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 spermidine to the nucleoside adenosine were studied. The first route involved a proposed Wittig or Julia olefination reaction to form the critical 5'-6' carbon-carbon bond between the nucleoside and polyamine moieties. This route failed due to a facile beta-elimination of a portion of the side chain from a carbanion intermediate during either coupling reaction. A second route involved a reductive amination approach and proved to be successful. The new inhibitor, given the trivial name adenosylspermidine, is the most potent inhibitor of spermidine synthase prepared to date.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Lakanen JR,Pegg AE,Coward JKdoi
10.1021/jm00014a023subject
Has Abstractpub_date
1995-07-07 00:00:00pages
2714-27issue
14eissn
0022-2623issn
1520-4804journal_volume
38pub_type
杂志文章abstract：:Quantitative structure-activity studies were carried out on a series of N-isopropylaryl hydrazides which inhibits monoamine oxidase (MAO). The inhibitory potencies of these compounds of MAO were found to correlate with the electron-withdrawing capacity of the aryl ring substituents as estimated by both empirical Hamme...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00227a005
更新日期：1976-05-01 00:00:00
abstract：:(4-Methoyx-2,3,6-trimethylphenyl)nonatetraenoic acids, esters, and amides (analogues of retinoic acid) bearing a fluorine atom(s) or a trifluoromethyl group on the polyene side chain were synthesized. The biological activities of these compounds and of 10-, 12-, and 14-fluororetinoic acid esters were evaluated in vivo...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00195a010
更新日期：1979-09-01 00:00:00
abstract：:Structure for the adduct of carbonic anhydrase II with 1-N-(4-sulfamoylphenyl-ethyl)-2,4,6-trimethylpyridinium perchlorate, a membrane-impermeant antitumor sulfonamide, is reported. The phenylethyl moiety fills the active site, making van der Waals interactions with side chains of Gln192, Val121, Phe131, Leu198, Thr20...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm050333c
更新日期：2005-09-08 00:00:00
abstract：:This study aims to identify inhibitors that bind at the interface of HIV-1 integrase (IN) and human LEDGF/p75, which represents a novel target for anti-HIV therapy. To date, only a few such inhibitors have been reported. Here structure-based virtual screening was performed to search for the inhibitors from an in-house...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm301226a
更新日期：2012-11-26 00:00:00
abstract：:A study of the effect of aromatic substitution on 5-HT2, D2, and alpha 1 receptor affinity in a subseries of new and previously synthesized 1-piperazino-3-phenylindans indicated that high 5-HT2 selectivity could be obtained in 5-substituted derivatives. Accordingly, a series of 5-substituted derivatives was synthesize...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00071a007
更新日期：1993-09-17 00:00:00
abstract：:Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 μM while displaying good selectivity, with an IC50 of 37.9 μM for cytotoxicity. As a promising mol...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01789
更新日期：2019-01-24 00:00:00
abstract：:From a series of small fragments that was designed to probe the histamine H(4) receptor (H(4)R), we previously described quinoxaline-containing fragments that were grown into high affinity H(4)R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the same in silic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm800876b
更新日期：2008-12-25 00:00:00
abstract：:Verrucarin A (2) was epoxidized to give the beta-9,10-epoxide 7 (major product) and alpha-9,10-epoxide 9 (minor product). The beta-epoxide 7 and its acetate 8 exhibit high in vivo antileukemic activity against P-388 mouse leukemia, whereas 2 and 9 are inactive. Epoxidation of verrucarin B (3) and roridin A (1) to thei...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00183a018
更新日期：1980-09-01 00:00:00
abstract：:From a micromolar high throughput screening hit 7, the successful complementary application of a chemogenomic approach and of a scaffold hopping exercise rapidly led to a low single digit nanomolar human vasopressin 1a (hV1a) receptor antagonist 38. Initial optimization of the mouse V1a activities delivered suitable t...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501745f
更新日期：2015-03-12 00:00:00
abstract：:Two analogues, 6-(2-aminopropyl)-5-methoxy-2,3-dihydrobenzofuran and 6-(2-aminopropyl)-5-methoxy-2-methyl-2,3-dihydrobenzofuran, of the hallucinogenic agent 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) were synthesized and tested in the two-lever drug discrimination paradigm. In rats trained to discriminate s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00152a022
更新日期：1986-02-01 00:00:00
abstract：:A method for preparing a variety of 7-alkyl-6,7- didehydromorphinans from the corresponding 6- morphinanones is described. The key intermediates in this sequence are the 7-formyl derivatives. The two epimeric B/C-trans-7-(1- hydroxypentyl ) morphinans ( 16a ,b) are stereochemically similar to the endo- ethanotetrahydr...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00371a013
更新日期：1984-05-01 00:00:00
abstract：:A number of 2-oxoquinoline-1-alkanoic acids that contain the N-acylglycine fragment found in several known inhibitors of aldose reductase were synthesized and tested in the rat lens assay. All of the target compounds were prepared by alkylation of the appropriate 2-oxoquinoline intermediates with a halo ester, followe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00160a038
更新日期：1986-10-01 00:00:00
abstract：:A series of nitrocoumarin and nitrochromene derivatives have been prepared and shown to inhibit the phosphatidylinositol-specific phospholipase C(PLC)(IC50 < 10 micrograms/mL) isolated from human melanoma. The inhibition of PLC by nitrocoumarin 4a was time-dependent and irreversible. The inhibition of PLC was shown to...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00040a016
更新日期：1994-07-08 00:00:00
abstract：:The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.6b01379
更新日期：2017-02-23 00:00:00
