含有二糖结构的核苷类似物的合成

利用Ferrier重排反应合成了两个系列的连有核音的2,3-不饱和糖苷(其中核耷包括尿苷、腺苷、肌苷等).这些新化合物的结构通过NMR和MS(HRFAB)得到证实.     

The Synthesis and Antimicrobial Screening of Some Novel AZA-Imidoxy Compounds as Potential Chemotherapeutic Agents

Some novel azaimidoxy compounds viz. 2-{[(4-chlorophenyl)diazenyl]oxy}-1H-isoindole-1,3-(2H)-dione (Va), and 1-{[1-naphthyldiazenyl]oxy}pyrrolidine-2,5-dione (IVc), etc. have been synthesized by a simple diazotization reaction followed by a coupling with 2-hydroxy-1H-isoindole-1,3(2H)-dione (III)/1-hydroxypyrrolidine-2,5-dione (II) of corresponding aromatic primary amine derivatives at a suitable pH. A similar reaction with a [1,3]thiazolo[4,5-b]pyridin-2-amine (VIII) lead us to some interesting results variable with a pH. The structure of all synthesized compounds has been established by IR, ¹H NMR, and mass studies. These compounds have been screened for antimicrobial activities in order to evaluate the possibility of the derivatives to be used as potential chemotherapeutic agents.     

Synthesis of 1,2‐Disubstituted Carbocyclic Nucleoside Analogues of Cytidine

The synthesis of new 1,2‐disubstituted, five‐ or six‐ring‐carbocyclic nucleoside analogues of cytidine, compounds 1 and 2a – d , are described. These compounds were obtained by aminolysis, starting from the corresponding uracil derivative, via nucleophilic displacement of a triazolyl (Scheme 1) or a (2,4,6‐triisopropylphenyl)sulfonyl (TPS) group (Scheme 2) at 4‐position of the pyrimidine ring.     

The Synthesis of Novel Iodinated Iminodiacetic Acid Analogues as Hepatobiliary Imaging Agents

Summary. The synthesis and characterization of N-[2-[[4-iodo-2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N-(carboxymethyl)glycine and N-[2-[(4-iodo-2,6-diethylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)glycine is presented, as well as a modified and improved synthesis of N-[2-[(2,4-diiodo-6-methylphenyl)amino]-2-oxoethyl]-N-(carboxymethyl)glycine. These compounds are new agents for hepatobiliary imaging.     

Synthesis of Silicate Zeolite Analogues Using Organic Sulfonium Compounds as Structure‐Directing Agents

A microporous crystalline silica zeolite of the MEL structure type and three other zeolite analogues composed of germanosilicate frameworks were synthesized using tributylsulfonium, triphenylsulfonium, or tri(para‐tolyl)sulfonium as the structure‐directing agent. The germanosilicates thus obtained had ISV, ITT, or a new zeolite structure depending on the synthesis conditions. The structure of the new germanosilicate was solved using X‐ray powder diffraction data with the aid of a charge‐flipping method. The solution indicated a crystal structure belonging to the P63/mmc space group with cell parameters of a=16.2003 Å and c=21.8579 Å. After calcination, the new germanosilicate material exhibited two types of accessible micropores with diameters of 0.61 and 0.78 nm.     

Membrane‐permeable Triphosphate Prodrugs of Nucleoside Analogues

The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. Rate‐limitations can be at the mono‐, but also at the di‐ and triphosphorylation steps. We developed a nucleoside triphosphate (NTP) delivery system (TriPPPro‐approach). In this approach, NTPs are masked by two bioreversible units at the γ‐phosphate. Using a procedure involving H‐phosphonate chemistry, a series of derivatives bearing approved, as well as potentially antivirally active, nucleoside analogues was synthesized. The enzyme‐triggered delivery of NTPs was demonstrated by pig liver esterase, in human T‐lymphocyte cell extracts and by a polymerase chain reaction using a prodrug of thymidine triphosphate. The TriPPPro‐compounds of some HIV‐inactive nucleoside analogues showed marked anti‐HIV activity. For cellular uptake studies, a fluorescent TriPPPro‐compound was prepared that delivered the triphosphorylated metabolite to intact CEM cells.     

