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2,4-Diamino-5-[3',4'-dimethoxy-5'-(5-carboxy-1-pentynyl)]benzylpyrimidine (6) and 2,4-diamino-5-[3',4'-dimethoxy-5'-(4-carboxyphenylethynyl)benzylpyrimidine (7) were synthesized from 2,4-diamino-5-(5'-iodo-3',4'-dimethoxybenzyl)pyrimidine (9) via a Sonogashira reaction with appropriate acetylenic esters followed by saponification, and were tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), Mycobacterium avium (Ma), and rat in comparison with the widely used antibacterial agent 2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine (trimethoprim, TMP). The selectivity index (SI) for each compound was calculated by dividing its 50% inhibitory concentration (IC(50)) against rat DHFR by its IC(50) against Pc, Tg, or Ma DHFR. The IC(50) of 6 against Pc DHFR was 1.0 nM, with an SI of 5000. Compound 7 had an IC(50) of 8.2 nM against Ma DHFR, with an SI of 11000. By comparison, the IC(50) of TMP was 12000 nM against Pc, 300 nM against Ma, and 180000 against rat DHFR. The potency and selectivity values of 6 and 7 were not as high against Tg as they were against Pc or Ma DHFR, but nonetheless exceeded those of TMP. Because of the outstanding selectivity of 6 against Pc and of 7 against Ma DHFR, these novel analogues may be viewed as promising leads for further structure-activity optimization. 相似文献
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Background
Whether inhaled corticosteroids suppress airway inflammation in chronic obstructive pulmonary disease (COPD) remains controversial. We sought to determine the effects of inhaled corticosteroids on sputum indices of inflammation in stable COPD.Methods
We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Databases for randomized, controlled clinical trials that used induced sputum to evaluate the effect of inhaled corticosteroids in stable COPD. For each chosen study, we calculated the mean differences in the concentrations of sputum cells before and after treatment in both intervention and control groups. These values were then converted into standardized mean differences to accommodate the differences in patient selection, clinical treatment, and biochemical procedures that were employed across original studies. If significant heterogeneity was present (p < 0.10), then a random effects model was used to pool the original data. In the absence of significant heterogeneity, a fixed effects model was used.Results
We identified six original studies that met the inclusion criteria (N = 162 participants). In studies with higher cumulative dose (≥ 60 mg) or longer duration of therapy (≥ 6 weeks), inhaled corticosteroids were uniformly effective in reducing the total cell, neutrophil, and lymphocyte counts. In contrast, studies with lower cumulative dose (< 60 mg) or shorter duration of therapy (< 6 weeks) did not demonstrate a favorable effect of inhaled corticosteroids on these sputum indices.Conclusions
Our study suggests that prolonged therapy with inhaled corticosteroids is effective in reducing airway inflammation in stable COPD. 相似文献5.
Six 2,4-diaminopyrido[2,3-d]pyrimidines with a 6-methylthio bridge to an aryl group were synthesized and biologically evaluated as inhibitors of Pneumocystis carinii (pc) and Toxoplasma gondii (tg) dihydrofolate reductase (DHFR). The syntheses of analogues 3-8 were achieved by nucleophilic displacement of 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine 14 with various arylthiols. The alpha-naphthyl analogue 4 showed the highest selectivity ratios of 3.6 and 8.7 against pcDHFR and tgDHFR, respectively, versus rat liver (rl) DHFR. The beta-naphthyl analogue 5 exhibited the highest potency within the series with an IC(50) value against pcDHFR and tgDHFR of 0.17 and 0.09 microM, respectively. Analogue 4 was evaluated for in vitro antimycobacterium activity and was shown to inhibit the growth of Mycobacterium tuberculosis H(37)Rv cells by 58% at a concentration of 6.25 microg/mL. 相似文献
6.
