共查询到20条相似文献,搜索用时 15 毫秒
1.
Guang Huan Shen Lien Kang Eunae Kim Joon Hee Hong 《Nucleosides, nucleotides & nucleic acids》2013,32(10):720-735
A very efficient synthetic route to novel 3′-hydroxymethyl 5′-deoxythreosyl phosphonic acid nucleosides was described. The discovery of threosyl phosphonate nucleoside (PMDTA, EC50 = 2.53 μM) as a potent antihuman immunodeficiency virus (anti-HIV) agent has led to the synthesis and biological evaluation of 3′-modified 5′-deoxy versions of the threosyl phosphonate nucleosides. 3′-Hydroxymethyl 5 ′-deoxythreosyl phosphonic acid nucleoside analogues 15, 19, 24, and 28 were synthesized from 1,3-dihydroxyacetone and tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 19 exhibits moderate in vitro anti-HIV-1 activity (EC50 = 10.2 μM). 相似文献
2.
Kyung Mi Kim 《Nucleosides, nucleotides & nucleic acids》2013,32(2):92-109
A series of purine 5′-deoxyphosphonate analogues were designed and synthesized to mimic naturally occurring purine monophosphate from 1,3-dihydroxyacetone as starting material. The discovery of threosyl phosphonate nucleoside (PMDTA, EC50 = 2.53 μM) as a potent anti-HIV agent has led to the synthesis and biological evaluation of 2′,3′-modified 5′-deoxyversions of the threosyl phosphonate nucleosides. The synthesized 2′-fluoro-3′-hydroxymethyl 5′-deoxythreosyl phosphonic acid nucleoside analogues 14, 18, 23, and 27 were tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 18 exhibits weak in vitro anti-HIV-1 activity (EC50 = 19.2 μM). 相似文献
3.
Anna Hartwich Nee Zdzienicka Dominique Schols Graciela Andrei Robert Snoeck 《Nucleosides, nucleotides & nucleic acids》2020,39(4):542-591
AbstractA new series of phosphonylated triazolo[4,5-b]pyridine (1-deaza-8-azapurine), imidazo[4,5-b]pyridine (1-deazapurine) and imidazo[4,5-b]pyridin-2(3H)-one (1-deazapurin-8-one) were synthesized from 2-chloro-3-nitropyridine and selected diethyl ?-aminoalkylphosphonates followed by reduction of the nitro group and cyclization. In the final step O,O-diethylphosphonates were transformed into the corresponding phosphonic acids. All synthesized compounds were evaluated in vitro for inhibitory activity against a broad variety of DNA and RNA viruses and their cytotoxic potencies were also established. Compound 12f showed marginal activity against cytomegalovirus Davis strain (EC50?=?76.47?μM) in human embryonic lung (HEL) cells while compounds 10g (EC50?=?52.53?μM) and 12l (EC50?=?61.70?μM) were minimally active against the varicella-zoster virus Oka strain in HEL cells. Compounds under investigation were not cytotoxic at the maximum concentration evaluated (100?µM). 相似文献
4.
Eunae Kim Guang Huan Shen Lien Kang Joon Hee Hong 《Nucleosides, nucleotides & nucleic acids》2013,32(7):396-410
The authors describe highly efficient synthetic routes for the preparation of novel 6′,6′-difluoro 5′-deoxycarbocyclic phosphonic acid nucleosides from 1,4-dihydroxy-2-butene. The discovery that the 6′-fluorinated carbocyclic nucleoside (2, EC50 = 0.16 μM) is a potent anti-HSV-1 agent led to the syntheses and biological evaluations of 6′-modified 5′-deoxyversions of carbocyclic phosphonate nucleosides. The synthesized nucleoside analogues 15, 18, 22, and 25 were tested for anti-HIV activity and for cytotoxicity. However, none of them showed significant anti-HIV-1 activity or cytotoxicity at concentrations up to 100 μM. 相似文献
5.
Peter Lorenz Michael Zeh Jens Martens-Lobenhoffer Harry Schmidt Gerald Wolf 《Free radical research》2013,47(5):535-545
We investigated the antioxidant and radical scavenging activity of polyphenolic isochromans. To assess the relation between structure and scavenging properties the natural occurring 1-(3′-methoxy-4′-hydroxy)phenyl-6,7-dihydroxy-isochroman (ISO-3, three OH groups) was compared with three newly synthesized derivatives that differ in their degree of hydroxylation by substitution with methoxy-groups (ISO-4: four OH groups; ISO-2: two OH groups and ISO-0: fully methoxylated). We found that ISO-4 is a 2-fold better scavenger for the artificial radical 1,1-diphenyl-2-picrylhydrazyl (DPPH, 100?μM) with an EC50=10.3?μM compared to the natural ISO-3 (EC50=22.4?μM) and to ISO-2 (EC50=25.1?μM), while ISO-0 did not react with DPPH. The scavenging capacity for superoxide enzymatically generated in a hypoxanthin-xanthinoxidase reaction was the highest for ISO-4 (EC50=34.3?μM) compared to those of ISO-3 (EC50=84.0?μM) and ISO-2 (EC50=91.8?μM), while ISO-0 was inactive. In analogy, ISO-4 scavenged peroxynitrite (ONOO?, EC25=23.0?μM) more effective than ISO-3, ISO-2 and ISO-0.When C6 rat glioma cells loaded with the reactive oxygen/nitrogen (ROS/RNS)-sensitive fluorochrome 2,7-dichlorodihydrofluorescein, were exposed to hydrogen peroxide, the lowest stress level as indicated by the fluorescence signal was detected when the cells were pretreated with ISO-4 or ISO-2 but to a much lesser extent with ISO-3, while ISO-0 did not show any effect. All tested hydroxyisochromans superceded the scavenging effect of trolox.The excellent radical and ROS/RNS scavenging features of the hydroxy-1-aryl isochromans and their simple synthesis let these compounds appear to be interesting candidates for pharmaceutical interventions that protect against the deleterious action of ROS/RNS. 相似文献
6.
