当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents.

The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents.

Abstract：

:Novel classical antifolates (3 and 4) and 17 nonclassical antifolates (11-27) were synthesized as antitumor and/or antiopportunistic infection agents. Intermediates for the synthesis of 3, 4, and 11-27 were 2,4-diamino-5-alkylsubstituted-7H-pyrrolo[2,3-d]pyrimidines, 31 and 38, prepared by a ring transformation/ring annulation sequence of 2-amino-3-cyano-4-alkyl furans to which various aryl thiols were attached at the 6-position via an oxidative addition reaction using I2. The condensation of alpha-hydroxy ketones with malonodinitrile afforded the furans. For the classical analogues 3 and 4, the ester precursors were deprotected, coupled with diethyl-L-glutamate, and saponified. Compounds 3 (IC50 = 60 nM) and 4 (IC50 = 90 nM) were potent inhibitors of human DHFR. Compound 3 inhibited tumor cells in culture with GI50 500-fold selectivity over human DHFR. Analogue 17 was 50-fold more potent than trimethoprim and about twice as selective against T. gondii DHFR.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Gangjee A,Jain HD,Queener SF,Kisliuk RL

doi

10.1021/jm800244v

subject

Has Abstract

pub_date

2008-08-14 00:00:00

pages

4589-600

issue

15

eissn

0022-2623

issn

1520-4804

journal_volume

51

pub_type

杂志文章

相关文献

JOURNAL OF MEDICINAL CHEMISTRY文献大全
  • Novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 2. Mechanism of inhibition and structure-based improvement of pharmaceutical properties.

    abstract：:The interaction between leukocyte function-associated antigen-1 (LFA-1) and intracellular adhesion molecule-1 (ICAM-1) has been implicated in inflammatory and immune diseases. Recently, a novel series of p-arylthio cinnamides has been described as potent antagonists of the LFA-1/ICAM-1 interaction. These compounds wer...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm000503f

    authors： Liu G,Huth JR,Olejniczak ET,Mendoza R,DeVries P,Leitza S,Reilly EB,Okasinski GF,Fesik SW,von Geldern TW

    更新日期：2001-04-12 00:00:00

  • Orally active 1,2,4-trioxanes: synthesis and antimalarial assessment of a new series of 9-functionalized 3-(1-arylvinyl)-1,2,5-trioxaspiro[5.5]undecanes against multi-drug-resistant plasmodium yoelii nigeriensis in mice.

    abstract：:Using easily accessible keto-trioxanes 7a-g as the starting materials, a series of new variously functionalized 1,2,4-trioxanes 10-36 have been prepared and evaluated for antimalarial activity against multi-drug-resistant Plasmodium yoelii nigeriensis in mice in the dose range of 24 mg/kg x 4 days to 96 mg/kg x 4 days...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm051130r

    authors： Singh C,Malik H,Puri SK

    更新日期：2006-05-04 00:00:00

  • Conformations and "nictinic" activites of cyclic analogues of choline aryl ether.

    abstract：:The synthesis of cis and trans isomers of N,N-N-trimethyl-2-phenoxycyclohexylammonium bromide, cis-N,N,-N-trimethyl-2(2',6'-xylyloxy)cyclohexylammonium bromide, and N,N-dimethyl-3-phenoxypiperidinium bromide is described. Their structures and conformations were determined by NMR and uv absorption spectroscopy, the min...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00227a022

    authors： Clark ER,Hughes IE,Smith CF

    更新日期：1976-05-01 00:00:00

  • Investigations on the effects of basic side chains on the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines.

    abstract：:Basic side chains determine the pharmacology of selective estrogen receptor modulators such as tamoxifen or raloxifene. In this study we tried to turn the hormonal profile of (4R,5S)/(4S,5R)-4,5-bis(4-hydroxyphenyl)-2-imidazolines from agonistic to antagonistic by introduction of a dimethylaminoethane, a piperidin-1-y...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm040855c

    authors： von Rauch M,Busch S,Gust R

    更新日期：2005-01-27 00:00:00

  • Synthesis, X-ray crystal structures, stabilities, and in vitro cytotoxic activities of new heteroarylacrylonitriles.