A J Kreuzman J M Zock J E Dotzlaf J T Vicenzi S W Queener W K Yeh 《Journal of industrial microbiology & biotechnology》1997,19(5-6):369-377
The serine hydroxymethyltransferase (SHMT) gene glyA was over-expressed in Escherichia coli and the enzyme was purified to near homogeneity. Reaction conditions for E. coli and rabbit liver SHMTs were optimized using succinic semialdehyde methyl ester (SSAME) and glycine. The catalytic efficiency
(k
cat/K
m) of E. coli SHMT for SSAME was 2.8-fold higher than that of rabbit liver enzyme. E. coli SHMT displayed a pH-dependent product distribution different from that of rabbit liver enzyme. For the pyridoxal-5′-phosphate
(PLP)-dependent reaction, E. coli and rabbit liver SHMTs showed a high product diastereospecificity. The stoichiometric ratio of PLP to the dimeric E. coli SHMT was 0.5–0.7, indicating a requirement for external PLP for maximal activity. Using SSAME or its analog at a high temperature,
E. coli SHMT mediated efficient condensation via a lactone pathway. In contrast, at a low temperature, the enzyme catalyzed efficient
conversion of 4-penten-1-al via a non-lactone mechanism. Efficient conversion of either aldehyde type to a desirable diastereospecific
product was observed at a pilot scale. E. coli SHMT exhibited a broad specificity toward aldehyde substrates; thus it can be broadly useful in chemo-enzymatic synthesis
of a chiral intermediate in the manufacture of an important carbacephem antibiotic.
Received 02 December 1996/ Accepted in revised form 24 February 1997 相似文献
7.
Significance of nucleotide sequence alignments: a method for random sequence permutation that preserves dinucleotide and codon usage 总被引:10,自引:0,他引:10
The similarity of two nucleotide sequences is often expressed in terms of
evolutionary distance, a measure of the amount of change needed to
transform one sequence into the other. Given two sequences with a small
distance between them, can their similarity be explained by their base
composition alone? The nucleotide order of these sequences contributes to
their similarity if the distance is much smaller than their average
permutation distance, which is obtained by calculating the distances for
many random permutations of these sequences. To determine whether their
similarity can be explained by their dinucleotide and codon usage, random
sequences must be chosen from the set of permuted sequences that preserve
dinucleotide and codon usage. The problem of choosing random dinucleotide
and codon-preserving permutations can be expressed in the language of graph
theory as the problem of generating random Eulerian walks on a directed
multigraph. An efficient algorithm for generating such walks is described.
This algorithm can be used to choose random sequence permutations that
preserve (1) dinucleotide usage, (2) dinucleotide and trinucleotide usage,
or (3) dinucleotide and codon usage. For example, the similarity of two
60-nucleotide DNA segments from the human beta-1 interferon gene
(nucleotides 196-255 and 499-558) is not just the result of their nonrandom
dinucleotide and codon usage.
相似文献
8.
Khushbu Shah Xin Lin Sherry F. Queener Vivian Cody Jim Pace Aleem Gangjee 《Bioorganic & medicinal chemistry》2018,26(9):2640-2650
To combine the potency of trimetrexate (TMQ) or piritrexim (PTX) with the species selectivity of trimethoprim (TMP), target based design was carried out with the X-ray crystal structure of human dihydrofolate reductase (hDHFR) and the homology model of Pneumocystis jirovecii DHFR (pjDHFR). Using variation of amino acids such as Met33/Phe31 (in pjDHFR/hDHFR) that affect the binding of inhibitors due to their distinct positive or negative steric effect at the active binding site of the inhibitor, we designed a series of substituted-pyrrolo[2,3-d]pyrimidines. The best analogs displayed better potency (IC50) than PTX and high selectivity for pjDHFR versus hDHFR, with 4 exhibiting a selectivity for pjDHFR of 24-fold. 相似文献
9.
