Abstract：
:The dipeptide D-alanyl-D-alanine is an essential precursor of bacterial peptidoglycan; thus, blocking its formation is a possible target for the design of novel antibacterial agents. The synthesis of this dipeptide by bacterial D-alanine:D-alanine ligase requires ATP. In analogy with glutamine synthetase, we hypothesized a mechanism for this enzyme involving the intermediacy of D-alanyl phosphate. Several (3-amino-2-oxoalkyl)phosphonic acids and their analogues have been synthesized as possible inhibitory mimics of this proposed intermediate. The most active of them, (3(R)-amino-2-oxobutyl)phosphonic acid (8a) and the corresponding aza analogue (22), were effective ligase inhibitors although they had no significant antibacterial activity. The ligase inhibition of these compounds is consistent with an acyl phosphate displacement step in the mechanism of DAla-DAla ligase.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Chakravarty PK,Greenlee WJ,Parsons WH,Patchett AA,Combs P,Roth A,Busch RD,Mellin TNdoi
10.1021/jm00128a033subject
Has Abstractpub_date
1989-08-01 00:00:00pages
1886-90issue
8eissn
0022-2623issn
1520-4804journal_volume
32pub_type
杂志文章abstract：:Anaplastic lymphoma kinase (ALK) is a valid target for anticancer therapy; however, potent ALK inhibitors suitable for clinical use are lacking. Because the majority of described kinase inhibitors bind in the ATP pocket of the kinase domain, we have characterized this pocket in ALK using site-directed mutagenesis, inh...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060380k
更新日期：2006-09-21 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：:Treatment of 14 beta-nitrocodeinone with sodium borohydride gave the codeine derivative which was reduced with zinc dust in acetic anhydride-acetic acid solution to give 14 beta-acetamidocodeine 6-acetate. 14 beta-Thiocyanatocodeinone was obtained from the reaction of thebaine with thiocyanogen and was reduced to 14 b...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00176a011
更新日期：1980-02-01 00:00:00
abstract：:Hyperfibrinolytic situations can lead to life-threatening bleeding, especially during cardiac surgery. The approved antifibrinolytic agents such as tranexamic acid, ε-aminocaproic acid, 4-aminomethylbenzoic acid, and aprotinin were developed in the 1960s without the structural insight of their respective targets. Crys...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01060
更新日期：2020-02-27 00:00:00
abstract：:From the whole plant of Euphorbia peplus L., five new diterpenes based on a jatrophane skeleton (pepluanins A-E, 1-5) were isolated, together with two known analogues (6 and 7), which served to divulge in detail the structure-activity relationships within this class of P-glycoprotein inhibitors. The results revealed t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm030951y
更新日期：2004-02-12 00:00:00
abstract：:(N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity as A(3) adenosine receptor (AR) agonists (5'-uronamides) or antagonists (5'-truncated). Here, these two series were modified in parallel at the adenine C2 position. N(6)-3-Chlorobenzyl-5'-N-m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900426g
更新日期：2009-12-10 00:00:00
abstract：:A number of novel alpha-melanotropin (alpha-MSH) analogues have been designed, synthesized, and assayed for bioactivity at the melanocortin-1 (MC1) receptor from Xenopus frog skin, and selected potent analogues were examined at recombinant human MC1, MC3, and MC4 receptors expressed in human embryonic kidney (HEK) cel...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm020355o
更新日期：2003-02-27 00:00:00
abstract：:9,10-Didehydro-6-methyl-8beta-arylergolines 2, in which the carboxyl group of lysergic acid and isolysergic acid is replaced by various aryl groups, were prepared in two steps by alkylation of aromatic substrates with the tetracyclic allylic alcohol 3, followed by aromatization with MnO2. The new ergolines 2 have mode...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00218a025
更新日期：1977-08-01 00:00:00
abstract：:A family of analogues of des-AA(1,2,5)-[DTrp(8)/D2Nal(8)]-SRIF that contain a 4-(N-isopropyl)-aminomethylphenylalanine (IAmp) at position 9 was identified that has high affinity and selectivity for human somatostatin receptor subtype 1 (sst1). The binding affinities of des-AA(1,2,5)-[DTrp(8),IAmp(9)]-SRIF (c[H-Cys-Lys...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010037+
更新日期：2001-06-21 00:00:00
abstract：:Gene therapy based on gene delivery is a promising strategy for the treatment of human disease. Here we present data on structure/biological activity of new biodegradable cholesterol-based cationic lipids with various heterocyclic cationic head groups and linker types. Enhanced accumulation of nucleic acids in the cel...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901022t
更新日期：2009-11-12 00:00:00
abstract：:The alpha- and beta-D-lyxofuranosyl analogues of the naturally occurring nucleosides have been synthesized and their antiviral properties examined. The alpha anomers were prepared by glycosylation of purine and pyrimidine aglycons with tetra-O-acetyl-alpha-D-lyxofuranose, followed by removal of the blocking groups. Th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00389a005
更新日期：1987-06-01 00:00:00
abstract：:The synthesis and biological activities of a series of N-substituted cis-4a,5,6,7,8,8a-hexa- and cis-4a,5,8,8a-tetrahydro-2H-phthalazin-1-ones are described. It was found that compounds bearing a cycloalkyl group at the 2-position exhibit the highest PDE4 inhibitory activities (pIC(50) = 8.6-9.4). The N-cycloheptyl- a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0110340
更新日期：2002-06-06 00:00:00
abstract：:Increasing evidence suggests that iron plays an important role in tissue damage both during chronic iron overload diseases (i.e., hemochromatosis) and when, in the absence of actual tissue iron overload, iron is delocalized from specific carriers or intracellular sites (inflammation, neurodegenerative diseases, postis...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm021022u
更新日期：2002-12-19 00:00:00
