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PubMed2005

Stereo-specificity for pro-(R) hydrogen of NAD(P)H during enzyme-catalyzed hydride transfer to CL-20.

A dehydrogenase from Clostridium sp. EDB2 and a diaphorase from Clostridium kluyveri were reacted with CL-20 to gain insights into the enzyme-catalyzed hydride transfer to CL-20, and the enzyme's stereo-specificity for either pro-R or pro-S hydrogens of NAD(P)H. Both enzymes biotransformed CL-20 at rates of 18.5 and 24nmol/h/mg protein, using NADH and NADPH as hydride-source, respectively, to produce a N-denitrohydrogenated product with a molecular weight of 393Da. In enzyme kinetics studies using reduced deuterated pyridine nucleotides, we found a kinetic deuterium isotopic effect of 2-fold on CL-20 biotransformation rate using dehydrogenase enzyme against (R)NADD as a hydride-source compared to either (S)NADD or NADH. Whereas, in case of diaphorase, the kinetic deuterium isotopic effect of about 1.5-fold was observed on CL-20 biotransformation rate using (R)NADPD as hydride-source. In a comparative study with LC-MS, using deuterated and non-deuterated NAD(P)H, we found a positive mass-shift of 1Da in the N-denitrohydrogenated product suggesting the involvement of a deuteride (D(-)) transfer from NAD(P)D. The present study thus revealed that both dehydrogenase and diaphorase enzymes from the two Clostridium species catalyzed a hydride transfer to CL-20 and showed stereo-specificity for pro-R hydrogen of NAD(P)H.

Aza Compounds↗
PubMed2006

Expression proteomics to p53 mutation reactivation with PRIMA-1 in breast cancer cells.

PRIMA-1 has emerged as a small molecule that restores the wild type function to mutant p53. To identify molecular targets that are involved in PRIMA-1-induced apoptosis, we used a proteomics approach with two-dimensional gel electrophoresis coupled with liquid chromatography-tandem mass spectrometry for protein identification. By comparing the proteome of the PRIMA-1-treated MDA-231 breast carcinoma cells with that of MCF-7 cells, we have identified seven proteins that upregulated only in MDA-231 cells as a result of PRIMA-1-induced apoptosis. The identified proteins are involved in anaerobic glycolysis and in mitochondrial intrinsic apoptosis. Treatment of MDA-231 cells with PRIMA-1 resulted in the release of mitochondrial cytochrome c as well as the activation of caspase-3, which are essential for the execution of apoptosis. We present evidence to suggest that PRIMA-1-induced apoptosis in breast cancer cells with mutated p53 function involved the expression of proteins required for the activation of mitochondrial intrinsic pathway that is glycolysis-relevant.

Aza Compounds↗
PubMed2004

Synthesis and evaluation of glycosidase inhibitory activity of octahydro-2H-pyrido[1,2-a]pyrimidine and octahydro-imidazo[1,2-a]pyridine bicyclic diazasugars.

An efficient chiron approach for the synthesis of bicyclic diazasugars 4a and 4b having both -CH(2)OH and -OH functionality at the same carbon atom (C-6) is reported. Thus, easily available alpha-D-xylo-pentodialdo-1,4-furanose 5, obtained from D-glucose, on aldol-crossed Cannizzaro reaction followed by hydrogenolysis afforded 7. The regio-selective beta- and alpha-sulfonylation of hydroxymethyl groups in 7 afforded 8a (beta-sulfonylation) and 11 (alpha-sulfonylation) in good yields. The cleavage of the 1,2-acetonide functionality, individually in 8a and 11, followed by reaction with ethylenediamine gave in situ formation of sugar aminals that undergo concomitant nucleophilic displacement of the sulfonyloxy group, by amino functionality, to give hitherto unknown bicyclic diazasugars 4a and 4b, respectively. The inhibitory potency of the earlier reported bicyclic diazasugars 3a,b and 4a,b was evaluated against alpha- and beta-glycosidases and they were found to be potent and specific against the beta-glycosidases with IC(50) and K(1) values in the micro molar range.

Aza Compounds↗
PubMed2004

Design, synthesis, and evaluation of aza inhibitors of chorismate mutase.

A series of aza inhibitors (4-9) of chorismate mutase (E.C. 5.4.99.5) was designed, prepared, and evaluated against the enzyme by monitoring the direct inhibition of the chorismate, 1, to prephenate, 2, conversion. None of these aza inhibitors displayed tighter binding to the enzyme than the native substrate chorismate or greater inhibitory action than the previously reported ether analogue, 3. Furthermore, no time-dependent loss of enzyme activity was observed in the presence of the two potentially reactive aza inhibitors (7 and 9). These results in conjunction with inhibition data from a broader series of chorismate mutase inhibitors allowed a novel proposal for the mechanistic role of chorismate mutase to be developed. This proposed mechanism was computationally verified and correlated with crystallographic studies of various chorismate mutases.

Aza Compounds↗
PubMed2006

Synthesis, characterization and biological activity of complexes of lanthanum(III) with 2-(1'-phenyl- 2'-carboxyl-3'-aza-n-butyl)-1,10-phenanthroline and 2-(1'-p-phenol-2'-carboxyl-3'-aza-n-butyl)-1,10-phenanthroline.