Y-R Chen S Usui S W Queener C-A Yu 《Journal of industrial microbiology & biotechnology》1995,15(1):10-18
A procedure for purifying to homogeneity a microbially produced biocatalyst useful for deblocking intermediates in the manufacture of beta-lactam antibiotics is reported. In aqueous solution the purifiedp-nitrobenzyl (PNB) carboxy-esterase was soluble, monomeric (molecular weight: 54 000 by SDS-PAGE or by gel filtration) and exhibited an acidic pl, 4.1. The PNB carboxy-esterase catalyzed rapid ester hydrolysis for simple organic esters such as PNB-acetate, benzyl acetate and -naphthyl acetate and catalyzed deblocking (ester hydrolysis) of beta-lactam antibiotic PNB esters such as cephalexin-PNB and loracarbef-PNB. TheN-terminal amino acid sequence and the amino acid composition are reported. A serine residue is involved in ester hydrolysis: the PNB carboxy esterase was inhibited by phenylmethylsulfonyl fluoride and diethylp-nitrophenyl phosphate; one mole of diisopropyl fluorophosphate titration was required per mole of PNB carboxy-esterase for complete inhibition. When the [3H]-diisopropyl fluorophosphate-treated biocatalyst was digested with Lys C and the resulting peptides separated by HPLC, a single [3H]-labeled peptide was obtained; its amino acid sequence is reported. Inhibition of the PNB carboxy esterase by diethyl pyrocarbonate suggests that a histidinyl residue (or residues) is (are) also involved in the catalytic site of the esterase.Abbreviations used -ME
-mercaptoethanol
- Cf
cefaclor
- Cf
nucleus-PNB
- (6R, 7R)
7-amino-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, (4-nitrophenyl)methyl ester
- Cp
cephalexin
- Cp-PNB
p-nitrobenzyl carboxy-ester of cephalexin
- DEPC
diethyl, pyrocarbonate
- DFP
diisopropyl fluorophosphate
- DMSO
dimethyl sulfoxide
- DNP
diethylp-nitrophenyl phosphate
- EDTA
ethylenediaminetetraacetic acid
- EGTA
ethylene, glycol-bis(aminoethyl ether)
-
N,N,NN
tetracetic acid
- Lc
loracarbef
- Lc-PNB
p-nitrobenzyl carboxy-ester of loracarbef
- Lc
nucleus-PNB
- (6R, 7S)
7-amino-3-chloro-8-oxo-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid, (4-nitrophenyl)methyl ester
- Lys C
an endoproteinase specifically cleaving at C terminal lysine residues
- MWr
relative molecular weight
- PAGE
polyacrylamide gel electrophoresis
- PMSF
phenylmethylsulfonylfluoride
- PNB
p-nitrobenzyl
- PNBCE
p-nitrobenzyl carboxy-esterase
- SDS
sodium dodecyl sulfate 相似文献
10.
Richard H. Baltz Margaret A. McHenney Cathleen A. Cantwell Stephen W. Queener Patricia J. Solenberg 《Antonie van Leeuwenhoek》1997,71(1-2):179-187
Several transposons have been developed from the streptomycete insertion sequence IS493. They have broad host specificity in Streptomyces species and insert relatively randomly into a consensus target sequence of gNCaNTgNNy. Collectively, they have specialized features that facilitate the following: cloning of DNA flanking insertions; physical mapping of insertions; construction of highly stable mutants; and efficient construction of mutant libraries. All of the transposons can be introduced into streptomycetes by conjugation from E. coli, and can be delivered by curing the temperature sensitive delivery plasmid. Tn5099 was used to physically map genes involved in daptomycin and red pigment production in Streptomyces roseosporus, and to clone daptomycin biosynthetic genes. Tn5099 was also used in Streptomyces fradiae to identify and clone a neutral genomic site for the insertion of a second copy of the tylF gene. Recombinants containing two copies of the tylF gene carried out the no rmally rate limiting conversion of macrocin to tylosin very efficiently, thus causing substantial increases in tylosin yield. 相似文献