Potential bile acid metabolites. 25. Synthesis and chemical properties of stereoisomeric 3alpha,7alpha,16- and 3alpha,7alpha,15-trihydroxy-5beta-cholan-24-oic acids

Epimeric 3alpha,7alpha,16- and 3alpha,7alpha,15-trihydroxy-5beta-cholan-24-oic acids and some related compounds were synthesized from chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), respectively. The key reaction involved one-step remote oxyfunctionalization of unactivated methine carbons at C-17 of CDCA and at C-14 of UDCA as their methyl ester-peracetate derivatives with dimethyldioxirane (DMDO). After dehydration of the resulting 17alpha- and 14alpha-hydroxy derivatives with POCl(3) or conc. H(2)SO(4), the respective Delta(16)- and Delta(14)-unsaturated products were subjected to hydration via hydroboration followed by oxidation to yield the 3,7,16- and 3,7,15-triketones, respectively. Stereoselective reduction of the respective triketones with tert-butylamine-borane complex afforded the epimeric 3alpha,7alpha,16- or 3alpha,7alpha,15-trihydroxy derivatives exclusively. A facile formation of the corresponding epsilon-lactones between the side chain carboxyl group at C-24 and the 16alpha- (or 16beta-) hydroxyl group in bile acids is also clarified.     

Competing excited state intramolecular proton transfer pathways from phenol to anthracene moieties

Four new 9-(2'-hydroxyphenyl)anthracene derivatives 7-10 were synthesized and their potential excited state intramolecular proton transfer (ESIPT) reaction investigated. Whereas 7 reacted via the anticipated (formal) ESIPT reaction (proton transfer to the 10-position of the anthracene), derivatives 8-10 reacted via ESIPT to both 9- and 10-positions, giving rise to two types of intermediates, quinone methides (e.g., 29) and zwitterions (e.g., 30). These intermediates are trapped by solvent (water or methanol) giving addition products that can readily revert back to starting material. However, on extended photolysis, the products that are isolated can best be rationalized as being due to competing elimination and intramolecular cyclization of zwitterions 30 and 37. These results show that it is possible to structurally tune ESIPT in (hydroxyphenyl)anthracenes to either result in a completely reversible reaction or give isolable anthracene addition or rearrangement products.     

Synthesis of 4-thiouridine, 6-thioinosine, and 6-thioguanosine 3',5'-O-bisphosphates as donor molecules for RNA ligation and their application to the synthesis of photoactivatable TMG-capped U1 snRNA fragments

4-Thiouridine, 6-thioguanosine, and 6-thioinosine 3',5'-bisphosphates (9, 20, and 28) were synthesized in good yields by considerably improved methods. In the former two compounds, uridine and 2-N-phenylacetylguanosine were converted via transient O-trimethylsilylation to the corresponding 4- and 6-O-benzenesulfonyl intermediates (2 and 13), which, in turn, were allowed to react with 2-cyanoethanethiol in the presence of N-methylpyrrolidine to give 4-thiouridine (3) and 2-N-phenylacetyl-6-thioguanosine derivatives (14), respectively. In situ dimethoxytritylation of these thionucleoside derivatives gave the 5'-masked products 4 and 15 in high overall yields from 1 and 11. 6-S-(2-Cyanoethyl)-5'-O-(4,4'-dimethoxytrityl)-6-thioinosine (23) was synthesized via substitution of the 5'-O-tritylated 6-chloropurine riboside derivative 22 with 2-cyanoethanethiol. These S-(2-cyanoethyl)thionucleosides were converted to the 2'-O-(tert-butyldimethylsilyl)ribonucleoside 3'-phosphoramidite derivatives 7, 18, and 26 or 3',5'-bisphosphate derivatives 8, 19, and 27. Treatment of 8, 19, and 27 with DBU gave thionucleoside 3',5'-bisphosphate derivatives 9, 20, and 28, which were found to be substrates of T4 RNA ligase. These thionucleoside 3',5'-bisphosphates were examined as donors for ligation with m3(2,2,7) G5'pppAmUmA, i.e., the 5'-terminal tetranucleotide fragment of U1 snRNA, The 4-thiouridine 3',5'-bisphosphate derivative 9 was found to serve as the most active substrate of T4 RNA ligase with a reaction efficiency of 96%.     

