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The synthesis and influenza neuraminidase inhibitory activity of a new series of C3-aza carbocyclic neuraminidase inhibitors are described. Analogues 3c and 3j, bearing a 3-pentyl group, exhibit influenza A inhibitory activities comparable to that of 1.
A new route to 17 beta-substituted-6-azaandrost-4-en-3-ones, potent dual inhibitors of type 1 and 2 steroidal 5 alpha-reductase, is described.
A series of azapeptides was prepared and assessed as inhibitors of the human rhinovirus 3C protease. Boc-VLFaQ-OPh was a slow-turnover substrate that gave transient (ca. 1-2 h) inhibition as it underwent hydrolysis. Boc-VLFaG-OPh gave very slow but essentially irreversible inhibition.
A series of 3-(3-phenylisoxazol-5-yl)methylidene-1-azabicycles synthesized showed different binding characteristics to acetylcholine receptors depending on the substituents on the phenyl ring. Small polar substituents gave preferential binding affinity to nicotinic receptors, and large hydrophobic substituents to muscarinic receptors.
The structure of a homonojirimycin isomer isolated from Aglaonema treublii and originally proposed as alpha-3,4-di-epi-homonojirimycin was revised to alpha-4-epi-homonojirimycin 3 ("alpha-homoallonojirimycin") on the basis of NMR analysis and synthetic studies. Its activity as a glycosidase inhibitor is compared to that of other homonojirimycin isomers.
A modified nucleoside was synthesized with adenine and a 6-membered azasugar, and it was converted to the phosphoramidite which was used for the incorporation into oligonucleotides. The hybridization properties of the modified oligonucleotides with DNA and RNA were studied.
N-Aminoazaaromatics were found to react with nitric oxide in the presence of oxygen to afford deaminated products in high yields. The reaction proceeded almost instantaneously in various solvents including water, and one to two equivalent of NO was consumed depending upon the amount of oxygen coexisted, and 1 equivalent of N2O was released in the reaction. In addition, N-aminoazoles were deaminated by potassium superoxide to give parent azoles in good yields. Two equivalents of superoxide was consumed, and about half equivalents of both nitrite and nitrate ion were released. The results demonstrated that N-aminoazoles have ability to protect the biological system against the oxidation promoted by radicals such as nitrogen oxides and superoxide.
Nonimmunosuppressant ligands, exemplified by GPI 1046 (1), for the peptidyl-prolyl isomerase FKBP12 have been found to unexpectedly possess powerful neuroprotective and neuroregenerative effects in vitro and in vivo. We have extensively explored the therapeutic utility of FKBP12 ligands based on analogues of proline and pipecolic acid. As part of our ongoing program to explore novel structural classes of FKBP12 ligands, we herein wish to report a new class of FKBP12 ligands containing aza-proline and aza-pipecolic acid analogues. Details of the synthetic studies, together with biological activity will be presented.
The normal co-ordinate analysis have been carried out for 7-methyl-1,5,7-triazabicyclo[4,4,0]dec-5-ene (MTBD) and its three possible protonated tautomeric forms. The calculations and measured infrared (IR) spectra are consistent with a tautomeric species in which the proton is attached to an imine nitrogen atom.
We review data on the in-vitro, ex-vivo, in-vivo, and clinical effects of fluoroquinolones on the synthesis of cytokines and their mechanisms of immunomodulation. In general, most fluoroquinolone derivatives superinduce in-vitro interleukin 2 synthesis but inhibit synthesis of interleukin 1 and tumour necrosis factor (TNF)alpha; furthermore, they enhance significantly the synthesis of colony-stimulating factors (CSF). Fluoroquinolones affect in-vivo cellular and humoral immunity by attenuating cytokine responses. Interleukins 10 and 12 have an important role in the functional differentiation of immunocompetent cells and trigger the initiation of the acquired immune response. In addition, certain fluoroquinolones were seen to enhance haematopoiesis by increasing the concentrations of CSF in the lung as well as in the bone marrow and shaft. Those fluoroquinolones exerting significant effects on haematopoiesis were those with a cyclopropyl moiety at position N1 of their quinolone core structure. Mechanisms that could explain the various immunomodulatory effects of fluoroquinolones include: (1) an effect on intracellular cyclic adenosine-3',5'-monophosphate and phosphodiesterases; (2) an effect on transcription factors such as nuclear factor (NF)kappaB, activator protein 1, NF-interleukin-6 and nuclear factor of activated T cells; and (3) a triggering effect on the eukaryotic equivalent of bacterial SOS response with its ensuing intracellular events. Further studies are required, especially in the clinical setting to exploit fully the potential of the immunomodulatory effect of fluoroquinolones during, for example, immunosuppression, chronic airway inflammatory diseases, and sinusitis.
