazole moieties removed the weight reducing p...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm8011933
更新日期：2009-06-11 00:00:00
abstract：:Inhibitor of apoptosis proteins (IAPs) are promising anticancer targets, given their roles in the evasion of apoptosis. Several peptidomimetic IAP antagonists, with inherent selectivity for cellular IAP (cIAP) over X-linked IAP (XIAP), have been tested in the clinic. A fragment screening approach followed by structure...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00900
更新日期：2018-08-23 00:00:00
abstract：:Osteoclast-mediated bone matrix resorption has been attributed to cathepsin K, a cysteine protease of the papain family that is abundantly and selectively expressed in osteoclast. Inhibition of cathepsin K could potentially be an effective method to prevent osteoporosis. Structure-activity studies on a series of rever...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030373l
更新日期：2004-01-29 00:00:00
abstract：:Based on the known biological activity of a variety of guanidine-containing agents, several N-substituted 3,4-dihydroquinazolines were synthesized. These compounds can be considered to be rigid analogues of phenylguanidines. In anesthetized rats the compounds decreased blood pressure and were antagonists of the presso...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00185a026
更新日期：1980-11-01 00:00:00
abstract：:p38 MAP kinase has received considerable interest in the pharmaceutical industry and remains a valid and interesting target for the treatment of inflammation. To discover novel p38 inhibitors, we applied the ligand-based virtual screening technique, FieldScreen, to 1.2 million commercially available compounds. Fifty-e...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm801399r
更新日期：2009-07-23 00:00:00
abstract：:A series of 2,2-diarylethylamine derivatives has been examined for potential antidepressant activity in the tetrabenazine (TBZ) test. Diethanolamine 4 (McN-4187) was one of the more potent compounds despite its polar alcohol functionalities [ED50 values of 15 mg/kg (exploratory activity) and 1.5 mg/kg (ptosis)]. Struc...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00374a022
更新日期：1984-08-01 00:00:00
abstract：:The regulation of lipid metabolism and it's effect on glucose control and diabetes has received intense interest. Hormone-sensitive lipase (HSL) is a vital enzyme in lipid metabolism. A series of novel pyrrolopyrazinediones has been discovered that demonstrate submicromolar activity both in the enzyme assay and in a (...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020460y
更新日期：2003-03-27 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：:A series of structurally different Gd(III) conjugates incorporating a bile acid moiety have been prepared. Polyaminopolycarboxylic ligands such as diethylenetriaminepentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) have been selected as chelating subunit for the Gd(III) ion. Ch...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0310683
更新日期：2004-07-01 00:00:00
abstract：:4-[4-(N-Substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives such as KN1022 are potent inhibitors of the phosphorylation of platelet derived growth factor receptor (PDGFR). Structure activity relationships in the (thio)urea moiety, the phenyl ring itself, the linker between these two moieti...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0201114
更新日期：2002-09-26 00:00:00
abstract：:Human melanocortin receptors (hMCRs) have been challenging targets to develop ligands that are explicitly selective for each of their subtypes. To modulate the conformational preferences of the melanocortin ligands and improve the biofunctional agonist/antagonist activities and selectivities, we have applied a backbon...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b00102
更新日期：2015-08-27 00:00:00
abstract：:In the framework of the design and development of TGR5 agonists, we reported that the introduction of a C(23)(S)-methyl group in the side chain of bile acids such as chenodeoxycholic acid (CDCA) and 6-ethylchenodeoxycholic acid (6-ECDCA, INT-747) affords selectivity for TGR5. Herein we report further lead optimization...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901390p
更新日期：2009-12-24 00:00:00