Synthesis, structure and properties of pyrazole type tetrakis compounds

A series of pyrazole type tetrakis compounds has been synthesized by reaction of aromatic or heterocyclic dialdehydes and pyrazolone derivatives. Structure and tautomerism of the products were investigated by spectroscopic methods and X-ray analysis. Several tetrakis compounds form inclusion complexes with solvents like alcohols, ethers, and ketones in a definite ratio via hydrogen bonds.     

2,6-Diacylnaphthalene-1,8:4,5-bis(dicarboximides): synthesis, reduction potentials, and core extension

2,6-Diacyl derivatives of naphthalene-1,8:4,5-bis(dicarboximide)s have been synthesized via Stille coupling reactions of the corresponding 2,6-distannyl derivative with acyl halides. Reaction of these diketones with hydrazine gave phthalazino[6,7,8,1-lmna]pyridazino[5,4,3-gh][3,8]phenanthroline-5,11(4H,10H)-dione fused-ring derivatives. The products were characterized by UV-vis absorption spectroscopy and electrochemistry, modeled using density functional theory calculations, and, in some cases, studied and compared using single-crystal X-ray diffraction.     

Synthesis and single cell pharmacology of potential heterocyclic bioisosteres of the excitatory amino acid antagonist glutamic acid diethyl ester

A series of heterocyclic analogues of glutamic acid diethyl ester (GDEE), an antagonist at central excitatory amino acid receptors, have been synthesized and tested biologically. (RS)-Ethyl alpha-amino-alpha-(3-ethoxyisoxazol-5-yl)acetate (7), (RS)-ethyl 2-amino-3-(3-ethoxy-5-methylisoxazol-4-yl)propionate (16) and closely related analogues were synthesized. Compound 7, a diethyl derivative of the naturally occurring excitatory amino acid ibotenic acid (IBO), was synthesized from 3-hydroxy-5-methylisoxazole (1) via 3-ethoxyisoxazol-5-ylacetic acid (5) and its ethyl ester. Nitrosation of this ester followed by catalytic reduction gave 7. The ethyl ester of IBO, 9, was synthesized in a similar manner from 3-benzyloxyisoxazol-5-ylacetic acid (8). Ethyl derivatives of the synthetic excitatory amino acid 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) were synthesized from 3-hydroxy-4,5-dimethylisoxazole (10) through a diethyl acetylaminomalonate derivative, which upon deprotection gave the 3-ethoxy derivative of AMPA (15). Esterification of 15 gave the diethyl derivative 16 and the ethyl ester of AMPA (18) as well as N-ethylated derivatives of AMPA, 21 and 22 were synthesized. The final products were tested microelectrophoretically. The derivatives 7, 9, 15, 16 and 18 were weak and non-selective excitatory amino acid antagonists, whereas 21 and 22 were found to be inactive.     

Synthesis,PM3‐Semiempirical,and Biological Evaluation of Pyrazolo[4,3‐c]quinolinones

A series of α,β‐unsaturated ketones containing quinolone moieties 2 , 3 , 4 , 5 , 6 were synthesized by condensation of 7‐methoxyquinoline‐2,4(1H,3H)‐dione ( 1 ) with different aryl aldehydes. Pyrazole derivatives 8 , 9 , 10 , 11 were also synthesized via refluxing of α,β‐unsaturated ketones 2 , 3 , 4 , 5 , 6 with hydrazine derivatives. Newly synthesized compounds were characterized by elemental analyses, spectral data, and screened for their antioxidant and antitumor activities. Geometrical optimizations of the molecular structures for different synthesized compounds were studied.     

