Synthesis and biological activities of lipid A analogs: modification of a glycosidically bound group with chemically stable polar acidic groups and lipophilic groups on the disaccharide backbone with tetradecanoyl or N-dodecanoylglycyl groups.

Six novel lipid A analogs were synthesized. The first two analogs, 4 and 5, have an alpha-glycosidically bound carboxymethyl or 1,3-dicarboxyisopropyl group on the disaccharide backbone with four tetradecanoyl groups. The next three analogs, 6, 7 and 8, have two or four N-dodecanoylglycyl groups on the 1-alpha-O-phosphonooxyethylated disaccharide backbone. Analog 6 bears N-dodecanoylglycyl groups on the hydroxyl functions at positions 3 and 3', and tetradecanoyl groups on the amino functions at positions 2 and 2'. Analog 7 is a 2, 3, 2' and 3'-tetrakis(N-dodecanoylglycyl) derivative, and analog 8 resembles compound 6, but the binding of the N-dodecanoylglycyl and tetradecanoyl groups at positions 2, 2' and 3, 3' are reversed. The third analog, 9, has the same acyl group configuration as compound 6, but has a 1,3-dicarboxyisopropyl group at position C-1. Compounds 4 and 5 exhibited definite antitumor activity against Meth A fibrosarcoma, indicating that the phosphate group at the C-1 position in lipid A could be replaced by the carboxylic acid without reducing the antitumor activity. In rabbits, compounds 6 and 9 exhibited potent antitumor activity, but their toxicity was extremely low. On the other hand, compounds 7 and 8 showed no antitumor activity. The levels of antitumor activity of 6 and 9 were similar to those of the natural-type lipid A. The antitumor activities of analogs with a N-dodecanoylglycyl group on the disaccharide backbone depended on the connecting sites of the acyl groups.     

Fingerprint patterns from laser-induced Azido photochemistry of spin-labeled photoaffinity ATP analogs in matrix-assisted laser desorption/ionization mass spectrometry

The photochemical reaction of azide derivatives induced by ultraviolet (UV) laser in matrix-assisted laser desorption/ionization mass spectrometry (MALDI) is reported. A novel synthesized class of azide aromatic derivatives, spin-labeled photoaffinity non-nucleoside adenosine triphosphate (ATP) analogs which are useful probes in study of muscle contraction mechanism, is used in this investigation. In the negative ion MALDI spectra of these ATP analogs, “fingerprint” peaks corresponding to [M − 10 − 1]⁻, [M − 12 − 1]⁻, [M − 16 − 1]⁻, [M − 26 − 1]⁻, [M − 28 − 1]⁻, [M − 41 − 1]⁻, and [M − 42 − 1]⁻ were observed with relative intensities depending on the MALDI matrix. Only the [M − 16 − 1]⁻ is present in the similar mass spectra of the analog in which the azido group is replaced by a hydrogen. A model is suggested for the photochemical reactions of azide derivatives under UV laser irradiation. The photoreaction fingerprint information is diagnostically useful in characterization of azido compounds, especially for spin-labeled photoaffinity non-nucleoside ATP analogs.     

Investigation of reactions postulated to occur during inhibition of ribonucleotide reductases by 2'-azido-2'-deoxynucleotides

Model 3'-azido-3'-deoxynucleosides with thiol or vicinal dithiol substituents at C2' or C5' were synthesized to study reactions postulated to occur during inhibition of ribonucleotide reductases by 2'-azido-2'-deoxynucleotides. Esterification of 5'-(tert-butyldiphenylsilyl)-3'-azido-3'-deoxyadenosine and 3'-azido-3'-deoxythymidine (AZT) with 2,3-S-isopropylidene-2,3-dimercaptopropanoic acid or N-Boc-S-trityl-L-cysteine and deprotection gave 3'-azido-3'-deoxy-2'-O-(2,3-dimercaptopropanoyl or cysteinyl)adenosine and the 3'-azido-3'-deoxy-5'-O-(2,3-dimercaptopropanoyl or cysteinyl)thymidine analogs. Density functional calculations predicted that intramolecular reactions between generated thiyl radicals and an azido group on such model compounds would be exothermic by 33.6-41.2 kcal/mol and have low energy barriers of 10.4-13.5 kcal/mol. Reduction of the azido group occurred to give 3'-amino-3'-deoxythymidine, which was postulated to occur with thiyl radicals generated by treatment of 3'-azido-3'-deoxy-5'-O-(2,3-dimercaptopropanoyl)thymidine with 2,2'-azobis-(2-methyl-2-propionamidine) dihydrochloride. Gamma radiolysis of N(2)O-saturated aqueous solutions of AZT and cysteine produced 3'-amino-3'-deoxythymidine and thymine most likely by both radical and ionic processes.     

