Abstract:
:We report, for the first time, the biological activities of four-carbon-atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS), and folylpolyglutamate synthetase (FPGS) as well as antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine (1) and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine (2), afforded two four-carbon bridged antifolates, analogues 5 and 6, with enhanced FPGS substrate activity and inhibitory activity against tumor cells in culture (EC(50) < or = 10(-7) M) compared with the two-carbon bridged analogues. These results support our original hypothesis that the distance and orientation of the side chain p-aminobenzoyl-L-glutamate moiety with respect to the pyrimidine ring are a crucial determinant of biological activity. In addition, this study demonstrates that, for classical antifolates that are substrates for FPGS, poor inhibitory activity against isolated target enzymes is not necessarily a predictor of a lack of antitumor activity.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Gangjee A,Zeng Y,McGuire JJ,Kisliuk RLdoi
10.1021/jm058213skeywords:
subject
Has Abstractpub_date
2005-08-11 00:00:00pages
5329-36issue
16eissn
0022-2623issn
1520-4804journal_volume
48pub_type
杂志文章abstract::A series of 1,2,4-oxadiazoles has been prepared as ester bioisosteres and tested against 15 human rhinovirus serotypes, and the MIC80, the concentration which inhibits 80% or 12 of the serotypes tested, was determined. Homologation of the alkyl group attached to the oxadiazole ring resulted in a reduction in activity ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00041a022
更新日期:1994-07-22 00:00:00
abstract::Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidom...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm1002777
更新日期:2010-08-12 00:00:00
abstract::Protein kinase B (PKB)-selective inhibitors were designed, synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase); PKA has been used as a surrogate for other members of this family and indeed for protein kinases in general. The high homology betwe...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm049701n
更新日期:2005-01-13 00:00:00
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::Dihydrocodeinone oxime (1) under Beckmann rearrangement conditions gave a product (2) that facilitated the preparation of (-)-11 alpha-substituted 1,2,3,4,5,6-hexahydro-6 alpha,7-(methyleneoxy)-2,6-methano-3-benzazocines, a hitherto little-examined series of morphine partial structures. Compounds 7a and 12 gave good l...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00160a022
更新日期:1986-10-01 00:00:00
abstract::Polyamine transport is elevated in many tumor types, suggesting that toxic polyamine-drug conjugates could be targeted to cancer cells via the polyamine transporter (PAT). We have previously reported the use of Chinese hamster ovary (CHO) cells and its PAT-deficient mutant cell line, CHO-MG, to screen anthracene-polya...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701198s
更新日期:2008-01-24 00:00:00
abstract::Several 1,2-dihydro-5-(substituted phenyl)-2(1H)-pyridinones were synthesized and evaluated for inotropic activity. 1,2-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-6-methyl-2-oxo-3- pyridinecarbonitrile (5a) and the corresponding unsubstituted analogue 14a were the most potent positive inotropic agents in this series. Alth...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00389a011
更新日期:1987-06-01 00:00:00
abstract::2,6-Dipeptidyl-anthraquinones are a promising class of nucleic acid-binding compounds that act as NC inhibitors in vitro. We designed, synthesized, and tested new series of 2,6-disubstituted-anthraquinones, which are able to bind viral nucleic acid substrates of NC. We demonstrate here that these novel derivatives int...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b01494
更新日期:2016-03-10 00:00:00
abstract::Treatment with HIV-1 protease inhibitors, a component of highly active antiretroviral therapy (HAART), often results in viral resistance. Structural and biochemical characterization of a 6X protease mutant arising from in vitro selection with compound 1, a C 2-symmetric diol protease inhibitor, has been previously des...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800149m
更新日期:2008-10-23 00:00:00
abstract::A potent new class of inhibitors of phenylalanyl-tRNA synthetase from Escherichia coli B is described. N-Benzyl-2-phenylethylamine is a competitive inhibitor with respect to L-phenylalanine and appears to possess the structural features required for near-optimal binding. Hydrophobic substituents at the ortho position ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00233a002
更新日期:1976-11-01 00:00:00
abstract::A novel series of optically active 2,6-disubstituted alkylphenols with improved anesthetic profiles compared to widely used propofol were synthesized. The incorporation of the cyclopropyl group not only increased the steric effect but also introduced stereoselective effects over their anesthetic properties. Compounds ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b00254
更新日期:2017-05-11 00:00:00
abstract::Aiming to image NTS1 overexpressing tumors, the diarylpyrazole glycoconjugate 8, derived from the potent NTS1 antagonist SR142948A, was synthesized taking advantage of the palladium-catalyzed aminocarbonylation reaction. The glycoconjugate 8 displayed excellent affinity and selectivity toward NTS1. Radiosynthesis proc...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm401491e
更新日期:2013-11-27 00:00:00
abstract::A series of quinolone and naphthyridine antibacterial agents possessing as the C7-heterocycle bicyclic 2,5-diazabicyclo[n.2.m]alkanes, where n = 2, 3 and m = 1, 2, and a series including 4-aminopiperidine and 3-amino-8-azabicyclo[3.2.1]octanes have been prepared and evaluated in vitro and in vivo for antibacterial act...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00106a029
更新日期:1991-02-01 00:00:00
abstract::Molecular modeling methods have been used to design a novel series of conformationally constrained cyclic peptide inhibitors of human renin. Three goals were defined: enhanced inhibitory potency, high specificity for renin, and increased metabolic stability. Three cyclic compounds were synthesized with ring sizes 10, ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00397a003