    abstract：:Twenty-three acrylonitriles, substituted at position 2 with either triazoles or benzimidazoles and at position 3 with various substituted furan, thiophene, or phenyl rings, were prepared by Knoevenagel condensation and tested for in vitro cytotoxic potency on 11 human cancer cell lines. X-ray crystal analysis of two r...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0311036

    authors： Saczewski F,Reszka P,Gdaniec M,Grünert R,Bednarski PJ

    更新日期：2004-06-17 00:00:00

  • Dimethyl-diphenyl-propanamide derivatives as nonsteroidal dissociated glucocorticoid receptor agonists.

    abstract：:A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactiva...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm100957a

    authors： Yang BV,Weinstein DS,Doweyko LM,Gong H,Vaccaro W,Huynh T,Xiao HY,Doweyko AM,McKay L,Holloway DA,Somerville JE,Habte S,Cunningham M,McMahon M,Townsend R,Shuster D,Dodd JH,Nadler SG,Barrish JC

    更新日期：2010-12-09 00:00:00

  • Design, Synthesis, and Evaluation of Novel 2,6-Disubstituted Phenol Derivatives as General Anesthetics.

    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

    authors： Qin L,Ren L,Wan S,Liu G,Luo X,Liu Z,Li F,Yu Y,Liu J,Wei Y

    更新日期：2017-05-11 00:00:00

  • Discovery of AZD3147: a potent, selective dual inhibitor of mTORC1 and mTORC2.

    abstract：:High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identify...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm501778s

    authors： Pike KG,Morris J,Ruston L,Pass SL,Greenwood R,Williams EJ,Demeritt J,Culshaw JD,Gill K,Pass M,Finlay MR,Good CJ,Roberts CA,Currie GS,Blades K,Eden JM,Pearson SE

    更新日期：2015-03-12 00:00:00

  • Synthesis of human CCK26-33 and CCK-33 related analogues on 2,4-DMBHA and TMBHA.

    abstract：:New analogues of human cholecystokinin in which the Tyr(SO3H) has been replaced by Phe(p-CH2SO3Na), methionines by norleucines, and tryptophan by 2-naphthylalanine([Phe(p-CH2- SO3Na)27,Nle28,31,Nal30]-CCK26-33 and [Phe(p-CH2SO3Na)27,Nle7,28,31,Nal30]-CCK-33) were synthesized by Fmoc solid phase methodology on two diff...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00064a001

    authors： Miranda MT,Liddle RA,Rivier JE

    更新日期：1993-06-11 00:00:00

  • Targeting the Allosteric Pathway That Interconnects the Core-Functional Scaffold and the Distal Phosphorylation Sites for Specific Dephosphorylation of Bcl-2.

    abstract：:Protein phosphorylation is the most significant post-translational modification for regulating cellular activities, but site-specific modulation of phosphorylation is still challenging. Using three-dimensional NMR spectra, molecular dynamics simulations, and alanine mutations, we identified that the interaction networ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/acs.jmedchem.0c01290

    authors： Wang Z,Song T,Guo Z,Cao K,Chen C,Feng Y,Wang H,Yin F,Zhou S,Dai J,Zhang Z

    更新日期：2020-11-25 00:00:00

  • Selective antiproliferative activity of hydroxynaphthyl-beta-D-xylosides.

    abstract：:The antiproliferative activity of the 14 isomeric monoxylosylated dihydroxynaphthalenes has been tested in vitro toward normal HFL-1 and 3T3 A31 cells as well as transformed T24 and 3T3 SV40 cells. The antiproliferative effect toward HFL-1 cells was correlated with the polarity of the compounds. However, in the case o...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm0512488

    authors： Jacobsson M,Ellervik U,Belting M,Mani K

    更新日期：2006-03-23 00:00:00

  • Synthesis and biological activity of CCK heptapeptide analogues. Effects of conformational constraints and standard modifications on receptor subtype selectivity, functional activity in vitro, and appetite suppression in vivo.