Synthesis and Reactivity of Enaminones: Synthesis of Some 1,3,4‐Thiadiazole Linked to Pyrazole,Pyridine, Benzimidazolopyrimidine,Pyrazolopyrimidine, Pyrazolotriazine and Triazolotriazine Derivatives

1,3,4‐Thiadiazole‐enaminone ( 6 ) was synthesized via reaction of the benzamide ( 5 ) with DMF‐DMA. The simple thiadiazole‐enaminone ( 6 ) was used as a synthetic precursor for the synthesis of a wide variety of new heterocyclic compounds, including the 5‐substituted‐1,3,4‐thiadiazole derivatives ( 7 ), ( 8 ), ( 16 ), ( 17 ) and ( 18 ), which were obtained via reactions of ( 6 ) with nitrogen nucleophiles. Also, reactions of enaminone ( 6 ) with carbon nucleophiles afforded the respective 1,3,4‐thiadiazoles ( 10a , 10b ). Diazotization of the benzamide ( 20 ) with the heteroaromatic amine salts gave the hydrazone derivatives ( 21 ) and ( 22 ). Cyclization of the latter hydrazones yielded the corresponding pyrazolotriazine and 1,2,4‐triazolotriazine derivatives ( 23 ) and ( 24 ), respectively. All newly synthesized compounds were elucidated by considering the data of both elemental and spectral analysis.     

新型香豆素类Mannich碱荧光功能化合物的合成及性质研究

以4-卤代间苯二酚为原料经甲酰化反应合成了2,4-二羟基-5-卤代苯甲醛,再通过Knoevenagel缩合反应合成了5种香豆素衍生物,最后经Mannich反应获得了5种未见文献报道的香豆素类荧光功能化合物.所得的荧光化合物的结构均用1H NMR,IR,MS和元素分析等方法进行了表征,并且对该类化合物的荧光性质及对金属离子的响应进行了研究.结果发现,由于光诱导电子转移(PET)的作用,在Mannich反应后,目标产物的荧光强度弱于反应前,而当该产物与金属离子配合后,PET作用减弱,荧光强度得到恢复.     

Multicomponent reactions for the synthesis of functionalized 1, 4-oxathiane-3-thiones under microwave irradiation in water

A series of substituted 1,4-oxathiane-3-thione derivatives were synthesized via one-pot multicomponent reactions of nitromethane, carbon disulfide and oxiranes in the presence of Et3N in water as the solvent under microwave irradiation. Particularly valuable features of this method include high yields of products, broad substrate scope, short reaction time and straightforward procedure.     

Synthesis of novel substituted pyridines from 1-(3-aminophenyl)-3-(1<Emphasis Type="Italic">H</Emphasis>-indol-3-yl)prop-2-en-1-one and their anticancer activity

A series of novel substituted pyridine derivatives have been synthesized via the reaction of 3-indole carboxaldehyde with 3-aminoacetophenone. The products structures have been elucidated from elemental analysis as well as IR, ¹H NMR, ¹³C NMR, and MS spectroscopy data. All the synthesized compounds have shown anticancer activity against HEPG2 and MCF-7 in vitro; some of them have exhibited the in vivo activity.     

Sulfation of deoxynivalenol,its acetylated derivatives,and T2-toxin

The synthesis of several sulfates of trichothecene mycotoxins is presented. Deoxynivalenol (DON) and its acetylated derivatives were synthesized from 3-acetyldeoxynivalenol (3ADON) and used as substrate for sulfation in order to reach a series of five different DON-based sulfates as well as T2-toxin-3-sulfate. These substances are suspected to be formed during phase-II metabolism in plants and humans. The sulfation was performed using a sulfuryl imidazolium salt, which was synthesized prior to use. All protected intermediates and final products were characterized via NMR and will serve as reference materials for further investigations in the fields of toxicology and bioanalytics of mycotoxins.     