Kengo Onitsuka Ryoh Tokuda Nobuyo Kuwata-Higashi Hiroki Kumamoto Manabu Aoki Masayuki Amano 《Nucleosides, nucleotides & nucleic acids》2020,39(4):518-529
AbstractHepatitis B virus (HBV) infection is a major worldwide health problem that requires the development of improved antiviral therapies. Here, a series of 4′-Azido-thymidine/4′-Azido-2′-deoxy-5-methylcytidine derivatives (6, 10–15) were synthesized, and their anti-HBV activities evaluated. Compounds 10–15 were synthesized via an SNAr reaction of 18, in which the 4-position of the thymine moiety was activated as the 2,4,6-triisopropylbenzenesulfonate. Compounds 11–15 showed no antiviral activity. However, 4′-Azido thymidine (6) and 4′-Azido-2′-deoxy-5-methylcytidine (10) displayed significant anti-HBV activity (EC50 = 0.63 and 5.99?µM, respectively) with no detectable cytotoxicity against MT-2 cells up to 100?µM. 相似文献
7.
Satoshi Yamauchi Tuti Wukirsari Yoshiaki Ochi Hisashi Nishiwaki Kosuke Nishi Takuya Sugahara Koichi Akiyama Taro Kishida 《Bioorganic & medicinal chemistry letters》2017,27(17):4199-4203
The new lignano-9,9′-lactones (α,β-dibenzyl-γ-butyrolactone lignans), which showed the higher cytotoxicity than arctigenin, were synthesized. The well-known cytotoxic arctigenin showed activity against HL-60 cells (EC50 = 12 μM), however, it was inactive against HeLa cells (EC50 > 100 μM). The synthesized (3,4-dichloro, 2′-butoxy)-derivative 55 and (3,4-dichloro, 4′-butyl)-derivative 66 bearing the lignano-9,9′-lactone structures showed the EC50 values of 10 μM and 9.4 μM against HL-60 cells, respectively. Against HeLa cells, the EC50 value of the derivative 66 was 27 μM. By comparing the activities with the corresponding 9,9′-epoxy structure (tetrahydrofuran compounds), the importance of the lactone structure of 55 and 66 for the higher activities was shown. The substituents on the aromatic ring of the lignano-9,9′-lactones affected the cytotoxicity level, observing more than 10-fold difference. 相似文献
8.
Maria Stefania Sinicropi Anna Caruso Mariangela Marrelli Hussein El Kashef Jean-charles Lancelot 《Journal of enzyme inhibition and medicinal chemistry》2013,28(5):1148-1153
The synthesis and the biological evaluation of pyrano[3,2-e]indoles and their reaction intermediates are described. The compounds prepared were evaluated for their inhibition of NO production, antioxidant activity and also for their ability to inhibit in vitro the growth of four human tumor cell lines: large lung carcinoma (COR-L23), alveolar basal epithelial carcinoma (A549), amelanotic melanoma (C32) and melanoma (A375). The two reaction intermediates, 5a and 5b, showed the highest inhibition of NO production in murine monocytic macrophage (IC50?=?1.1?μM and IC50?=?2.3 μM respectively). Compound 5a was the most active against melanotic melanoma (IC50?=?11.8?μM) while the other compounds exhibited weak cytotoxicity with IC50 values >50?μM on all cell lines. 相似文献
9.
Novel 5′-deoxycarbocyclic purine phosphonic acid analogs with the 4′-electropositive moiety, fluorine were designed, and synthesized from glyceraldehyde. The cyclopentenol intermediate, 9, was successfully synthesized by the ring-closing metathesis of divinyl 8. The condensation reaction of cyclopentanol 15 with purine bases under Mitsunobu conditions successfully afforded the desired phosphonate analogs. The synthesized nucleoside phosphonic acid analogs, 19, 22, 26, and 29, were subjected to antiviral screening against human immunodeficiency virus (HIV)-1. Guanine phosphonic acid analog 29 showed significant anti-HIV activity (EC50 = 10.3 μM). 相似文献
10.