Two novel ligands 2-(1'-phenyl-2'-carboxyl-3'-aza-n-butyl)-1,10-phenanthroline (L1) and 2-(1'-p-phenol-2'-carboxyl-3'-aza-butyl)-1,10-phenanthroline (L2), and their La(III) complexes of La(III)L1, La(III)(L1)(2), La(III)L2, and La(III)(L2)(2), were synthesized and characterized by (1)H NMR, elemental analysis, IR, thermal analysis and conductance measurement. All complexes have been assayed for anticancer activity in vitro against HL-60 (human leukocytoma) cells, PC-3MIE8 (human prostate carcinoma) cells, BGC-823 (human stomach carcinoma) cells, MDA-MB-435 (human galactophore carcinoma) cells, Bel-7402 (human liver carcinoma) cells, and HeLa (human cervix carcinoma) cells. Results showed that the two complexes La(III)L1 and La(III)(L1)(2) exhibited good cytotoxic activity against different cell lines in general; and La(III)(L1)(2) is more effective than cisplatin against all six cell lines. DNA-binding studies indicated that, besides the intercalation, the complexes bind to DNA by the other interaction(s).

Aza Compounds↗
PubMed2004

Aggregation and G-quadruplex DNA-binding study of 6a,12a-diazadibenzo-[a,g]fluorenylium derivative.

The aggregation and DNA binding behavior of a new G-quadruplex selective ligand, 6a,12a-diazadibenzo-[a,g]fluorenylium derivative, was studied by UV-vis absorption and fluorescence spectroscopy. The formation of ligand aggregates with different spectral characteristics was observed at low and high concentration of NaCl, respectively. The ligand binds to G-quadruplex with much higher affinity than to single- and double-stranded DNA.

Aza Compounds↗
PubMed2004

Aza-boronic acids as non-beta-lactam inhibitors of AmpC-beta-lactamase.

With the aim of improving the ability of non-beta-lactam inhibitors to inhibit AmpC-beta-lactamase, a series of 3-aza-phenyl-boronic acid derivatives was obtained using in parallel synthesis. The molecules were tested against Escherichia coli AmpC-beta-lactamase. The best inhibitors, 3-(2-hydroxy-naphthalen-1-ylazo)-phenyl-boronic acid (12) and 3-(2,4-dihydroxy-naphthalen-1-ylazo)-phenyl-boronic acid (14), showed apparent inhibition constant values (K(i)) of 0.3 and 0.45 microM and increased the potency of the semi-synthetic cephalosporin antibiotic, ceftazidime, lowering its minimum inhibitory concentration (MIC) value of 50%, against Gram-negative bacteria strains, producing high levels of AmpC-beta-lactamase.

Aza Compounds↗
PubMed2004

Azaadamantane benzamide 5-HT4 agonists: gastrointestinal prokinetic SC-54750.

Azaadamantanone 1 was converted to a series of aminoazaadamantane benzamides 9a-d, which were profiled for serotonin receptor activity. Aminomethylazaadamantane SC-54750 is a potent 5-HT(4) agonist and 5-HT(3) antagonist with in vivo efficacy in gastroparesis models and also inhibits cisplatin-induced emesis.

Adamantane↗
PubMed2005

Concise synthesis and voltammetric studies of dielsiquinone, a cytotoxic azaanthraquinone.

We have developed a concise synthesis of dielsiquinone 1, a potent cytotoxic agent related to anthraquinones. Electrochemical studies have shown that dielsiquinone is reduced to a semiquinone radical that does not react with O2 to generate toxic reactive oxygen species. These results strongly suggest that 1 should be less cardiotoxic than anthracyclines used in clinic and may therefore provide the basis for the development of safer anticancer drugs.

Animals↗
PubMed2005

Discovery and activity of (1R,4S,6R)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl]-2-methyl-2-azabicyclo[2.2.2]octane-6-carboxamide (3, RY764), a potent and selective melanocortin subtype-4 receptor agonist.

A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.

Animals↗
PubMed2005

Synthesis and activity of N-acyl azacyclic urea HIV-1 protease inhibitors with high potency against multiple drug resistant viral strains.

As part of our efforts to identify potent HIV-1 protease inhibitors that are active against resistant viral strains, structural modification of the azacyclic urea (I) was undertaken by incorporating acyl groups as P(1)' ligands. The extensive SAR study has yielded a series of N-acyl azacyclic ureas (II), which are highly potent against both wild-type and multiple PI-resistant viral strains.

Aza Compounds↗
PubMed2005

Aza-analogues of the marine pyrroloquinoline alkaloids wakayin and tsitsikammamines: synthesis and topoisomerase inhibition.

Two aza-analogues of the marine pyrroloquinoline alkaloids wakayin and tsitsikammamines A and B have been synthesized. The strategy used was based on a 1,3-dipolar cycloaddition reaction between indole 4,7-dione and a diazo-aminopropane derivative. One of the two analogues partially inhibits human topoisomerase I, whereas synthetic intermediates inhibit the enzyme DNA cleavage activity at a concentration comparable to that of the control drug camptothecin.

Animals↗
PubMed2005

Aza-retinoids as novel retinoid X receptor-specific agonists.

A new structurally simple series of potent lipophilic aza-retinoids RXR agonists has been developed. SAR studies for the N-alkyl-azadienoic acids described here demonstrate that the RXR activity profile is sensitive to the N-alkyl chain length. Further, we have expanded the work to include azadienoic acids, which exhibited many accessible conformations leading to a better understanding of the SAR around the series.

Aza Compounds↗