Eco-friendly synthesis of guanidinyltetrazole compounds and 5-substituted 1H-tetrazoles in water under microwave irradiation

We have developed simple, short time, cost effective, purification of products by non-chromatographic methods and environmentally benign protocol for the synthesis of guanidinyltetrazoles and 5-substituted 1H-tetrazoles derivatives via [2,3]cyclo-addition reaction of nitriles and azide derivatives in water under microwave irradiation. All the synthesized products are screened for their in vitro antimicrobial activity. The synthesized compounds were obtained in excellent yield (85–98%).     

Improved,Highly Efficient,and Green Synthesis of Bromofluorenones and Nitrofluorenones in Water

A series of bromo-, nitro-, and bromonitrofluorenones were synthesized chemo- and regioselectively in 90–98% yield via electrophilic aromatic bromination and nitration under mild conditions using water as the sole solvent. These synthetic methods involve simple workup procedures and use only minimal amounts of organic solvents during the purification of products. The newly developed methods have the advantages of being cost-effective and environmentally friendly and could potentially be used for the large-scale synthesis of fluorenone derivatives.     

Synthesis and Antioxidant Evaluation of Some Novel Thiophene,Pyrazole, Chromene,Pyrazolotriazine Derivatives Bearing Sulfonamide Moiety

As a part of ongoing studies in developing new potent antioxidant agents, N‐[4‐(aminosulfonyl)phenyl]‐2‐cyanoacetamide ( 3 ) was utilized as key intermediate for the synthesis of some new thiophene, chromene, and pyrazolotriazine pyridine derivatives. The structures of the newly synthesized compounds were confirmed by elemental analysis, IR, ¹H‐NMR, and mass spectral data. Representative compounds of the synthesized products were tested and evaluated as antioxidant. Compounds 7 and 30 are promising compounds.     

Efficient Synthesis of Urea Derivatives via a Sequential One-Pot Nucleophilic Addition/Ugi Five-Component Reaction Under Solvent-Free Conditions

Urea polyfunctional derivatives were successfully synthesized via a one-pot, five-component nucleophilic addition/Ugi reaction sequence. Simplicity, solvent-free conditions, and good yields of products are advantages of this method.     

Dapson in Heterocyclic Chemistry,Part II: Antimicrobial and Antitumor Activities of Some Novel Sulfone Biscompounds Containing Biologically Active Thioureido,Carbamothioate, Quinazoline,Imidazolidine, and Thiazole Moieties

The reaction of 4,4′-diisothiocyanato-1,1-diphenylsulfone 2 with aromatic amines and phenol derivatives afforded the corresponding thioureio derivatives 3–9 , respectively. Also, the reaction of 2 with catechol gave the corresponding carbamothioate derivative 11. Quinazoline derivatives 14 and 15 were obtained in good yield via reaction of 2 with anthranlic acid derivatives. Imidazolidine biscompounds 16 and 17 were readily synthesized from the reaction of 2 with N-(4-substituted-phenyl)cyanothioformanilides. The structure of the products was confirmed from elemental analysis as well as spectral data. Most of the synthesized compounds showed remarkable antimicrobial activity compared with chloramphenicol and Grisofluvine as positive controls. Compound 6 was almost as active an antitumor agent as the reference drug Doxorubicin.     