Asymmetric Synthesis of Polyhydroxy Pyrrolidinonyl Nucleoside Analogues from Tartaric acid

Modificationofnucleosideisanefficientproceduretodevelopnewpotentagentsagainsthumantum0r0rvirusesl.Morechallengingistosynthesizenew0pticallyactivepolyhydroxynucleosideanalogues.Becauseofthelimitationofresources,itseemsaratherardu0usworkt0synthesizeopticallyactivecarbocyclicorotherheterocyclicnucleosideanalogueswithmorethantwochiralcarb0ns,thoughnaturalsugarsareavaiIablestartingmaterialstooxa-cyclicnucleosides,suchasfuran0sylorpyranosylones.Inthispaper,wereportanefficientandgeneralsyntheticroute…     

新的依托泊苷衍生物作为细胞毒药物的设计, 合成和生物活性评价

Five novel compounds composed of etoposide and 5-fluorouracil derivatives joined by an ester linkage were prepared and evaluated for their antitumor potential. Most of these analogues have exhibited promising in vitro cytotoxic activity against cell cultures of murine leukaemia P-388 and human lung carcinoma A-549. The results presented herein challenged the long-standing structure-activity relationships, which proposed that a free 4＇-hydroxyl group is essential structural requirement for etoposide-like activity. And in addition, the 4＇-position was suggested to tolerate chemical modifications such as esterification. The preliminary testing results also indicated that the design and synthesis of these compounds were beneficial for therapeutic values of etoposide.     

Synthesis and Biological Evaluation of Novel 2‐Aryl Benzimidazoles as Chemotherapeutic Agents

Here, we describe the synthesis and preliminary biological evaluation of novel N‐unsubstituted and N‐methylated 2‐aryl benzimidazole derivatives that contain fluorinated or hydroxylated alkyl substituents in the 4‐N‐aryl position and different substitution patterns (H vs Br vs I) in the benzimidazole ring. For the selected compounds and for comparison purposes, the congener benzothiazoles were also tested. The cytotoxic effect of 11 benzazole derivatives was evaluated in a panel of human cancer cell lines, such as breast (MCF7), melanoma (A375), cervix (HeLa), and glioblastoma (U87). In general, the compounds exerted a moderate cytotoxic activity against all cells tested. In particular, for the A375 and HeLa cells, the N‐unsubstituted benzimidazoles 2 and 3 displayed a better cytotoxic profile than the respective N‐methylated benzimidazole congeners ( 5 and 7 ). The biodistribution of compound 2 , which has shown the highest cytotoxic activity active in the U87 glioblastoma cells (IC₅₀ = 45.2 ± 13.0), was evaluated in CD1 mice using its ¹⁸F‐labeled counterpart ( [¹⁸F]2 ). These studies showed that compound 2 can cross the blood brain barrier with a reasonable brain uptake (1.24 and 2.81%I.A./g at 5 and 60 min p.i., respectively), which is a crucial issue for systemic chemotherapy of glioblastoma. Altogether, the in vitro antitumoral activity of benzimidazole 2 against the U87 cells and the ability of its ¹⁸F‐congener to cross the blood brain barrier provide a strong rationale to consider the reported fluoroalkylated 2‐aryl benzimidazoles as lead candidates for the generation of chemotherapeutic agents, in particular, against highly aggressive brain tumors such as glioblastoma.     

