Abstract：
:We report X-ray crystallographic structures of three inhibitors bound to dehydrosqualene synthase from Staphylococcus aureus: 1 (BPH-651), 2 (WC-9), and 3 (SQ-109). Compound 2 binds to the S2 site with its -SCN group surrounded by four hydrogen bond donors. With 1, we report two structures: in both, the quinuclidine headgroup binds in the allylic (S1) site with the side chain in S2, but in the presence of PPi and Mg(2+), the quinuclidine's cationic center interacts with PPi and three Mg(2+), mimicking a transition state involved in diphosphate ionization. With 3, there are again two structures. In one, the geranyl side chain binds to either S1 or S2 and the adamantane headgroup binds to S1. In the second, the side chain binds to S2 while the headgroup binds to S1. These results provide structural clues for the mechanism and inhibition of the head-to-head prenyl transferases and should aid future drug design.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Lin FY,Liu YL,Li K,Cao R,Zhu W,Axelson J,Pang R,Oldfield Edoi
10.1021/jm300208psubject
Has Abstractpub_date
2012-05-10 00:00:00pages
4367-72issue
9eissn
0022-2623issn
1520-4804journal_volume
55pub_type
杂志文章abstract：:The agonist selectivities of central (medullary) and peripheral (vascular) alpha-adrenoceptors were compared in order to investigate a possible similarity among these two alpha-adrenoceptor populations. Linear regression equations were derived between the alpha-adrenergic potencies, mediated by these two types of alph...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00137a006
更新日期：1981-05-01 00:00:00
abstract：:ACTIBIND and its human homologue RNASET2 are T2 ribonucleases (RNases). RNases are ubiquitous and efficient enzymes that hydrolyze RNA to 3' mononucleotides and also possess antitumorigenic and antiangiogenic activities. Previously, we have shown that ACTIBIND and RNASET2 bind actin and interfere with the cytoskeletal...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm1015507
更新日期：2012-02-09 00:00:00
abstract：:A series of substituted chromone-2-carboxylic acids was synthesized and tested as antagonists of SRS-A induced contractions of isolated guinea pig ileum. This work led to the discovery of sodium 7-[3-(4-acetyl-3hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylate (FPL 55712) which is...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00213a012
更新日期：1977-03-01 00:00:00
abstract：:Glucuronidation and transporter-mediated efflux into bile are important in the elimination of xeno- and endobiotics, including the natural biladienone pigment bilirubin. The mechanisms of these processes and the structural factors that dictate whether cholephilic compounds are excreted directly in bile or require prio...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0609521
更新日期：2007-02-08 00:00:00
abstract：:4,6,6a,7,8,12b-Hexahydroindolo[4,3-ab]phenanthridines ("benzergolines") was the first structural class of potent and selective dopamine D1 agonists lacking a catechol group. In order to determine the enantioselectivity of the 7-methyl derivative in the adenylate cyclase assay, its 5,5a-dihydro precursor was resolved a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00060a004
更新日期：1993-04-16 00:00:00
abstract：:Biaryl ethers were recently reported as potent NNRTIs. Herein we disclose a detailed SAR study that led to the biaryl ether 6. This compound possessed excellent potency against WT RT and key clinically observed RT mutants and had an excellent pharmacokinetic profile in rats, dogs, and rhesus macaques. The compound als...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm901230r
更新日期：2009-11-26 00:00:00
abstract：:A series of 2-(2-nitrobenzoyl)cyclohexane-1,3-dione analogues (1-9) were designed, synthesized, and evaluated for inhibition of 4-hydroxyphenylpyruvate dioxygenase (4-HPPD), a key enzyme involved in the catabolism of tyrosine which catalyzes the conversion of 4-hydroxyphenylpyruvate to homogentisate. The correlations ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010568y
更新日期：2002-05-23 00:00:00
abstract：:The poor solubility of the thymidylate synthase (TS) inhibiting antifolate 10-propargyl-5,8-dideazafolic acid has posed problems for its clinical use and is probably responsible for its renal toxicity. The insolubility is caused by the 2-amino-3,4-dihydro-4-oxopyrimidine moiety of the drug which stabilizes the solid s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00124a018
更新日期：1989-04-01 00:00:00
abstract：:Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17). This m...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm980299k
更新日期：1998-11-05 00:00:00
abstract：:A series of UTP, UDP, and UMP derivatives and analogues were synthesized and evaluated at the human pyrimidinergic P2Y receptor subtypes P2Y2, P2Y4, and P2Y6 stably expressed in 1321N1 astrocytoma cells. Substituents at N3 of UTP were poorly tolerated by P2Y2 and P2Y4 receptors. In contrast, a large phenacyl substitue...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm060848j
更新日期：2006-11-30 00:00:00
abstract：:The accessible surface, described by Lee and Richards (the L&R surface: J. Mol. Biol. 1971, 55, 379), has remarkably useful properties for displaying ligand-protein interactions. The surface is placed one van der Waals radius plus one probe radius away from the protein atoms. The ligands are displayed in skeletal form...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00088a002
更新日期：1992-05-15 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：:We have found that (R,S)-1-(phenylthio)-aminopropane (4a), a synthetic alternate substrate for the terminal enzyme of norepinephrine biosynthesis, dopamine beta-monooxygenase (DBM), is both an indirect sympathomimetic and a potent antihypertensive agent in spontaneously hypertensive rats. We demonstrate herein that th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00107a031
更新日期：1991-03-01 00:00:00
abstract：:A series of imidazo[1,5-alpha]quinoxalin-4-ones and imidazo[1,5-alpha]quinoxaline ureas containing substituted phenyl groups at the 3-position was developed. Compounds within the imidazo[1,5-alpha]quinoxaline urea series had high affinity for the GABAA/benzodiazepine receptor complex with varying in vitro efficacy, al...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm960070+