Recent efforts to develop pharmacologic agents that restore function to mutant forms of p53 hold significant promise in cancer therapy. Here, we examine the effects of such pharmacologic activation of p53 function using a small molecule, PRIMA-1, and a model system employing a p53 protein fused to a mutant steroid binding domain of the murine estrogen receptor (p53ERtam) that renders it responsive only in the presence of 4-hydroxytamoxifen. In either case, p53 activation triggered apoptosis that was not inhibited by the presence of macromolecular synthesis inhibitors. This p53-induced, transcription-independent apoptosis is Bax dependent, proceeds in the absence of a nucleus, and involves Bax translocation and cytochrome c release. Hence, pharmacologic p53 modulators can activate a transcription-independent apoptotic program.
Rattus norvegicus infestations on six farmsteads were poisoned with 0.5% 5-p-chlorophenyl silatrane and those on another six with 2.5% zinc phosphide. Both poisons were applied in pinhead oatmeal bait containing also 5% corn oil, after pre-baiting. The result of each treatment was assessed by comparing the take of pre-bait with that of a census bait (wheat) laid after the poisoning.The zinc phosphide treatments were generally more effective than those done with 5-p-chlorophenyl silatrane, but the latter were somewhat detrimentally affected by cautious baiting on the part of one of the operators.The results are discussed and it is concluded that although they indicate that 0.5% 5-p-chlorophenyl silatrane may have approached zinc phosphide in effectiveness under the conditions of the trial, it would in most circumstances be significantly less effective and possibly less safe to use than the latter, well-tried poison.
The performance of the rodenticide 5-p-chlorophenyl silatrane at 0.5% in a wholemeal flour/pinhead oatmeal/corn oil bait was compared with that of zinc phosphide at 3% in the same base in poison treatments carried out against urban infestations of the house mouse (Mus musculus L.). Each poison treatment was conducted for 1 day and after 3 days' pre-baiting. The success of the treatments was assessed from census baitings conducted before and after treatment. Treatment success varied considerably with both poisons used but in general 5-p-chlorophenyl silatrane proved to be at least as effective as zinc phosphide, a commonly used acute rodenticide for the control of mice.
We have analyzed by nucleotide analog interference mapping (NAIM) pools of precursor or mature tRNA molecules, carrying a low level of Rp-RMPalphaS (R = A, G, I) or Rp-c7-deaza-RMPalphaS (R = A, G) modifications, to identify functional groups that contribute to the specific interaction with and processing efficiency by Escherichia coli RNase P RNA. The majority of interferences were found in the acceptor stem, T arm, and D arm, including the strongest effects observed at positions G19, G53, A58, and G71. In some cases (interferences at G5, G18, and G71), the affected functional groups are candidates for direct contacts with RNase P RNA. Several modifications disrupt intramolecular tertiary contacts known to stabilize the authentic tRNA fold. Such indirect interference effects were informative as well, because they allowed us to compare the structural constraints required for ptRNA processing versus product binding. Our ptRNA processing and mature tRNA binding NAIM analyses revealed overlapping but nonidentical patterns of interference effects, suggesting that substrate binding and cleavage involves binding modes or conformational states distinct from the binding mode of mature tRNA, the product of the reaction.
