Synthesis and antiviral and antineoplastic activities of some novel carbocyclic guanosine analogues with a cyclobutane ring.

Cyclobutyl nucleoside analogues containing guanine and 8-azaguanine (compounds 5-10) were prepared from (1R,cis)-3-aminomethyl-2,2-dimethylcyclobutylmethanol (1). All were evaluated as antiviral and antitumoral agents in a variety of assay systems. Compounds 6 and 7 showed a noteworthy activity against a respiratory syncytial virus and compound 10 was moderately active against vaccinia virus. Only compound 5 showed some cytostatic activity.     

Ring-expanded analogues of natural oxetanocin

Synthesis of ring-expanded analogs of the natural compound, oxetanocin is described. The starting material for the synthesis of the series, 4-7, was d-glucosamine and introduction of the base moiety was done through the stereochemically appropriate epoxide. For the enantiomeric series, 8-11, the starting material was d-glucose and preparation of the key intermediate involved a rearrangement reaction. The structures of the target molecules were established by NMR, HRMS, optical rotation and UV data. Single-crystal X-ray data confirmed the enantiomeric structural assignments.     

Synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses

The synthesis of difluorinated carbocyclic analogues of 5-deoxypentofuranoses is described. The sequence involves an addition of PhSeCF₂TMS to carbohydrate-derived aldehydes followed by a radical cyclization, and provides a secure strategy for a future synthesis of pentofuranoses and nucleoside analogues.     

Synthesis and structural study of carbocyclic analogues of 1,2-disubstituted nucleosides

The compounds (±)-cis- and (±)-trans-9-[(2-hydroxymethyl) cyclopentyl]guanine (1 and 2 respectively) were efficiently synthesized by the construction of the purine base on the primary amino group of cis- and trans-2-aminocyclopentylmethanol. The 3D structures of these two 1,2-disubstituted carbanucleosides in DMSO were determined using molecular dynamics calculations with experimental NMR restraints on the basis of the information obtained from a ROESY spectrum. These structures were compared with those obtained in vacuo using molecular dynamics and AM1 semiempirical calculations. The global structures of the two compounds are very similar in the two environments studied, meaning that the structural determination in the gas phase can be extrapolated to molecular simulation studies in solution for compounds of this type.     

Cyclopentene carbocyclic nucleosides related to the antitumor nucleoside clitocine and their conversion to 8-Aza-neplanocin analogues. Synthesis and antiviral activity

Synthesis of the cyclopentene carbocyclic analogue of the naturally occurring nucleoside clitocine ( 1 ) is reported. Starting with racemic cyclopentenylamine ( 10 ), the heterocyclic moieties of the clitocine analogue 4 and related 1,6-dihydro-6-oxo, 5 , and 2-amino-1,6-dihydro-6-oxo, 6 , analogues were constructed. These compounds were respectively converted to 8-aza-neplanocin A (7) , 8-aza-neplanocin D ( 8 , the inosine analogue), and the corresponding 8-aza-guanosine analogue 9 after reduction of the nitro group followed by nitrous acid cyclization. Extensive antiviral evaluation revealed that only 8-aza-neplanocin A ( 7 ) had enough antiviral activity to warrant further studies. This compound showed weak antiviral activity against HSV-1, HSV-20 and the thymidine kinase deficient (TK-) HSV-1. However, it displayed good antiviral activity against human cytomegalovirus (HCMV) at a concentration of 0.40–2.50 μg/ml, well below the cytotoxicity threshold. This activity profile is consistent with a mechanism of action involving the inhibition of the enzyme adenosylhomo-cysteine hydrolase.     

Synthesis and antiviral activity of scopadulcic acids analogues

The synthesis and antiviral properties of several scopadulcic acid analogues functionalized at C-6/C-7 and C-13 is reported. The preparation of advanced intermediates for the synthesis of scopadulcic acid B/scopadulciol analogues is also described. The biological study revealed the importance of polar groups at C-13, while the stereochemistry at C-8 was not critical for activity.     