Synthesis,cytotoxic assessment,and molecular docking studies of 2,6-diaryl-substituted pyridine and 3,4- dihydropyrimidine-2(1H)-one scaffolds

Cancer is one of the main global health problems. In order to develop novel antitumor agents, we synthesized 3,4-dihydropyrimidine-2(1H)-one (DHPM) and 2,6-diaryl-substituted pyridine derivatives as potential antitumor structures and evaluated their cytotoxic effects against several cancer cell lines. An easy and convenient method is reported for the synthesis of these derivatives, employing cobalt ferrite (CoFe ₂ O ₄ @SiO ₂ -SO ₃ H) magnetic nanoparticles under microwave irradiation and solvent-free conditions. The structural characteristics of the prepared nanocatalyst were investigated by FTIR, XRD, SEM, and TGA techniques. In vitro cytotoxic effects of the synthesized products were assessed against the human breast adenocarcinoma cell line (MCF-7), gastric adenocarcinoma (AGS), and human embryonic kidney (HEK293) cells via MTT assay. The results indicated that compound 4r (DHPM derivative) was the most toxic molecule against the MCF-7 cell line (IC ₅₀ of 0.17 μg/mL). Moreover, compounds 4j and 4r (DHPM derivatives) showed excellent cytotoxic activities against the AGS cell line, with an IC ₅₀ of 4.90 and 4.97 μg/mL, respectively. Although they are pyridine derivatives, compounds 5g and 5m were more active against the MCF-7 cell line. Results showed that the candidate compounds exhibited low cytotoxicity against HEK293 cells. The kinesin Eg5 inhibitory potential of the candidate compounds was evaluated by molecular docking. The docking results showed that, among the pyridine derivatives, compound 5m had the most free energy of binding (–9.52 kcal/mol) and lowest Ki (0.105 μM), and among the pyrimidine derivatives, compound 4r had the most free energy of binding (–7.67 kcal/mol) and lowest Ki (2.39 μM). Ligand-enzyme affinity maps showed that compounds 4r and 5m had the potential to interact with the Eg5 binding site via H-bond interactions to GLU116 and GLY117 residues. The results of our study strongly suggest that DHPM and pyridine derivatives inhibit important tumorigenic features of breast and gastric cancer cells. Our results may be helpful in the further design of DHPMs and pyridine derivatives as potential anticancer agents.     

Synthesis of L-epi-capreomycidine derivatives via C-H amination

The L-epi-capreomycidine (Cpm) derivatives were efficiently and stereoselectively synthesized via nitrene C-H insertion starting from a readily available D-Tyr. Design of a substrate that takes into account hydrogen bonding is a critical feature in order to achieve high selectivity. Our synthetic strategy could be a new access to epi-Cpm and its derivatives, which are found in several biologically active natural products.     

Synthesis,characterization, and determination of photophysicochemical properties of peripheral and nonperipheral tetra‐7‐oxy‐3,4‐dimethylcoumarin substituted zinc,indium phthalocyanines

The photochemical and photophysical properties of peripheral and nonperipheral zinc and indium phthalocyanines containing 7‐oxy‐3,4‐dimethylcoumarin synthesized were investigated in this study. 7‐Hydroxy‐3,4‐dimethylcoumarin ( 1 ) was synthesized via Pechmann condensation reaction and then the phthalonitrile derivatives [4‐(7‐oxy‐3,4‐dimethylcoumarino)phthalonitrile ( 2 ) and 3‐(7‐oxy‐3,4‐dimethylcoumarino)phthalonitrile ( 3 )] were synthesized by nucleophilic aromatic substitution. Phthalocyanine compounds containing coumarin units on peripheral ( 4 and 5 ) and nonperipheral ( 6 and 7 ) positions were prepared via cyclotetramerization of phthalonitrile compounds. All compounds' characterizations were performed by spectroscopic methods and elemental analysis. The phthalocyanine derivatives' ( 4–7 ) photochemical and photophysical properties were studied in DMF. The photophysical (fluorescence quantum yields and lifetimes) and photochemical (singlet oxygen and photodegradation quantum yields) properties of these novel phthalocyanines ( 4 – 7 ) were studied in DMF. They produced good singlet oxygen (e.g., Φ_Δ = 0.93 for 7 ) and showed appropriate photodegradation (in the order of 10^?5), which is very important for photodynamic therapy applications.