Abstract：
:Reformatski condensation of benzyl 2-bromopropionate with 4-carbomethoxybenzaldehyde, followed by dehydration afforded benzyl 2-methyl-p-carbomethoxycinnamate (4a). Hydrogenation over a Pd catalyst gave the hydrocinnamic acid 5a. Conversion to the chloromethyl (6a) and azidomethyl ketone (7a) was followed by hydrogenation to the aminomethyl ketone (8a). Direct N-alkylation by 2,4-diamino-5-nitro-6-chloropyrimidine followed by reductive ring closure in Zn-HOAc and subsequent saponification of the benzoate ester yielded 4-amino-4-deoxy-9-methyl-10-deazapteroic acid (11a). Coupling with diethyl L-glutamate and saponification afforded 9-methyl-10-deazaminopterin (13a). The 9-ethyl analogue (13b) was similarly prepared from benzyl 2-bromobutyrate. The 9-methyl analogue (13a) was 21 times more potent than MTX as an inhibitor of cell growth in L1210 cells. The reason for this enhanced cytotoxicity in L1210 is unclear, since enzyme inhibition and transport parameters were similar to those of MTX. In human Manca leukemia cells growth inhibition was not dramatic and paralleled MTX.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
DeGraw JI,Christie PH,Kisliuk RL,Gaumont Y,Sirotnak FMdoi
10.1021/jm00163a035subject
Has Abstractpub_date
1990-01-01 00:00:00pages
212-5issue
1eissn
0022-2623issn
1520-4804journal_volume
33pub_type
杂志文章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：:A series of N(6)-alkyl-2-alkynyl derivatives of adenosine (Ado) have been synthesized and evaluated for their affinity at human A(1), A(2A), and A(3) receptors and for their potency at A(2B) adenosine receptor subtypes. The corresponding 2-(1-alkynyl) derivatives of 5'-N-ethylcarboxamidoadenosine (NECA) and Ado are us...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0109762
更新日期：2002-07-18 00:00:00
abstract：:The adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O(6)-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC(50) = 9.5 nM and 5.4 nM vs CDK1/cyclinB and C...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm0311442
更新日期：2004-07-15 00:00:00
abstract：:In this study we present the synthesis and some pharmacological properties of nine new analogues of arginine vasopressin modified in the N-terminal part of the molecule with 2-aminoindane-2-carboxylic acid (Aic). The peptides were tested for their in vitro uterotonic and in vivo pressor and antidiuretic activities. On...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm070174s
更新日期：2007-06-14 00:00:00
abstract：:Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. P-glycoprotein (P-gp), a promiscuous drug efflux pump, has been extensively studied for its association with MDR due to overexpression in cancer cells. Several P-gp inhibitors or modulators have been investigated in clinical trials in hope ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章,评审
doi：10.1021/acs.jmedchem.7b01457
更新日期：2018-06-28 00:00:00
abstract：:To design and synthesize new potent and selective antagonists of the human A(3) adenosine receptor, pharmacophoric hypotheses were generated with the software Catalyst for a comprehensive set of compounds retrieved from previous literature. Three of these pharmacophores were used to drive the optimization of a molecul...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm051112+
更新日期：2006-07-13 00:00:00
abstract：:Starting with a previously reported linear breast cancer targeting decapeptide WxEAAYQkFL, here we report the synthesis of a novel cyclic peptide analogue cyclic WXEAAYQkFL. The N- to C-terminus amide cyclized peptide with one d-amino acid (k) displayed higher uptake by breast cancer cells, with minimal uptake by the ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00163
更新日期：2017-06-22 00:00:00
abstract：:(-)-P7C3-S243 is a neuroprotective aminopropyl carbazole with improved druglike properties compared with previously reported compounds in the P7C3 class. It protects developing neurons in a mouse model of hippocampal neurogenesis and protects mature neurons within the substantia nigra in a mouse model of Parkinson's d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm401919s
更新日期：2014-05-08 00:00:00
abstract：:Novel 3,5-bis(benzylidene)-1-[3-(2-hydroxyethylthio)propanoyl]piperidin-4-ones (3a-e) display potent cytotoxicity and a preferential lethality toward various neoplasms compared to some normal cells. The corresponding sulfonic acid analogues 5a-e and an isostere 4 demonstrated substantially lower activity. The leads 3d...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm101595p
更新日期：2011-05-12 00:00:00
abstract：:The insertion of single 1,4-disubstituted 1,2,3-triazoles as metabolically stable bioisosteres of trans-amide bonds (triazole scan) was recently applied to the 177Lu-labeled tumor-targeting analog of minigastrin, [Nle15]MG11. The reported novel mono-triazolo-peptidomimetics of [Nle15]MG11 showed either improved resist...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01937
更新日期：2020-05-14 00:00:00
abstract：:N-Methylation of two retinoidal amide compounds, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benz oic acid (3, Am80) and 4-[[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)carbonyl]amino]benzoic acid (5, Am580), resulted in the disappearance of their potent differentiation-inducing act...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00130a011
更新日期：1989-10-01 00:00:00
abstract：:The discovery of isozyme-selective histone deacetylase (HDAC) inhibitors is critical for understanding the biological functions of individual HDACs and for validating HDACs as drug targets. The isozyme HDAC10 contributes to chemotherapy resistance and has recently been described to be a polyamine deacetylase, but no s...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.8b01936
更新日期：2019-05-09 00:00:00
abstract：:Ketanserin is the prototypic 5-HT2 serotonin antagonist; although it has been an important tool for the study of serotonin pharmacology, it has had relatively little impact on drug design because remarkably little is known about its structure-affinity relationships. Furthermore, ketanserin also binds at 5-HT1C recepto...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00104a017
更新日期：1992-12-25 00:00:00