Synthesis of Methylenecyclopropane Analogues of Antiviral Nucleoside Phosphonates

Synthesis of methylenecyclopropane analogues of nucleoside phosphonates 6a, 6b, 7a and 7b is described. Cyclopropyl phosphonate 8 was transformed in four steps to methylenecyclopropane phosphonate 16. The latter intermediate was converted in seven steps to the key Z- and E-methylenecyclopropane alcohols 23 and 24 separated by chromatography. Selenoxide eliminations (15→16 and 22→23+24) were instrumental in the synthesis. The Z- and E-isomers 23 and 24 were transformed to bromides 25a and 25b, which were used for alkylation of adenine and 2-amino-6-chloropurine to give intermediates 26a, 26b, 26c and 26d. Acid hydrolysis provided the adenine and guanine analogues 6a, 6b, 7a and 7b. Phosphonates 6b and 7b are potent inhibitors of replication of Epstein-Barr virus (EBV).     

Design,Synthesis, and Evaluation of Some Novel Heterocycles Bearing Pyrazole Moiety as Potential Anticancer Agents

1,3‐Diphenylpyrazole‐4‐carboxylaldehyde and o‐hydroxyacetophenone were exploited as starting materials for the synthesis of novel substituted chalconated pyrazole derivative. The proclivity of this compound towards carbon and nitrogen nucleophiles such as malononitrile, diethyl malonate, ethyl cyanoacetate, ethyl acetoacetate, semicarbazide, thiosemicarbazide, and hydroxylamine has been investigated. The structures of all synthesized compounds were ascertained by analytical and spectral data. The antitumor activity of the target synthesized compounds was tested against a panel of two human tumor cell lines, namely, hepatocellular carcinoma (liver) HepG2 and mammary gland breast MCF‐7.     

Synthesis of Novel 1,3-Dioxolane Nucleoside Analogues

Novel 1,3-dioxolane C-nucleoside analogues of tiazofurin 2-(2-hydroxymethyl-1,3-dioxolan-4-yl)-1,3-thiazole4-carboxamide as well as N-nucleoside analogues of substituted imidazoles 1-(2-hydroxymethyl-1,3-dioxolan4-yl)-4-nitroimidazole and 1-(2-hydroxymethyl-1,3-dioxolan-4-yl)-4,5-dicyanoimidazole were synthesized from methyl acrylate through a multistep procedure. Their structures were confirmed by IR,^1H NMR,^13C NMR spectraand elemental analysis.     

Synthesis and in vitro Biological Evaluation of Some Novel Triazole‐Based Heterocycles as Potential Antimicrobial Agents

A series of novel 6‐{5‐aryl‐4H‐1,2,4‐triazol‐3‐ylthio}methyl‐3‐substituted‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazoles and 2‐{(5‐aryl‐4H‐1,2,4‐triazol‐3‐ylthio)‐N‐4‐aryl}acetamides containing 1,2,4‐triazole moiety were synthesized and characterized by ¹H, ¹³C, DEPT, and D₂O. The synthesized compounds were evaluated for their antibacterial activity against three strains of bacteria along with antifungal activity against five fungal species. It has been found that tested compounds showed moderate activity.     

Design,Synthesis of Novel Thiourea and Pyrimidine Derivatives as Potential Antitumor Agents

1,3‐Bis‐(arylidene)thiourea derivatives ( 11a‐c ) were prepared by reacting thiourea ( 9 ) with bezaldehyde, p‐chlorobenzaldehyde or p‐anisaldehyde ( 10a‐c ) respectively. Further reaction of ( 11b ) with acetyl acetone, ethyl acetoacetate, malononitrile and acetic anhydride gave tetrahydropyrimidine‐2‐thiones ( 12‐14 ) and 1,3‐diacetyl thiourea ( 15 ). Compound ( 11b ) reacted with chloroacetyl chloride to give the corresponding pyrimidin‐4‐one derivative ( 16 ). Reaction of ( 12‐14 ) with acetic acid in aqueous sodium nitrite yielded the corresponding oxime derivatives ( 17‐19 ). The triazole ( 20 ) was achieved via refluxing of ( 19 ) in dimethylformamide. Reaction of ( 16 ) with mercaptoacetyl chloride gave the sulfanyl‐acetic acid ( 21 ) which afforded the dihydrazinyl ( 22 ) up on treatment with hydrazine hydrate. Newly synthesized compounds ware characterized by elemental analyses and spectral data (IR, ¹H‐NMR, ¹³C‐NMR and mass spectra). The investigated compounds were screened for their cytotoxicity, i.e. compounds 19 , 20 and 22 exhibited highly potential antitumor activity.     