Synthesis and antiviral evaluation of some carbonucleoside analogues

1,2‐O‐Isopropylidene‐α‐L‐threofuranosyl heterocyclic derivatives were synthesized from 1,2‐O‐iso‐propylidene‐α‐D‐xilopentadialdo‐1,4‐furanose and tested for antiviral activity against herpes simplex virus type 1, dengue virus type 2 and Junin virus. For comparative propose, the antiviral activity of some of their pyranosyl analogues were also tested. The furanosyl derivatives showed to be moderate inhibitors of Junin virus and, in general, proved to be more effective than the pyranosyl analogues.     

Synthesis and antiviral activities of some 4,4'-dihydroxytriphenylmethanes

4,4'-Dihydroxytriphenylmethanes were synthesized using Br?nsted acid or Lewis acid in yields of 24-86% as target compounds for developing antiviral agents. Most of the 4,4'-dihydroxytriphenylmethanes showed significant activity against herpes simplex virus type 1 (anti-HSV-1 activity) in a plaque reduction assay. Higher cytotoxicity was observed generally in halogenated 4,4'-dihydroxytriphenylmethanes (2a-d) than in non-halogenated derivatives. The non-halogenated derivative, 4,4',4"-trihydroxy-3"-methoxytriphenylmethane (3), showed remarkable antiviral activity with an EC(50) value of 1.8 microg/ml.     

Synthesis and antiviral activities of synthetic glutarimide derivatives

A series of novel glutarimide compounds were synthesized and their antiviral activities were evaluated. The compounds displaying the strongest antiviral activities included 5, 6f, 7e and 9 against coxsackievirus B3 (Cox B3), 10 and 6f against influenza virus A (influenza A) and 7a against herpes simplex virus 2 (HSV-2). However, most of the synthetic glutarimides showed comparatively much weaker activity against influenza A, Cox B3 and HSV-2 than the natural glutarimide compounds tested. Based on the results, it seemed likely that a conjugated system at the β-substituted moiety provides stronger antiviral activity.     

Stereoselective route to oxetanocin carbocyclic analogues based on a [2 + 2] photocycloaddition to a chiral 2(5H)-furanone

The synthesis of the trisubstituted cyclobutane 7, which is a suitable precursor for the preparation of oxetanocin carbocyclic analogues, is described. The key step involves a regio- and diastereoselective [2 + 2] photochemical reaction of ketene diethyl acetal with (S)-5-pivaloyloxymethyl-2(5H)-furanone, 3. As an application of this methodology, (-)-cyclobut-A has been prepared from the intermediate 7.     

Synthesis and photo DNA-damaging activities of fluoroquinolone analogues

Fluoroquinolone (FLQ) analogues were synthesized and their DNA photocleaving abilities were assayed. The photo-bioactivities of the fluoroquinolones were dependent on the carbonyl moieties attached to quinolone ring.     

Conformational studies of some carbocyclic nucleoside analogues

Proton NMR spectra of some carbocyclic nucleoside analogs of tuberculin have been analyzed at 100 MHz in DMSO-d₆. The spectral characteristics and nuclear Overhauser effects indicate a preferential syn conformation about the glycosidic bond when a hydroxyl group, oriented toward the base, is available for intramolecular hydrogen bond formation.     

Synthesis and antiviral evaluation of novel N-6 substituted adenosine analogues

A series of adenosine analogues were synthesized and their biological evaluation was tested against Coxsackie virus B3 (CVB3) and Herpes simplex virus type 1(HSV-1) in HEp-2 cells. The hydrophobic constant, acute toxicity, carcinogenicity and mutagenicity were calculated. Analogues with piperazine derivatives 8b showed promising activities against CVB3 with a lower IC₅₀value and higher selectivity index, their efficacy was better than that of the commercialized medicine, Ribavirin. These described adenosine analogues exhibit potent antiviral activities against several viruses, and offer new leads for further development.     