abstract：:A novel series of diaminoanthraquinones was discovered initially as protein kinase C inhibitors with IC50s in the 50-100 microM range. They exhibited potent tumor cell growth inhibitory activity in vitro without cross resistance to adriamycin. Further evaluation of two of the most active compounds NSC 639365 (3) and N...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00101a001
更新日期：1992-11-13 00:00:00
abstract：:A new series of 11-[(aminoalkyl)carbonyl] derivatives of 6,11-dihydrodibenzo[c,f][1,2,5]thiadiazepine 5,5-dioxide (10-39) were synthesized and evaluated for potential antidepressant activity in the apomorphine-induced hypothermia (Apo 16) test. Effects on reserpine-induced hypothermia and toxicity for the most potent ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00108a018
更新日期：1991-04-01 00:00:00
abstract：:The construction of bioactive peptides using β-amino acid-containing sequence patterns is a very promising strategy to obtain analogues that exhibit properties of high interest for medicinal chemistry applications. β-Amino acids have been shown to modulate the conformation, dynamics, and proteolytic susceptibility of ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm5010896
更新日期：2014-12-11 00:00:00
abstract：:To enhance the ability of indirubin derivatives to inhibit CDK2/cyclin E, a target of anticancer agents, we designed and synthesized a new series of indirubin-3'-oxime derivatives with combined substitutions at the 5 and 5' positions. A molecular docking study predicted the binding of derivatives with OH or halogen su...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm100080z
更新日期：2010-05-13 00:00:00
abstract：:It is now plausible to dock libraries of 10 million molecules against targets over several days or weeks. When the molecules screened are commercially available, they may be rapidly tested to find new leads. Although docking retains important liabilities (it cannot calculate affinities accurately nor even reliably ran...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.5b02008
更新日期：2016-05-12 00:00:00
abstract：:The paullones represent a novel class of small molecule cyclin-dependent kinase (CDK) inhibitors. To investigate structure-activity relationships and to develop paullones with antitumor activity, derivatives of the lead structure kenpaullone (9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one, 4a) were synthesiz...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9900570
更新日期：1999-07-29 00:00:00
abstract：:Short peptide-based inhibition of fusion remains an attractive goal in antihuman immunodeficiency virus (HIV) research based on its potential for the development of technically and economically desirable antiviral agents. Herein, we report the use of the dithiol bisalkylation reaction to generate a series of m-xylene ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b00882
更新日期：2019-10-10 00:00:00
abstract：:Two 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [9-Me(Et)] (syn-huprines) have been obtained by condensation of known 7-alkylbicyclo[3.3.1]non-6-en-3-ones with 2-(trifluoromethyl)aniline, followed by basic cyclization of the resulting imine, and chromatographic separation of the regioiso...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010949b
更新日期：2001-12-20 00:00:00
abstract：:Water soluble 2'-taxol poly(ethylene glycol) (PEG) esters have been synthesized and shown to function in vitro as prodrugs. However, in vivo experiments clearly establish that in order for these prodrugs to behave in a predictable fashion, the molecular weight of PEG must be of such magnitude so as to maintain a t1/2(...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950475e
更新日期：1996-01-19 00:00:00
abstract：:Several 1,3-disubstituted and 1-substituted derivatives of 5-propionoxy-5-(1-phenylethyl)barbituric acid were synthesized and evaluated for analgesic activity. Three of these compounds, 1,3-bis(methoxymethyl)-5-propionoxy-5-(1-phenylethyl)barbituric acid (2), 1,3-dimethyl-5-propionoxy-5-(1-phenylethyl)barbituric acid...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00241a010
更新日期：1975-07-01 00:00:00
abstract：:Three rationally designed pyrrolobenzodiazepine (PBD) drug-linkers have been synthesized via intermediate 19 for use in antibody-drug conjugates (ADCs). They lack a cleavable trigger in the linker and consist of a maleimide for cysteine antibody conjugation, a hydrophilic spacer, and either an alkyne (6), triazole (7)...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00736
更新日期：2017-12-14 00:00:00
abstract：:The in vitro antineoplastic activity of many phosphorus-containing (e.g., phosphocholines) and non-phosphorus-containing (e.g., quaternary ammonium salts) ether lipids has been evaluated in the HL-60 promyelocytic cell line. These compounds are analogues of ET-18-OMe (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphochol...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00066a011
更新日期：1993-07-09 00:00:00
abstract：:We have designed and evaluated 45 linear analogues of the natural constrained cyclopeptide TMC-95A. These synthetically less demanding molecules are based on the tripeptide sequence Y-N-W of TMC-95A. Structural variations in the amino acid side chains and termini greatly influenced both the efficiency and selectivity ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0701324
更新日期：2007-06-14 00:00:00
abstract：:c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm502018y
更新日期：2015-03-12 00:00:00
abstract：:The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01681
更新日期：2020-03-12 00:00:00
abstract：:A series of 9-hydrazono-4H-pyrido[1,2-a]pyrimidin-4-ones was prepared. The compounds were evaluated in the rat passive cutaneous anaphylaxis test for antiallergic activity. Structure-activity relationship studies revealed that the presence of a monosubstituted hydrazone moiety in position 9 and an unsubstituted 2-posi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00362a008
更新日期：1983-08-01 00:00:00
abstract：:A series of novel 3-quinolinecarboxamides that are structurally similar to the quinolone class of antibacterial agents possess excellent antiherpetic properties. By modifying the quinoline ring at the 1-, 2-, 3-, and 7-positions, analogues were identified that have up to 5-fold increased HSV-2 plaque-reduction potency...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00063a008
更新日期：1993-05-28 00:00:00