Synthesis,Spectral Characterization,and In Vitro Biological Evaluation of Some Novel Isoquinolinone‐based Heterocycles as Potential Antitumor Agents

A series of new N‐substituted isoquinolin‐1,3‐dione derivatives were prepared, starting from reaction of (Z)‐4‐((E)‐3‐phenylallylidene)isochromane‐1,3‐dione 4 with different nitrogen nucleophiles. The assigned structures of the prepared compounds were elucidated by spectral methods (IR, ¹H NMR, ¹³C NMR, and mass spectroscopy). Some of the newly prepared compounds were tested in vitro against a panel of three human tumor cell lines, namely, hepatocellular carcinoma (liver) HepG2, colon cancer HCT‐116, and mammary gland breast MCF‐7. Also, they were tested as antioxidants. Some of the tested compounds showed very strong cytotoxic activity with respect to the standard.     

Efficient Synthesis of New Nucleoside Analogues with a Methylenecyclobutane Unit

Synthesis of eight nucleoside analogues 4–11 with a methylenecyclobutane unit is described. Wittig reaction with 2‐hydroxymethylcyclobutanone 12 gave a mixture of Z (13) and E (14) derivatives, which was separated before functional modifications. The heterocyclic moieties were introduced via a Mitsunobu reaction either on the saturated chain or on the unsaturated chain. When adenine was used in this reaction, only the N‐9 substitution products were obtained. Removal of the protecting groups provided the target products.     

The Synthesis of Epiboxidine and Related Analogues as Potential Pharmacological Agents

Methyl epiboxidine‐N‐carboxylate ( 8 ) was synthesized from 7 under reductive Heck conditions (Scheme 2). The C? C coupling of the new epiboxidine analog 9 with aryl and heteroaryl halides gave by hydroarylation C‐aryl, N‐(3‐methylisoxazol‐5‐yl)‐substituted tricyclic imides 10a – 10f (Table). The [3+2] cycloaddition of 9 with nitrile oxides yielded the bridged dihydroisoxazole derivatives 11a – 11d with potential biological activity (Scheme 4).     

Synthesis of Some Novel Furan‐tagged Thienopyrimidine Derivatives as Antibacterial Agents

Cyclization of 2‐furan‐2‐yl‐4‐mercapto‐6‐methylpyrimidine‐5‐carbonitrile 1 with ethyl chloroacetate gave o‐aminoester thienopyrimidine derivative 3 , which was reacted with a variety of reagents to give a series of novel thienopyrimidines including tetrazolyl thienopyrimidine, pyrrolylthienopyrimidine, pyrimidothienotriazine, and thienodipyrimidines. Some of the synthesized compounds were tested for their antibacterial activities against Gram‐positive and Gram‐negative bacteria.     

Design,Synthesis and Biological Evaluation of Bengamide Analogues as ClpP Activators

To combat multidrug‐resistant Gram‐positive bacteria, new antimicrobials particularly those with novel mechanism of action are badly needed. Different with conventional antibiotics which are typical inhibitors, small‐molecule activators of bacterial ClpP represent a new class of antibiotics. No ClpP activator has been developed for clinical trial. Herein, we conducted a screening on our library of bengamide‐like ring‐opened analogues and found that L472‐2 possesses a low minimum inhibitory concentration (MIC) against S.aureus and shows no activity for ClpP activation in vitro, but it displayed reduced antibacterial activity against S. aureus with clpP deletion. In order to obtain bengamide analogues that activate ClpP in vitro as well as possess antibacterial activity, we perform further structural modifications starting from L472‐2 . Compound 37 remains the antimicrobial activity and activation of ClpP protein in vitro, which could be viewed as a new chemical scaffold for ClpP activators and worthy of further investigation.