3-(Carboxymethyl)-3-azapentanedioic acid (NTA), 3,12-bis(carboxymethyl)-6,9-dioxa-3,12-diazatetradecanedioic acid (EGTA), and 1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid (DOTA) structures having a 4-nitrophenyl substituent attached via an alkyl spacer to the methylene carbon atom of one carboxymethyl arm of the chelator were obtained by alkylation of 4-nitrophenylalanine with bromoacetic acid (NTA), by reductive alkylation of 1,8-diamino-3,6-dioxaoctane with (4-nitrophenyl)-pyruvic acid followed by alkylation with bromoacetic acid (EGTA), and by alkylation of the trimethyl ester of 1,4,7,10-tetraazacyclododecane-N,N',N"-triacetic acid with the methyl ester of alpha-bromo-4-(4-nitrophenyl)pentanoic acid and subsequent saponification (DOTA). The nitrophenyl-substituted chelators were converted to the corresponding amines by hydrogenation then reacted with thiophosgene to give the protein-reactive aryl isothiocyanate derivatives.
Nitric oxide is a gaseous, short-living free radical which behaves as an important signaling molecule with pleiotropic capacities including vasodilatation, neurotransmission, and microbial and tumor cell killing, as well as in tissue damage and organ-specific autoimmune disorders. Here, a synthesized, dinuclear copper complex system in vitro obtained by the simple aza-phenolic ligand 2,6-bis[[bis-(2-aminoethyl)amino]methyl]phenol (L) and Cu(II) ion has been used. The stability constants of ligand L with Cu(II) ion were determined through potentiometric measurements in aqueous solution (37.1 +/- 0.1 degrees C, I = 0.15 M of NaCl) to mimic the biological medium. The measurements demonstrated that [Cu(2)H(-1)L(OH)](2+) (DCu) is the predominant species present in solution at pH 7.4. The molecular structure of the ligand in this species permits the cooperation of the two copper ions in assembling the substrate, thus the complex can be used as a receptor for small molecules such as NO. As a biological model, we chose the production of NO catalyzed by inducible nitric oxide synthase obtained from RAW 264.7 murine macrophage cell line stimulated with LPS, which enabled us to prove that NO is coordinated by the DCu complex, modifying its EPR spectra. The coordination of NO with DCu reduces the level of nitrite in the culture medium of stimulated RAW 264.7 macrophages without any inhibition in the expression of iNOS.
2'-O-Methyl oligoribonucleotides bearing a 3'-[2,6-dioxo-3,7-diaza-10-(1,5,9-triazacyclododec-3-yl)decyl phospate conjugate group have been shown to cleave in slight excess of Zn(2+) ions complementary oligoribonucleotides at the 5'-side of the last base-paired nucleotide. The cleavage obeys first-order kinetics and exhibits turnover. The acceleration compared to the monomeric Zn(2+) 1,5,9-triazacyclododecane chelate is more than 100-fold. In addition, 2'-O-methyl oligoribonucleotides having the 1,5,9-triazacyclododec-3-yl group tethered to the anomeric carbon of an intrachain 2-deoxy-beta-d-erythro-pentofuranosyl group via a 2-oxo-3-azahexyl, 2,6-dioxo-3,7-diazadecyl, or 2,9-dioxo-3,10-diazatridecyl linker have been studied as cleaving agents. These cleave as zinc chelates a tri- and pentaadenyl bulge opposite to the conjugate group approximately 50 times as fast as the monomeric chelate and show turnover. The cleavage rate is rather insensitive to the length of linker. Interestingly, a triuridyl bulge remains virtually intact in striking contrast to a triadenyl bulge. Evidently binding of the zinc chelate to a uracil base prevents its catalytic action. Replacement of Zn(2+) with Cu(2+) or Ni(2+) retards the cleaving activity of all the cleaving agents tested.
A bis-hydrated Gd3+ complex based on tris acetic acid-1,4,7,10-tetraazacyclododecane (DO3A) that was functionalized with aza-15-crown-5 demonstrated a nearly optimal water-exchanging rate (k(ex) = 3.1 x 10(7) s(-1)) and low acute cytotoxicity. Efficient magnetic resonance signal intensity enhancements and prolonged residence lifetime induced by this small molecular complex in vivo were demonstrated even with one-fifth of the standard dosage used in the clinic.