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A series of 4-aza-5 alpha-androstane compounds with one or two aromatic moieties in the carbamoyl group at the C-17 position were synthesized and their inhibitory activities for rat and human prostatic testosterone 5 alpha-reductase were tested in vitro. Compounds with one aromatic moiety in the carbamoyl group showed high inhibitory activity for rat 5 alpha-reductase, but little for human prostatic 5 alpha-reductase. On the other hand, compounds with two aromatic moieties had potent inhibitory activities for both rat and human 5 alpha-reductase. The structural requirements for potent inhibition for both enzymes are discussed in relation to the spatial arrangement of the C-17 carbamoyl group.
Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.
[Reaction: see text]. Condensation of a readily available 5-amino-2-alkenoate ester with alpha-unsubstituted aliphatic aldehydes leads to substituted 1,2,3,4-tetrahydropyridines. Subsequent manipulation of the ester and enamine functions gives a quick access to 2-azabicyclo[3.3.1]nonane-containing compounds.
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Some new oleanolic acid derivatives with lactame and thiolactame structures in the A- or C-ring were prepared and tested as percutaneous transport promoters in vitro. Their activity was comparable with activity of N-dodecylcaprolactame (Azone). A-Thiolactame derivative of methyl oleanolate (13) was the most effective compound.
New diazabicycloundecenium and phosphazenium derivatives of purines are introduced for mild and efficient preparation of nucleoside analogs via in situ alkylation. Diazabicycloundecenium salts of purines were obtained directly as a result of an unusual reaction between two corresponding amino compounds.
We recently identified PRIMA-1 as a low molecular weight compound that restores tumor suppressor function to mutant p53 proteins and has anti-tumor activity in vivo (1). Here we report the statistical analysis of the effect of PRIMA-1 on a panel of human tumor cell lines using information available in a database at the Developmental Therapeutics Program of the National Cancer Institute (NCI). We extracted growth inhibition profiles for PRIMA-1 and 44 known anticancer agents, p53 status of cell lines, population doubling time, and level of p53 protein expression from the NCI database. The data were analyzed by linear regression, Wilcoxon matched pairs test, and cluster analysis. In a subset of human cell lines derived from colon, ovarian, renal, and non-small cell lung cancer and melanoma, the level of mutant p53 expression correlated with cell population doubling time, r = -0.53, P = 0.018. The GI(50) values for PRIMA-1 correlated with levels of mutant p53, r = -0.75, P = 0.0002. PRIMA-1 showed a statistically significant preference at P = 0.04 for growth inhibition of tumor cell lines expressing mutant p53 as compared with lines expressing wild-type p53. In contrast, none of several known anticancer drugs showed such preference. PRIMA-1 inhibited the growth of cell lines derived from various human tumor types in a mutant p53-dependent manner. This distinguishes PRIMA-1 from known anticancer drugs and supports the idea that PRIMA-1 can serve as a lead for the development of novel therapeutic compounds.
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Compounds were synthesized where oxygen in the ethoxypiperidine region of raloxifene is replaced with carbon, sulfur, or nitrogen linkages. Thia- and aza-substituted compounds were prepared by novel methodology. The compounds were evaluated in vitro as selective estrogen receptor modulators (SERMs). Calculations suggested the compounds exhibit an ER-alpha binding affinity/conformational energy relationship.
Selected species of the tribe Antidesmeae (Euphorbiaceae, subfamily Phyllanthoideae) have been screened for antidesmone occurrence and its content by quantitative HPLC (UV) and qualitative LC-MS/MS analysis. The LC-MS analysis allowing the additional detection of 17,18-bis-nor-antidesmone, 18-nor-antidesmone, 8-dihydroantidesmone and 8-deoxoantidesmone was carried out in the selected reaction monitoring (SRM) mode. Leaf material from herbarium specimens of 13 Antidesma spp., Hyeronima alchorneoides and Thecacoris stenopetala (all subtribe Antidesminae), as well as Maesobotrya barteri, Aporosa octandra (both Scepinae) and Uapaca robynsii (Uapacinae) were analysed. Additionally, freshly collected samples of different plant parts of two Antidesma spp. were investigated to ensure the significance of the results on herbarium specimens and to compare the antidesmone content in bark, root and leaves. Antidesmone could be unambiguously identified in 12 of 13 Antidesma spp., as well as in the two other investigated genera of subtribe Antidesminae, in levels of up to 65 mg/kg plant dry weight. Antidesmone was not found in specimens from other subtribes. Antidesmone-derived compounds occur in much lower concentrations than antidesmone.