Synthesis and Anti‐HIV Activity of Triazolo‐Fused 2′,3′‐Cyclic Nucleoside Analogs Prepared by an Intramolecular Huisgen 1,3‐Dipolar Cycloaddition

Triazolo‐fused 2′,3′‐cyclic nucleoside analogs were synthesized by an intramolecular 1,3‐dipolar cycloaddition of nucleoside‐derived azido alkynes in a regio‐ and stereospecific manner. The uracil base in these target compounds was successfully transformed to the corresponding cytosine. The synthesized compounds were examined in a MAGI assay for their anti‐HIV activities, and in a H9 T lymphocytes assay for their cell toxicities.     

Versatile introduction of azido moiety into oligonucleotides through diazo transfer reaction

The use of a diazo transfer (DZT) reagent enables clean and efficient conversion of aminated oligodeoxyribonucleotides (ODNs) into their azido counterparts under mild conditions. ODNs bearing an amino tether at the 3', 5', or any internal position could be modified in this manner thus demonstrating the versatility of this reaction. Easy access to such azido-modified ODNs is of great interest for conjugation in particular through copper catalyzed 1,3-dipolar cycloaddition (CuAAC reaction).     

Rational modification of a selection strategy leads to deoxyribozymes that create native 3'-5' RNA linkages

We previously used in vitro selection to identify several classes of deoxyribozymes that mediate RNA ligation by attack of a hydroxyl group at a 5'-triphosphate. In these reactions, the nucleophilic hydroxyl group is located at an internal 2'-position of an RNA substrate, leading to 2',5'-branched RNA. To obtain deoxyribozymes that instead create linear 3'-5'-linked (native) RNA, here we strategically modified the selection approach by embedding the nascent ligation junction within an RNA:DNA duplex region. This approach should favor formation of linear rather than branched RNA because the two RNA termini are spatially constrained by Watson-Crick base pairing during the ligation reaction. Furthermore, because native 3'-5' linkages are more stable in a duplex than isomeric non-native 2'-5' linkages, this strategy is predicted to favor the formation of 3'-5' linkages. All of the new deoxyribozymes indeed create only linear 3'-5' RNA, confirming the effectiveness of the rational design. The new deoxyribozymes ligate RNA with k(obs) values up to 0.5 h(-1) at 37 degrees C and 40 mM Mg2+, pH 9.0, with up to 41% yield at 3 h incubation. They require several specific RNA nucleotides on either side of the ligation junction, which may limit their practical generality. These RNA ligase deoxyribozymes are the first that create native 3'-5' RNA linkages, which to date have been highly elusive via other selection approaches.     

A solid phase approach to PDMP analogs：A general strategy for combinatorial library

The present work reports the first solid phase synthesis of biologically interesting D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol(D-threo-PDMP)derivatives.This synthetic strategy includes facile preparation of versatile azido intermediate(5) in a relatively short sequence and the subsequent derivatization of 5,which led to a series of sulfonamide,urea and heterocycle substituted PDMP analogs(10 and 10’).With this method,a 5280-member compound library has been successfully built by IRORI Nanokan? system.     

Preparation and Evaluation of Arylazide-Substituted Pyridine Adenine Dinucleotides for Photoaffinity Labeling Experiments

Two pyridine-modified NAD'analogs, 3–(3-azido benzo-yl) pyridine adenine dinucleotide 1 and N -(3-azido-5-car-boxyl) phenyl nicotinamide adenine dinucleotide 2 have been prepared and evaluated for photoaffinity labeling experiments. The syntheses were accomplished via a mammalian NADase-catalyzed base exchange reaction. The new NAD⁺ analogs retained the carbonyl or carhox-amido functional group at the 3 position of the pyridine ring. The analog 1 is the first pyridine-modified azido derivative of NAD⁺ that has shown coenzyme activity in a stereospecific hydride transfer reaction catalyzed by a dehydrogenase. Both NAD⁺ analogs have shown potential for the study of active sites of NAD⁺-utilizing enzymes.     

Synthesis and conformational analysis of fructose-derived scaffolds: molecular diversity from a single molecule

Bi- and tricyclic compounds were synthesized starting from fructose. The different hydroxyl groups present in fructose were exploited in the formation of a number of conformationally constrained sugar-based scaffolds, including azido acids. Introduction of an azido group and carboxy terminus into different bicyclic iodo ethers, allowed the synthesis of different conformationally constrained azido acids. Conformational analysis of compounds 10, 11, 17, and 20 by NMR experiments assisted by molecular mechanics, allowed the determination of the distances between the relevant functional groups, that is the azido and carboxy functionalities.     