    abstract：:A series of modifications of the CCK7 analogue (des-NH2)Tyr(SO3-)-Nle-Gly-Trp-Nle-Asp-Phe-NH2 was prepared and tested for binding to guinea pig CCK-A and CCK-B receptors and in CCK-A-mediated functional assays. Selected analogues also were tested for appetite suppressant activity in rats. Several conformationally rest...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00094a001

    authors： Holladay MW,Bennett MJ,Tufano MD,Lin CW,Asin KE,Witte DG,Miller TR,Bianchi BR,Nikkel AL,Bednarz L

    更新日期：1992-08-07 00:00:00

  • Studies on 1,2,3-triazoles. 10. Synthesis and antiallergic properties of 9-oxo-1H,9H-benzothiopyrano[2,3-d]-1,2,3-triazoles and their S-oxides.

    abstract：:Selected derivatives of 9-oxo-1H,9H-benzothiopyrano[2,3-d]-1,2,3-triazole, a new heterocyclic ring system, and their S-oxides have been prepared and evaluated for antiallergic activity in the rat passive cutaneous anaphylaxis screen. Several of the compounds show intravenous potencies similar to or greater than that o...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00368a021

    authors： Buckle DR,Rockell CJ,Smith H,Spicer BA

    更新日期：1984-02-01 00:00:00

  • A physiological model for the estimation of the fraction dose absorbed in humans.

    abstract：:A physiologically based model for gastrointestinal transit and absorption in humans is presented. The model can be used to study the dependency of the fraction dose absorbed (F(abs)) of both neutral and ionizable compounds on the two main physicochemical input parameters (the intestinal permeability coefficient (P(int...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm030999b

    authors： Willmann S,Schmitt W,Keldenich J,Lippert J,Dressman JB

    更新日期：2004-07-29 00:00:00

  • Design, synthesis, and biological activity of a family of novel ceramide analogues in chemoresistant breast cancer cells.

    abstract：:Resistance to chemotherapy and endocrine therapy is a major cause of breast cancer treatment failure. We have synthesized six novel analogues using C8-ceramide as the lead analogue and studied their effect on hormone therapy resistant (MDA-MB-231) and chemoresistant (MCF-7TN-R) breast cancer cells. Pharmacologic inter...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm9009668

    authors： Antoon JW,Liu J,Gestaut MM,Burow ME,Beckman BS,Foroozesh M

    更新日期：2009-09-24 00:00:00

  • Structure-function correlation of chloroquine and analogues as transgene expression enhancers in nonviral gene delivery.

    abstract：:To understand how chloroquine (CQ) enhances transgene expression in polycation-based, nonviral gene delivery systems, a number of CQ analogues with variations in the aliphatic amino side chain or in the aromatic ring are synthesized and investigated. Our studies indicate that the aliphatic amino moiety of CQ is essent...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm060736s

    authors： Cheng J,Zeidan R,Mishra S,Liu A,Pun SH,Kulkarni RP,Jensen GS,Bellocq NC,Davis ME

    更新日期：2006-11-02 00:00:00

  • Synthesis and evaluation of novel radioligands for positron emission tomography imaging of metabotropic glutamate receptor subtype 1 (mGluR1) in rodent brain.

    abstract：:We designed three novel positron emission tomography ligands, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-[(11)C]methoxy-N-methylbenzamide ([(11)C]6), 4-[(18)F]fluoroethoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([(18)F]7), and 4-[(18)F]fluoropropoxy-N-[4-[6-(isopro...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm201590g

    authors： Fujinaga M,Yamasaki T,Yui J,Hatori A,Xie L,Kawamura K,Asagawa C,Kumata K,Yoshida Y,Ogawa M,Nengaki N,Fukumura T,Zhang MR

    更新日期：2012-03-08 00:00:00

  • Peptide sweeteners. 4. Hydroxy and methoxy substitution of the aromatic ring in L-aspartyl-L-phenylalanine methyl ester. Structure-taste relationships.