The in vitro activity of moxifloxacin, formerly BAY 12-8039, against gram-positive bacteria was tested by the agar dilution method. A total of 189 isolates that included Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, streptococci, rhodococci, leuconostocs, pediococci, lactobacilli, and diphtheroids were tested. Moxifloxacin showed greater potency than ciprofloxacin against S. aureus, streptococci, and enterococci, having Minimal Inhibitory Concentrations (MICs) lower than those of ciprofloxacin by 2- to 64-fold. This improved activity was most prominent for S. aureus. Moxifloxacin was active against Leuconostoc and Rhodococcus species. Time-kill studies using moxifloxacin at a concentration of 3 micrograms/mL against one isolate each of methicillin-resistant S. aureus (MSSA) (MIC, 0.031 microgram/mL), MRSA (MIC, 1 microgram/mL), two isolates of E. faecalis (MICs, 0.25 and 2 micrograms/mL), and two isolates of vancomycin-resistant E. faecium (MICs, 0.25 and 2 micrograms/mL) revealed an average decrease in colony forming unit (CFU) by 3.8, 0.4, 4.0, 2.0, 4.2, and 1.8 log10 CFU/mL at 24 h, respectively. Moxifloxacin is a new 8-methoxyquinolone with improved in vitro activity against gram-positive bacteria. Further studies of the in vivo activity of this compound appear warranted.
Population changes induced by acridine mustards in haploid and diploid cultured cell lines from Rana pipiens were compared to test the expectation that recessive mutations will be expressed in diploid cells with a frequency equal to the square of that in haploid cells, and to investigate the usefulness of such comparison for the screening of possible mutagens. The differences in survival frequency after treatment were much smaller than predicted on the basis of the expression of lethal (recessive) mutations alone. Survival was also affected by culture conditions, drug-resistance phenomena, and other cell properties. It is suggested that with the evolution of epigenetic processes for the production of stable phenotypes, the vertebrate cell also acquired more efficient means to prevent the expression of gene mutation and that the acridine compounds may affect both epigenetic and genetic changes.
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A pseudo-aza-monosaccharide and several pseudo-aza-disaccharide compounds were constructed based on replacement of the anomeric carbon with a nitrogen and the ring oxygen with a carbon. The inhibition constants of these compounds toward five different glycosidases, alpha-glucosidase, beta-glucosidase, isomaltase, alpha-mannosidase, and glucoamylase, were obtained. Isofagomine, the pseudo-aza-monosaccharide, shows a broad spectrum of strong inhibition against glycosidases. It is the most potent inhibitor of beta-glucosidase from sweet almonds reported to date and also a strong inhibitor of glucoamylase, isomaltase, and alpha-glucosidase. Isofagomine inhibits beta-glucosidase, glucoamylase, and isomaltase more strongly than 1-deoxynojirimycin where the ring oxygen has been replaced with a nitrogen. The alpha-1,6- linked pseudo-disaccharide showed very strong inhibition toward glucoamylase, being nearly as potent an inhibitor as acarbose. Pseudo-disaccharides in which the anomeric nitrogen was methylated to favor formation of either the alpha or beta substrate linkage generally had weakened inhibition for the glycosidases studied most likely due to steric interference with the various active sites. These results indicate that the presence of a basic group at the anomeric center is important for carbohydrase inhibition. The presence of a charged carboxylate group near the anomeric carbon which interacts with the basic nitrogen is suggested for these enzymes, particularly for beta-glucosidase. The presence of a second alpha-linked glucosyl residue is also critical for strong inhibition of glucoamylase.
1,3,8-Triazabicyclo[4.4.0]decan-2-ones and -thiones varying substituents at positions 3 and 8 have been synthesized. When tested in cotton rats for their antifilarial activity against Litomosoides carinii, some of the compounds showed moderate microfilaricidal activity.
The title compound, C(16)H(16)N(2)O, which contains a double bond connecting an azabicyclic ring system to an indol-3-ylmethylene group, crystallizes from a solution in ethyl acetate. The geometries of the two crystallographically independent molecules are nearly identical. The crystal packing of the title compound involves two types of intermolecular hydrogen bond.