更新日期：1996-09-13 00:00:00
abstract：:Hydroxyurea, hydroxyguanidine, and some thiosemicarbazones have been shown to have anticancer and antiviral activities. One of their possible sites of action is the enzyme ribonucleotide reductase (RR). Combination of the structural features of these compounds led to the design and synthesis of the Schiff bases of N-h...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00146a022
更新日期：1985-08-01 00:00:00
abstract：:The diphtheria toxin-like ADP-ribosyltransferases (ARTDs) are an enzyme family that catalyzes the transfer of ADP-ribose units onto substrate proteins by using nicotinamide adenine dinucleotide (NAD(+)) as a cosubstrate. They have a documented role in chromatin remodelling and DNA repair, and inhibitors of ARTD1 and 2...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm300746d
更新日期：2012-09-13 00:00:00
abstract：:A series of 1-amino- and 1-mercapto-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyrans was synthesized and subsequently evaluated in three rodent test systems for CNS activity. The structure-activity data generated indicate that, in general, a change of the 1-hydroxy group to an amine results in a retention of pharmacological ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00211a004
更新日期：1977-01-01 00:00:00
abstract：:A facile route to perillyl alcohol (POH) differential glycosylation and the corresponding synthesis of a set of 34 POH glycosides is reported. Subsequent in vitro studies revealed a sugar dependent antiproliferative activity and the inhibition of S6 ribosomal protein phosphorylation as a putative mechanism of represen...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm500870u
更新日期：2014-09-11 00:00:00
abstract：:(S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide (2) was synthesized as an orally bioavailable KCNQ2 potassium channel opener. In a rat model of migraine, 2 demonstrated significant oral activity in reducing the total number of cortical spreading depressions induced by potassium chloride. ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm034073f
更新日期：2003-07-17 00:00:00
abstract：:The concept of bioisosterism between benzimidazole and catechol was applied to the design and synthesis of benzimidazole analogues of norepinephrine, (R,S)-1-[5(6)-benzimidazolyl]-2-aminoethanol (2), and of isoproterenol, (R,S)-1-[5(6)-benzimidazolyl]-2-isopropylaminoethanol (4). Compound 2 was shown to be a partial b...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00199a013
更新日期：1978-01-01 00:00:00
abstract：:The effects of 3-position substitution of 9-aminomethyl-9,10-dihydroanthracene (AMDA) on 5-HT 2A receptor affinity were determined and compared to a parallel series of DOB-like 1-(2,5-dimethoxyphenyl)-2-aminopropanes substituted at the 4-position. The results were interpreted within the context of 5-HT 2A receptor mod...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800771x
更新日期：2008-11-13 00:00:00
abstract：:Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compoun...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401610c
更新日期：2013-12-27 00:00:00
abstract：:A topological substructural approach to molecular design (TOSS-MODE) has been introduced for the selection and design of anticancer compounds. A quantitative model that discriminates anticancer compounds from the inactive ones in a training series was obtained. This model permits the correct classification of 91.43% o...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm991172d
更新日期：2000-05-18 00:00:00
abstract：:A series of 2'- and 3'-fluorinated 2',3'-dideoxynucleosides and 3'-azido-2',3'-dideoxynucleosides were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus-1 (HIV-1) replication in MT-4 cells. Neither conversion of 3'-fluoro- or 3'-azido-2',3'-dideoxyadenosine to the correspondi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00128a013
更新日期：1989-08-01 00:00:00
abstract：:Discovery of novel effective and safe antimalarials has been traditionally focused on targeting erythrocytic parasite stages that cause clinical symptoms. However, elimination of malaria parasites from the human population will be facilitated by intervention at different life-cycle stages of the parasite, including th...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm4011466
更新日期：2013-10-10 00:00:00
abstract：:Thymidine phosphorylase plays an important role in angiogenesis, which is an attractive target for therapy of cancer and other diseases. In our continuous effort to develop novel inhibitors of thymidine phosphorylase, we have discovered that 6-halouracils substituted at position C5 by certain hydrophobic groups exhibi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070644i
更新日期：2007-11-29 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：:Lymphatic filariasis (elephantiasis) is a global public health problem caused by the parasitic nematodes Wuchereria bancrofti and Brugia malayi. We have previously reported anthraquinones from daylily roots with potent activity against pathogenic trematode Schistosoma mansoni. Here we report the synthesis of novel ant...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0492655
更新日期：2005-04-21 00:00:00
abstract：:Ergosterol, the predominant sterol of fungi, is postulated to have many cellular functions which include a bulk membrane role and a regulatory role. Studies with sterol auxotrophs show that, even in the presence of sterols which can fulfill the bulk membrane requirements, a small concentration of ergosterol is absolut...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm9605851
更新日期：1996-12-20 00:00:00
abstract：:A series of 8-phenylxanthine derivatives has been synthesized with oxyacetic acid on the para phenyl position to increase aqueous solubility and minimize nonspecific binding and iodinatable groups on the 1- or 3-position of the xanthine ring. The structure-activity relationship for binding of these compounds to A1 ade...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00399a010
更新日期：1988-04-01 00:00:00