    abstract：:A series of analogues of the dipeptide sweetener L-aspartyl-L-phenylalanine methyl ester having hydroxy and/or methoxy substitution on the aromatic ring was synthesized and tasted. The introduction of a methoxy group in the para position of the aromatic ring of the peptide sweetener is crucial to the reduction or dest...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00178a013

    authors： Kawai M,Chorev M,Marin-Rose J,Goodman M

    更新日期：1980-04-01 00:00:00

  • Nucleosides and nucleotides. 200. Reinvestigation of 5'-N-ethylcarboxamidoadenosine derivatives: structure-activity relationships for P(3) purinoceptor-like proteins.

    abstract：:The non-P(1) and non-P(2) muscle relaxant effect of ATP in rabbit thoracic aorta has recently been attributed to a putative P(3) purinoceptor, which is activated by either adenosine or ATP. Since the physiological roles of this putative P(3) purinoceptor and of a new [(3)H]-5'-N-ethylcarboxamidoadenosine (NECA)-bindin...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm000150k

    authors： Umino T,Yoshioka K,Saitoh Y,Minakawa N,Nakata H,Matsuda A

    更新日期：2001-01-18 00:00:00

  • Clonidine and related analogues. Quantitative correlations.

    abstract：:Twenty-two structural derivatives of clonidine [2-(2,6-dichlorophenylimino)imidazolidine] have been synthesized and their main physicochemical parameters (log P, deltaRM, pKa) determined. Quantitative correlations between the peripheral alpha-mimetic action (pithed rats) and physicochemical parameters pointed out the ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00230a014

    authors： Rouot B,Leclerc G,Wermuth CG

    更新日期：1976-08-01 00:00:00

  • Synthesis and in vitro photodynamic activity of oligomeric ethylene glycol-quinoline substituted zinc(II) phthalocyanine derivatives.

    abstract：:A new series of zinc(II) phthalocyanine derivatives have been synthesized and characterized. These macrocycles exhibited a sharp absorption band in the red visible region in DMF, which indicated that they were dissolved well and almost did not aggregate in this solvent. Compared with the unsubstituted zinc(II) phthalo...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm400722d

    authors： Jia X,Yang FF,Li J,Liu JY,Xue JP

    更新日期：2013-07-25 00:00:00

  • Application of regression analysis to the hypoglycemic activities of a series of substituted benzenesulfonamidopyrimidines.

    abstract：:Quantitative structure-activity relationship studies have been performed on two types of sulfonamides with hypoglycemic activity. In the case of the 2-benzenesulfonamidopyrimidines, substituted in the 5 position of the pyrimidine ring a correlation between hydrophobic forces, expressed as Rm values, and the binding to...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00237a002

    authors： Seydel JK,Ahrens H,Losert W

    更新日期：1975-03-01 00:00:00

  • Specific inhibition of benzodiazepine receptor binding by some N-(indol-3-ylglyoxylyl)amino acid derivatives: stereoselective interactions.

    abstract：:Several optically active N-(indol-3-ylglyoxylyl)amino acid derivatives were synthesized and tested for [3H]flunitrazepam displacing activity in bovine brain membranes. IC50 values were measured and revealed that the D form of the amino acid moiety of the compounds was more potent than both the L form and racemic form,...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00132a004

    authors： Primofiore G,Marini AM,Da Settimo F,Martini C,Bardellini A,Giannaccini G,Lucacchini A

    更新日期：1989-12-01 00:00:00

  • Potent inhibition of Grb2 SH2 domain binding by non-phosphate-containing ligands.

    abstract：:Development of Grb2 Src homology 2 (SH2) domain binding inhibitors has important implications for treatment of a variety of diseases, including several cancers. In cellular studies, inhibitors of Grb2 SH2 domain binding have to date been large, highly charged peptides which relied on special transport devices for cell...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm980388x

    authors： Yao ZJ,King CR,Cao T,Kelley J,Milne GW,Voigt JH,Burke TR Jr

    更新日期：1999-01-14 00:00:00

  • Methylene-gem-difluorocyclopropane analogues of nucleosides: synthesis, cyclopropene-methylenecyclopropane rearrangement, and biological activity.