Synthesis, characterization, and energetic properties of diazido heteroaromatic high-nitrogen C-N compound

The synthesis, characterization, and energetic properties of diazido heteroaromatic high-nitrogen C-N compound, 3,6-diazido-1,2,4,5-tetrazine (DiAT), are reported. Its normalized heat of formation (NDeltaHf), experimentally determined using an additive method, is shown to be the highest positive NDeltaHf compared to all other organic molecules. The unexpected azido-tetrazolo tautomerizations and irreversible tetrazolo transformation of DiAT are remarkable compared to all other polyazido heteroaromatic high-nitrogen C-N compounds, for example, 2,4,6-triazido-1,3,5-triazine; 4,4',6,6'-tetra(azido)hydrazo-1,3,5-triazine; 4,4',6,6'-tetra(azido)azo-1,3,5-triazine; and 2,5,8-tri(azido)-1,3,4,6,7,9,9b-heptaazaphenalene (heptazine).     

Synthesis, biological activity and modelling studies of two novel anti HIV PR inhibitors with a thiophene containing hydroxyethylamino core

An efficient method has been developed for the synthesis of a versatile intermediate bearing azido, hydroxyl and ester functions, a useful precursor for peptidomimetic compounds. The two main features for this synthesis were the use of the Sharpless asymmetric dihydroxylation on thiophene acrylate and the subsequent regioselective ring opening by sodium azide of the cyclic sulfite. Highly chemoselective reduction of the azido alcohol led to a key compound which was utilized for the synthesis of two analogues of commercial anti HIV PR such as nelfinavir and saquinavir. The biological activity and molecular modelling study on these two new potential drugs have been evaluated.     

Synthesis and biological evaluation of novel tert-azido or tert-amino substituted penciclovir analogs

tert-Azido or amino substituted penciclovir analogs, 1-3 were synthesized for the purpose of improving the efficacy and bioavailability of penciclovir and searching for novel antiviral agents. Among several methods attempted to insert an azido group into the alpha,beta-unsaturated ester 6, only Bronsted acid-catalysed 1,4-conjugate addition conditions (NaN3, 75% acetic acid, 80 degrees C) gave the desired tert-azido product 7. The synthesized final penciclovir analogs 1-3 were evaluated in vitro against several viruses such as HIV-1, HSV-1 and 2, poliovirus, VZV, and VSV. Compound 2 only showed weak antiviral activity against HSV-1 without cytotoxicity. Although the synthesized compounds did not exhibit an excellent antiviral activity, the successful method used in introducing the tert-azido group is expected to be generally utilized for the synthesis of nucleoside analogs with a tert-azido substituent.     

Comparative theoretical studies of energetic azo s-triazines

In this work, the properties of the synthesized high-nitrogen compounds 4,4',6,6'-tetra(azido)azo-1,3,5-triazine (TAAT) and 4,4',6,6'-tetra(azido)hydrazo-1,3,5-triazine (TAHT), and a set of designed bridged triazines with similar bridges were studied theoretically to facilitate further developments for the molecules of interests. The gas-phase heats of formation were predicted based on the isodesmic reactions by using the DFT-B3LYP/AUG-cc-PVDZ method. The estimates of the condensed-phase heats of formation and heats of sublimation were estimated in the framework of the Politzer approach. Calculation results show that the method gives a good estimation for enthalpies, in comparison with available experimental data for TAAT and TAHT. The crystal density has been computed using molecular packing calculations. The calculated detonation velocities and detonation pressures indicate that -NF(2), -NO(2), -N═N-, and -N═N(O)- groups are effective structural units for improving the detonation performance of the bridged triazines. The synthesized TAAT and TAHT are not preferred energetic materials due to their inferior detonation performance. The p→π conjugation effect between the triazine rings and bridges makes the molecule stable as a whole. The electrostatic behavior of the bridged triazines is characterized by an anomalous surface potential imbalance when incorporating the strongly electron-withdrawing -NF(2) and -NO(2) groups into the molecule. An analysis of the bond dissociation energies shows that all these derivatives have good thermal stability over RDX and HMX, and the -NH-NH- bridge is more helpful for improving the stability than -N═N(O)- and -N═N- bridges. Considering the detonation performance and thermal stability, three bridged triazines may be considered as the potential candidates of high-energy density materials (HEDMs).     

Vibrational spectra and structure of 1,2,4-trlazole derivatives

The frequencies and forms of the normal vibrations of 3-azido- and 3-azido-5-methyl-1,2,4-triazoles and their 1-deutero-substituted derivatives were calculated, the effect of the geometrical parameters of 3-azido-1,2,4-triazole on the vibrational spectra was investigated, and the most probable three-dimensional model of the molecule was selected. The solution of the inverse spectral problem was effected by the method of least squares, and the potential energy constants of the azidotriazoles were calculated. It is shown that the force constants of the azido group increase and the elastic constants of the ring decrease when an azido group is introduced into the 1,2,4-triazole molecule. The frequencies in the experimental spectra were assigned to the principal types of normal vibrations.     