更新日期:1988-02-01 00:00:00
abstract::A structure-activity relationship (SAR) study of the South African willow tree (Combretum caffrum) antineoplastic constituent combretastatin A-4 (3b) led to the discovery of a potent cancer cell growth inhibitor designated phenstatin (5a). This benzophenone derivative of combretastatin A-4 showed remarkable antineopla...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm000045a
更新日期:2000-07-13 00:00:00
abstract::Because several well-studied strains of rats manifest spontaneous hypertension, we set out to design a renin inhibitor suitable for use in this species. On the basis of the sequence of the renin substrate, a series of substrate analogue inhibitory peptides were synthesized by systematically modifying the P5, P3, P2, P...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00117a003
更新日期:1988-09-01 00:00:00
abstract::Ac-Tyr298-Ala299-Gly300-Thr301-Val302-I le303-Asn304-Asp305-Leu306-OH (Ac-VZV R2-(298-306)) represents the acetylated form of the C-terminus of varicella-zoster virus (VZV) ribonucleotide reductase subunit 2 (R2). This peptide possesses a high degree of homology with the C-terminus nonapeptide of the herpes simplex vi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00080a021
更新日期:1992-01-24 00:00:00
abstract::The synthesis and structure-activity relationships of C-terminal octapeptide analogues of anaphylatoxin C5a have been studied. The introduction of hydrophobic amino acids into the N-acetylated native octapeptide (N-Ac-His-Lys-Asp-Met-Gln-Leu-Gly-Arg-OH) (1) has led to an analogue with 100 times more activity than the ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00080a004
更新日期:1992-01-24 00:00:00
abstract::The AAA+ ATPase, p97, also referred to as VCP, plays an essential role in cellular homeostasis by regulating endoplasmic reticulum-associated degradation (ERAD), mitochondrial-associated degradation (MAD), chromatin-associated degradation, autophagy, and endosomal trafficking. Mutations in p97 have been linked to a nu...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.9b01318
更新日期:2020-03-12 00:00:00
abstract::Renin inhibitors 2-4 with the D-Lys renin inhibitory peptide (RIP) sequence, but containing Leu psi[CH2O]Ala (2), Leu psi[CH2O]Val (3), and Leu psi[CH2O]Leu (4) at the P1-P1' site, were of a comparable potency to RIP. N-Terminal Boc-protected inhibitors containing Pro psi[CH2O]Phe in positions P4-P3 were potent inhibi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00398a029
更新日期:1988-03-01 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::A series of new amine cyanoborane derivatives were synthesized and exhibited antifungal activity. A long alkyl chain attached to the nitrogen of the amine cyanoboranes and carboxyboranes enhances antifungal activity. An enhanced activity was also obtained upon the halogenation of the amine cyanoboranes as well as in t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm060476e
更新日期:2006-08-10 00:00:00
abstract::2,5-Dibutyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4' - yl]methyl]-3H-1,2,4-triazol-3-one, SC-51316, was synthesized as a potent and orally active angiotensin II (AII) receptor antagonist with a long duration of action. To explore the lipophilic pocket in the AII receptor interacting with the substituent ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00067a015
更新日期:1993-07-23 00:00:00
abstract::Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity, and metabolic stability. The focus has mostly been on constraining the backbone dihedral angles; however, the correct orientation of the amino acid side chains (χ-space) that constitute the peptide pharmacophore i...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章,评审
doi:10.1021/acs.jmedchem.6b01029
更新日期:2016-12-22 00:00:00
abstract::The synthesis of two new nucleotide analogues is described. 5'-Sulfamino-5'-deoxyadenosine (1) was prepared by reaction of 5'-amino-5'-deoxyadenosine with (CH3)3N.203, and 5'-sulfamino-5'-deoxythymidine (2) was prepared from 5'-amino-5'-deoxythymidine by a similar reaction. The 5'-sulfamino nucleosides are shown to be...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00205a024
更新日期:1978-07-01 00:00:00
abstract::Four novel steroidal alpha-methylene delta-lactones have been synthesized and shown to be active against human nasopharyngeal carcinoma (KB) cells in culture. The syntheses involved the use of known alpha-methylenation procedures. In addition, the lactone 6 was directly methylenated by reaction with CH2O/KOH or Et2NH/...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00175a019
更新日期:1980-01-01 00:00:00
abstract::Because of the double-edged nature of NO, the development of isoform-selective NOS substrates is a highly desirable goal. Given the striking similarity in the heme active sites of the three NOS isoforms, it presents an challenging problem. Several N-aryl-N'-hydroxyguanidines have recently been shown as substrates that...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0340703
更新日期:2003-06-05 00:00:00
abstract::The JAK-STAT3 pathway regulates genes that are important in cell proliferation and thus is a promising target for cancer therapy. A high-throughput screening (HTS) campaign using an Apo-ONE Homogenous Caspase 3/7 assay in U266 cells identified 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid ethyl ester 4 as a po...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm701271y
更新日期:2008-07-24 00:00:00
abstract::Several pairs of cannabinoid isomers were synthesized and tested for psychotropic activity in rhesus monkeys. Two regularities were observed: (a) In the absence of the other substituents, the equatorial stereochemistry of the substituent at C-1 determines activity. (b) Two groups of THC-type cannabinoids which differ ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00184a002
更新日期:1980-10-01 00:00:00
abstract::This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase i...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.7b01051
更新日期:2018-02-08 00:00:00