abstract：:When cephalosporins exert their biological activity by reacting with bacterial enzymes, opening of the beta-lactam ring can lead to expulsion of the 3'-substituent. A series of cephalosporins was prepared in which antibacterial quinolones were linked to the 3'-position through a quaternary nitrogen. Like the 3'-ester-...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00106a031
更新日期：1991-02-01 00:00:00
abstract：:A unique, dual-function, photoactivatable anticancer prodrug, RuEuL, has been tailored that features a ruthenium(II) complex linked to a cyclen-europium chelate via a π-conjugated bridge. Under irradiation at 488 nm, the dark-inactive prodrug undergoes photodissociation, releasing the DNA-damaging ruthenium species. U...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b01162
更新日期：2017-11-09 00:00:00
abstract：:Our exploratory study was based on the concept that a non-amidine factor Xa (fXa) inhibitor is suitable for an orally available anticoagulant. We synthesized and evaluated a series of N-(6-chloronaphthalen-2-yl)sulfonylpiperazine derivatives incorporating various fused-bicyclic rings containing an aliphatic amine expe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm049884d
更新日期：2004-10-07 00:00:00
abstract：:A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridines with dopaminergic activity is described. The structure-activity relationships of this series were studied by synthesis of analogs and evaluation of their affinities for the dopamine (DA) D2 receptor and inhibition of locomotor activity (LMA) in r...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950721m
更新日期：1996-08-02 00:00:00
abstract：:N5-Acetyl-N5-hydroxy-L-ornithyl-N5-acetyl-N5-hydroxy-L-ornithyl-N5-acety l- N5-hydroxy-L-ornithine, the functionally instrumental component of the albomycins and ferrichromes, has been incorporated as a "carrier" substructure into both carbacephalosporin and oxamazin type beta-lactam antibiotics. The previously synthe...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00107a014
更新日期：1991-03-01 00:00:00
abstract：:A series of 1-methyl-1H-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, Haemonchus contortus. These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indices, and were progresse...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.0c01793
更新日期：2021-01-14 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：:A series of renin inhibitors with novel modifications at the P2 site has been prepared. Structure-activity relationships reveal that for a particular P2 fragment the in vitro potency is highly dependent on the nature of the P2' portion in addition to the P1-P1' group. The length of the P2 side chain and choice of epsi...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00108a004
更新日期：1991-04-01 00:00:00
abstract：:Histone deacetylase 6 (HDAC6) is an emerging target for the treatment of cancer, neurodegenerative diseases, inflammation, and other diseases. Here, we present the multicomponent synthesis and structure-activity relationship of a series of tetrazole-based HDAC6 inhibitors. We discovered the hit compound NR-160 by inve...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.9b01888
更新日期：2020-09-24 00:00:00
abstract：:The simulated binding profiles of acetylcholine, ACh, and the inhibitor (+/-)-2,3-dihydro-5,6- dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-on e hydrochloride (E2020), 1, and some of its analogs to acetylcholinesterase, AChE, were determined using full force field energetics and allowing complete co...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm950596e
更新日期：1996-10-25 00:00:00
abstract：:A novel class of artemisinin analogs, N-alkyl-11-aza-9-desmethylartemisinins 17-29, were synthesized via ozonolysis and acid-catalyzed cyclization of precursor amides 5-16. These amides were prepared through condensation of an activated ester of the known intermediate acid 2 with the corresponding primary amine. The a...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00026a011
更新日期：1995-12-22 00:00:00
abstract：:Twelve 1,4-naphthoquinones have been tested against the ascitic form of sarcoma 180 in Swiss mice. Statistical analysis shows that the most important molecular parameter determining their effectiveness in prolonging the life of mice bearing this tumor is their redox potentials. Although the toxicities of the compounds...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00358a021
更新日期：1983-04-01 00:00:00
abstract：:A series of substituted benzenedisulfonamide carbonic anhydrase inhibitors is described and their anticonvulsant activities are listed. One compound, 4-(4-methoxypiperidinosulfonyl)-2-chlorobenzenesulfonamide (19, UK-12130), was found to have anticonvulsant activity in animals at a dose level that gave only a minimal ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00207a001
更新日期：1978-09-01 00:00:00
abstract：:A number of indole-3-glyoxylamides have previously been reported as tubulin polymerization inhibitors, although none has yet been successfully developed clinically. We report here a new series of related compounds, modified according to a strategy of reducing aromatic ring count and introducing a greater degree of sat...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.5b01312
更新日期：2015-12-10 00:00:00
abstract：:The weak antiallergic activity of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carbox yli c acid (1) in the rat reaginic passive cutaneous anaphylaxis test was enhanced by the introduction of an (arylamino)methylene moiety into position 9 of the pyridopyrimidine ring. Compound 34, (+)-6(S)-methyl-9-[...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00376a003
更新日期：1984-10-01 00:00:00
abstract：:Benzofuran, indan and tetrahydronaphthalene analogs of 3,4-(methylenedioxy)amphetamine (MDA) were prepared in order to examine the role of the dioxole ring oxygen atoms of MDA in interacting with the serotonin and catecholamine uptake carriers. The series of compounds was evaluated for discriminative stimulus effects ...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/jm00075a027
更新日期：1993-11-12 00:00:00
abstract：:The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [11C]-(R)-3 ([11C]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on e...
journal_title：Journal of medicinal chemistry
pub_type： 杂志文章
doi：10.1021/acs.jmedchem.7b00396
更新日期：2017-08-24 00:00:00