    abstract：:Alkylation-elimination of adenine and 2-amino-6-chloropurine with gem-difluorocyclopropane dibromide 10 gave E- and Z-methylene-gem-difluorocyclopropanes 11a, 11b, 12a, and 12b and gem-difluorocyclopropenes 13a and 13b. Debenzylation of intermediates 11a, 11b, 12a, and 12b afforded E- and Z-methylenecyclopropanes 4a, ...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm010191w

    authors： Wang R,Ksebati MB,Corbett TH,Kern ER,Drach JC,Zemlicka J

    更新日期：2001-11-08 00:00:00

  • Isothiazolopyridones: synthesis, structure, and biological activity of a new class of antibacterial agents.

    abstract：:We report the syntheses of first-generation derivatives of isothiazolopyridones and their in vitro evaluation as antibacterial agents. These compounds, containing a novel heterocyclic nucleus composed of an isothiazolone fused to a quinolizin-4-one (at C-2 and C-3 of the quinolizin-4-one), were prepared using a sequen...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm051066d

    authors： Wiles JA,Hashimoto A,Thanassi JA,Cheng J,Incarvito CD,Deshpande M,Pucci MJ,Bradbury BJ

    更新日期：2006-01-12 00:00:00

  • Spirovesamicols: conformationally restricted analogs of 2-(4-phenylpiperidino)cyclohexanol (vesamicol, AH5183) as potential modulators of presynaptic cholinergic function.

    abstract：:In an effort to develop selective inhibitors of vesicular acetylcholine storage, we have synthesized a series of semirigid vesamicol receptor ligands based on the structure of 2-(4-phenylpiperidino)-cyclohexanol (vesamicol, AH5183, 1). In these compounds, the planes of the phenyl and piperidyl moieties of the parent l...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00042a010

    authors： Efange SM,Khare AB,Foulon C,Akella SK,Parsons SM

    更新日期：1994-08-05 00:00:00

  • Phosphorus-nitrogen compounds. 22. Synthesis and antitumor activity of arylsulfonylhydrazone analogues.

    abstract：:A series of pyridine-2-carboxaldehyde N-oxide and pyridine-2-carboxaldehyde (thio)phosphoric hydrazones and two cupric chelates was synthesized. The hydrazones, chelates, and combinations of hydrazones and cupric chloride were tested against mice bearing P388 lymphocytic leukemia, Sarcoma 180, or Ehrlich carcinoma asc...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00209a011

    authors： Cates LA,Good DJ,Jones GS,Lemke TL

    更新日期：1978-11-01 00:00:00

  • Thrombin inhibitors. 2. Amide derivatives of N alpha-substituted L-arginine.

    abstract：:A series of N alpha-(arylsulfonyl)-L-arginine amide derivatives with substituted or unsubstituted naphthalene and heterocyclic compounds as the N alpha-substituent was prepared and tested as inhibitors of the clotting activity of thrombin. N-n-Butyl and N-n-butyl-N-methyl derivatives of N alpha-dansyl-L-arginine amide...

    journal_title：Journal of medicinal chemistry

    pub_type： 杂志文章

    doi：10.1021/jm00182a004

    authors： Kikumoto R,Tamao Y,Ohkubo K,Tezuka T,Tonomura S,Okamoto S,Funahara Y,Hijikata A

    更新日期：1980-08-01 00:00:00

  • Antioxidant-based inhibitors of leukotriene biosynthesis. The discovery of 6-[1-[2-(hydroxymethyl)phenyl]-1-propen-3-yl]-2,3-dihydro-5- benzofuranol, a potent topical antiinflammatory agent.

    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

    authors： Hammond ML,Zambias RA,Chang MN,Jensen NP,McDonald J,Thompson K,Boulton DA,Kopka IE,Hand KM,Opas EE

    更新日期：1990-03-01 00:00:00