Probing platinum azido complexes by 14N and 15N NMR spectroscopy

Metal azido complexes are of general interest due to their high energetic properties, and platinum azido complexes in particular because of their potential as photoactivatable anticancer prodrugs. However, azido ligands are difficult to probe by NMR spectroscopy due to the quadrupolar nature of (14)N and the lack of scalar (1)H coupling to enhance the sensitivity of the less abundant (15)N by using polarisation transfer. In this work, we report (14)N and (15)N NMR spectroscopic studies of cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))] (1) and trans,trans,trans-[Pt(N(3))(2)(OH)(2)(X)(Y)], where X=Y=NH(3) (2); X=NH(3), Y=py (3) (py=pyridine); X=Y=py (4); and selected Pt(II) precursors. These studies provide the first (15)N NMR data for azido groups in coordination complexes. We discuss one- and three-bond J((15)N,(195)Pt) couplings for azido and am(m)ine ligands. The (14)N(α) (coordinated azido nitrogen) signal in the Pt(IV) azido complexes is extremely broad (W(1/2)≈2124 Hz for 4) in comparison to other metal azido complexes, attributable to a highly asymmetrical electric field gradient at the (14)N(α) atom. Through the use of anti-ringing pulse sequences, the (14)N NMR spectra, which show resolution of the broad (14)N(α) peak, were obtained rapidly (e.g., 1.5 h for 10 mM 4). The linewidths of the (14)N(α) signals correlate with the viscosity of the solvent. For (15) N-enriched samples, it is possible to detect azido (15)N resonances directly, which will allow photoreactions to be followed by 1D (15)N NMR spectroscopy. The T(1) relaxation times for 3 and 4 were in the range 5.7-120 s for (15)N, and 0.9-11.3 ms for (14)N. Analysis of the (1)J((15)N,(195)Pt) coupling constants suggests that an azido ligand has a moderately strong trans influence in octahedral Pt(IV) complexes, within the series 2-pic相似文献   

Organotin compounds as energy-potentiated uncouplers of rat liver mitochondria

Triorganotins will titrate membrane potential (Δψ) and the accompanying pH gradient (ΔpH) in estimates of protonmotive force (Δp) in isolated rat liver mitochondria in an apparent concentrationdependent manner and in minimal halide media (5 μmol dm^?3). Under these conditions the concentrations of organotin required to produce a drop of 80–120mV in Δp approach or are in excess of those required to inhibit ATP-synthase activity, which are at least three-fold greater than those which inhibit ATP hydrolytic activity. The addition of exogenous chloride ion did not appreciably alter the steady-state or rate estimates of triorganotin-mediated membrane potential (Δψ) depolarization. The evidence indicates that triorganotins possess an uncoupling effect which is independent of halide/hydroxyl exchange or direct inhibition of the ATPase complex. The activity of various triorganotins may be best understood according to their abilities to uncouple or directly inhibit oxidative phosphorylation at the enzymic level, in the absence of halide/hydroxyl exchange.     

Tuning the regioselectivity of the Staudinger reaction for the facile synthesis of kanamycin and neomycin class antibiotics with N-1 modification

[reaction: see text] A novel method for achieving the desired regioselective reduction of the N-1 azido group on a tetraazidoneamine has been developed that leads to the synthesis of both kanamycin and neomycin class antibiotics bearing N-1 modification. Both classes of aminoglycosides are active against aminoglycoside-resistant bacteria carrying APH(3')-I and AAC(6')/APH(2').     

3-Substituted Anilines as Scaffolds for the Construction of Glutamine Synthetase and DXP-Reductoisomerase Inhibitors

Access to a series of truncated ATP analogs, as potential anti-tuberculosis agents, has been explored via alkylation and acylation of 3-aminophenol, whereas chloroacetylation, using chloroacetyl chloride, and subsequent Arbuzov phosphonation of a series of 3-substituted anilines have afforded a series of phosphonate derivatives as potential antimalarial agents.     

2'-Amino-alpha-chloroacetophenone as a valuable tool for the synthesis of conveniently-substituted alpha,beta-epoxychalcone derivatives

The synthesis of conveniently substituted 2'-amino-alpha,beta-epoxychalcones is described. They were obtained through Darzens condensation of 2'-amino-3',5'-dimethoxy-alpha-chloroacetophenone with benzaldehydes. The latter can undergo different cyclization possibilities and afford a variety of flavonoid analogs with biological potential.     

携带叠氮和氨侧基的脂肪族聚酯的合成和表征

通过丙交酯(LA)与环状碳酸酯单体共聚的方法制备了一种侧链带有溴原子的脂肪族聚酯, 并将溴原子用叠氮基团取代, 通过Cu(Ⅰ)催化的Click反应将其氨基化, 得到了侧链带有氨基的脂肪族聚酯.