abstract：:Isolated hepatocytes carry out the N-demethylation of dansylamide at near linear rates for up to 8 h. This reaction was measured by following the release of tritium into water on hydroxylation of 3H-labeled methyl groups. The competitive inhibition of dansylamide by dansylated amino acids was studied in this system as...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00233a013
更新日期：1976-11-01 00:00:00
abstract：:The chelating drugs BAL (2,3-dimercaptopropanol), EDTA (ethylenediaminetetraacetic acid), and penicillamine (2-amino-3-mercapto-3-methylbutanoic acid), which are used for metal poisoning, are toxic and there is a real need for alternatives, especially for severe cases. A novel approach for treatment of heavy-metal poi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00142a028
更新日期：1981-10-01 00:00:00
abstract：:Oligonucleotide-based therapeutics have made rapid progress in the clinic for treatment of a variety of disease indications. Unmodified oligonucleotides are polyanionic macromolecules with poor drug-like properties. Over the past two decades, medicinal chemists have identified a number of chemical modification and con...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.6b00551
更新日期：2016-11-10 00:00:00
abstract：:A series of C7-O- and C20-O-amidated 2,3-dehydrosilybin (DHS) derivatives ((+/-)-1a-f and (+/-)-2), as well as a set of alkenylated DHS analogues ((+/-)-4a-f), were designed and de novo synthesized. A diesteric derivative of DHS ((+/-)-3) and two C23 esterified DHS analogues ((+/-)-5a and (+/-)-5b) were also prepared ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm900735p
更新日期：2009-12-10 00:00:00
abstract：:A number of analogues of thapsigargin have been synthesized by alkylating or acylating O-11 and O-12 in the lactol obtained by reducing thapsigargicin. Introduction of alpha-disposed substituents decreased the Ca(2+)-ATPase inhibitory potency of the analogue, whereas the enzyme was more tolerant toward beta-disposed s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00002a009
更新日期：1995-01-20 00:00:00
abstract：:Anthelmintic efficacies of a series of 6-substituted methyl imidazo[1,2-alpha]pyridine-2-carbamates were compared to similarly substituted benzimidazole-2-carbamates. With only one exception, methyl 6-benzoylimidazo[1,2-alpha]pyridine-2-carbamate, both classes of compounds exhibited similar activity vs. Nematospiroide...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00144a030
更新日期：1981-12-01 00:00:00
abstract：:Pironetin, the only crystallographically confirmed natural product to target α-tubulin, displays potent cytotoxic activity against sensitive and resistant A2780 ovarian cancer cell lines but is only marginally active in vivo. We now report that pironetin has a short half-life (<7 min) in human liver microsomes, sugges...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01774
更新日期：2019-02-14 00:00:00
abstract：:A series of derivatives of the antimycobacterial natural product pyridomycin have been prepared with the C2 side chain attached to the macrocyclic core structure by a C-C single bond, in place of the synthetically more demanding enol ester double bond found in the natural product. Hydrophobic C2 substituents of suffic...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01457
更新日期：2020-02-13 00:00:00
abstract：:The sea anemone peptide APETx2 is a potent and selective blocker of acid-sensing ion channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on ASIC3 has impeded development of improved analogues. Here we present a detailed structure-ac...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm501400p
更新日期：2014-11-13 00:00:00
abstract：:Contilisant, a permeable, antioxidant, and neuroprotectant agent, showing high nM affinity at H3R and excellent inhibition of the monoamine oxidases and cholinesterases, is an affine and selective S1R agonist in the nanomolar range, based on the binding affinity and functional experiment, a result confirmed by molecul...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00848
更新日期：2018-08-09 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：:Several esters of beta-carboline-3-carboxylic acid were synthesized and tested in respect to their affinity for the benzodiazepine receptor in bovine cortex membranes. Out of these derivatives, the methyl, ethyl, and n-propyl ester were clearly the most potent, while the n-butyl, benzyl, and 3-pyridylmethyl ester were...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00358a008
更新日期：1983-04-01 00:00:00
abstract：:The inclusion of an azaspiroketal Mannich base in the membrane targeting antitubercular 6-methoxy-1- n-octyl-1 H-indole scaffold resulted in analogs with improved selectivity and submicromolar activity against Mycobacterium tuberculosis H37Rv. The potency enhancing properties of the spiro-fused ring motif was affirmed...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b00777
更新日期：2018-07-12 00:00:00
abstract：:Dimeric DNA cross-linking compounds have emerged as important new antitumor agents. We report the synthesis and biochemical evaluation of a select set of dimeric mitomycins in which the two mitomycin units are tethered at either the mitomycin C(7) amino or the aziridine N(1a) positions. Significantly, mitomycin C (1) ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010090y
更新日期：2001-10-11 00:00:00
abstract：:A computational chemistry study has been performed on a series of tetrahydropyrimidine-2-ones (THPs) as HIV-1 protease (HIV-1 PR) inhibitors. The present investigation focuses on the correlation of inhibitor-enzyme complexation energies (E(compl)), inhibitor solvation energies E(solv)[I], and both polar and nonpolar b...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm010417v
更新日期：2002-02-14 00:00:00
abstract：:Rebeccamycin analogues containing uncommon sugars and substitutions on the imide nitrogen have been synthesized. Their cytotoxicities were tested in colon cancer and leukemia cells. Their ability to target topoisomerase I was examined using the in vivo complex of the topoisomerase bioassay in Hela cells. Compared with...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0493764
更新日期：2005-04-07 00:00:00