姜黄素类似物合成与抗抑郁活性研究

<正>世界卫生组织(WHO)提出:抑郁是世界第四大健康问题,到2020年,抑郁将成为第二大健康负担[1,2]。尽管在三环类抗抑郁药和单胺氧化酶抑制剂(MAOIs)之后又陆续出现了新的抗抑郁药如:选择性5-HT再摄取抑制剂(SSRI,氟西汀);     

A novel approach to carbocyclic analogues of nucleosides

(±)-1-[(1α,3α,4α)-3-Hydroxy-4-hydroxymethlcyclopentyl]- (1H,3H-pyrimidin-2,4-dione (6) was synthesized starting from endo-5-norbornen-2-yl acetate via the urea derivative 5 in 32% overall yield.     

Synthesis of febrifuginol analogues and evaluation of their biological activities

A new series of febrifuginol analogues was prepared from l-glutamic acid. An antimalarial activity evaluation against chloroquine-sensitive (T96) and chloroquine-resistant (K1) Plasmodium falciparum indicated that all the tested compounds had very strong inhibitory activity. Compounds 4 and 17b′ were inactive against KB, MCF7, HepG2 and LU1 cell lines even at a concentration of 100 μM, while they exhibited significant inhibition towards P. falciparum. Comparison of the antimalarial activity and the cytotoxic properties revealed that the 2′S isomers were more active than the corresponding 2′R isomers for this series of febrifuginol analogues, indicating that the C-2′ position is critical for the biological activity of this class of compounds.     

Synthesis and antiviral activities of some 4,4'- and 2,2'-dihydroxytriphenylmethanes

We synthesized some 4,4'- and 2,2'-dihydroxytriphenylmethane derivatives 3a--e and 4a--c by condensation of phenol 1 and aromatic aldehyde 2 in moderate to good yields (30--83%). Most of them showed significant antiviral activity against herpes simplex virus type 1 (anti-HSV-1 activity) in a plaque reduction assay. The most potent antiviral activity (EC(50)=0.79 microg/ml) was observed in the 4,4'-dihydroxytriphenylmethane derivative 3b. This compound 3b showed lower cytotoxicity (CC(50)=30.2 microg/ml), compared to that of the prototype 3a.     

Synthesis and biological activities of conformationally restricted cyclopentenyl-glutamate analogues.

An efficient method for preparing conformationally restricted cyclopentenyl-glutamate analogues in a regioselective and diastereoselective manner has been developed using a formal [3 + 2] cycloaddition reaction of dehydroamino acids. Methods for preparing optically active versions of these compounds have also been devised. Of these compounds, (S)-2 is an agonist at the mGlu5 (EC(50) 18 microM) and mGlu2 (EC(50) 45 microM) receptors.     

Synthesis of novel apio carbocyclic nucleoside analogues as selective a(3) adenosine receptor agonists

On the basis of the biological activity of neplanocin A and apio-dideoxyadenosine (apio-ddA), novel apio-neplanocin A analogues 5a-d, combining the properties of two nucleosides, were stereoselectively synthesized. The apio moiety of the target nucleosides 5a-d was stereoselectively introduced by treating lactol 10 with 37% formaldehyde in the presence of potassium carbonate. The carbasugar moiety of neplanocin A was successively built by exposing diene 12 on a Grubbs catalyst in methylene chloride. The final nucleosides 5a-d were synthesized from the condensation of the glycosyl donor 14 with nucleic bases under the standard Mitsunobu conditions. Similarly, apio-aristeromycin 6 and (N)-apio-methanocarbaadenosine 7 were derived from the common intermediate 13 using catalytic hydrogenation and Simmons-Smith cyclopropanation as key steps. All of the final nucleosides 5a-d, 6, and 7 did not show significant inhibitory activity against S-adenosylhomocysteine hydrolase (SAH) up to 100 muM, maybe due to the absence of the secondary hydroxyl group at the C3'-position, which should be oxidized by cofactor-bound NAD(+). However, apio-neplanocin A (5a) showed potent and highly selective binding affinity (K(i) = 628 +/- 69 nM) at the A(3) adenosine receptor without any binding affinity at the A(1) and A(2A) adenosine receptors. In conclusion, we have first developed novel carbocyclic nucleosides with unnatural apio-carbasugars using stereoselective hydroxymethylation and RCM reaction and also discovered a new template of human A(3) adenosine receptor agonist, which play a great role in developing new A(3) adenosine receptor agonist as well as in identifying the binding site of the receptor.