Efficient synthetic route to novel 4′-trifluoromethylated 5′-deoxycarbocyclic nucleoside phosphonic acids was described from α-trifluoromethyl-α,β-unsaturated ester. Coupling of purine nucleosidic bases with cyclopentanol using a Mitsunobu reaction gave the nucleoside intermediates which were further phosphonated and hydrolyzed to reach desired nucleoside analogs. Synthesized nucleoside analogs were tested for anti-HIV activity as well as cytotoxicity. Adenine analog 22 shows significant anti-HIV activity (EC50 = 8.3 μM) up to 100 μM. 相似文献
11.
Novel 5′-deoxyapiosyl purine phosphonic acid analogues with a 2′-electropositive moiety, such as, a fluorine atom were designed and synthesized from commercially available hydroxylacetone. Condensation of a glycosyl donor 10 with purines under Vorbruggen conditions and cross-metathesis give the desired nucleoside phosphonic acid analogues 14, 17, 21, and 24. The synthesized nucleoside analogues were subjected to antiviral screening against HIV-1, and the adenine analogue 17 exhibited weak in vitro anti-HIV-1 activity (EC50 = 26.6 μM) 相似文献
12.
Yan-Yan Wang Fang-Zhou Xu Yun-Ying Zhu Baoan Song Dexia Luo Gang Yu Shunhong Chen Wei Xue Jian Wu 《Bioorganic & medicinal chemistry letters》2018,28(17):2979-2984
A series of pyrazolo[3,4-d]pyrimidine derivatives containing a Schiff base moiety were synthesized, characterised, and evaluated for their activity against tobacco mosaic virus (TMV). Biological assays indicated that several of the derivatives exhibited significant activity against TMV. In particularly, compounds 5y and 5aa displayed excellent inactivating activity against TMV, with half maximal effective concentration (EC50) values of 70.3 and 53.65?μg/mL, respectively, which were much better than that of ribavirin (150.45?μg/mL), and 5aa was superior to ningnanmycin (EC50?=?55.35?μg/mL). Interactions of compounds 5y and 5aa with TMV coat protein (TMV-CP) were investigated using microscale thermophoresis and molecular docking. Compounds 5y and 5aa displayed strong binding capability to TMV-CP with dissociation constant (Kd) values of 22.6 and 9.8?μM, respectively. These findings indicate that pyrazolo[3,4-d]pyrimidine derivatives containing a Schiff base may be potential antiviral agents. 相似文献
13.
Ting Zhou Qian Shi Chin-Ho Chen Hao Zhu Li Huang Phong Ho Kuo-Hsiung Lee 《Bioorganic & medicinal chemistry》2010,18(18):6678-6689
14.
Novel 5′-deoxyfuranosyl purine phosphonic acid analogues with 2 ′-electropositive moiety, such as spirocyclopropanoid, were designed and synthesized from commercially available diethyl malonate. Condensation reaction successfully proceeded from a glycosyl donor 15 at low reaction temperature in Vorbruggen conditions to give desired phosphonate analogues 16b and 23b. The synthesized nucleotide analogues 19, 22, 26, and 29 were subjected to antiviral screening against HIV-1. Adenine phosphonic acid analogue 22 shows significant anti-HIV activity (EC50 = 7.9 μM). 相似文献
15.
Yeong Hun Song Zia Uddin Young Min Jin Zuopeng Li Marcus John Curtis-Long Kwang Dong Kim 《Journal of enzyme inhibition and medicinal chemistry》2017,32(1):1195-1202
Protein tyrosine phosphatase 1B (PTP1B) and α-glucosidase are important targets to treat obesity and diabetes, due to their deep correlation with insulin and leptin signalling, and glucose regulation. The methanol extract of Paulownia tomentosa fruits showed potent inhibition against both enzymes. Purification of this extract led to eight geranylated flavonoids (1–8) displaying dual inhibition of PTP1B and α-glucosidase. The isolated compounds were identified as flavanones (1–5) and dihydroflavonols (6–8). Inhibitory potencies of these compounds varied accordingly, but most of the compounds were highly effective against PTP1B (IC50?=?1.9–8.2?μM) than α-glucosidase (IC50?=?2.2–78.9?μM). Mimulone (1) was the most effective against PTP1B with IC50?=?1.9?μM, whereas 6-geranyl-3,3′,5,5′,7-pentahydroxy-4′-methoxyflavane (8) displayed potent inhibition against α-glucosidase (IC50?=?2.2?μM). All inhibitors showed mixed type Ι inhibition toward PTP1B, and were noncompetitive inhibitors of α-glucosidase. This mixed type behavior against PTP1B was fully demonstrated by showing a decrease in Vmax, an increase of Km, and Kik/Kiv ratio ranging between 2.66 and 3.69. 相似文献
16.
Anber F. Mohammed Graciela Andrei Alaa M. Hayallah Samia G. Abdel-Moty Robert Snoeck Claire Simons 《Bioorganic & medicinal chemistry》2019,27(6):1023-1033
A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against herpes simplex virus 1 and 2 (HSV-1, HSV-2) and thymidine kinase deficient (ACV resistant) HSV-1. The tricyclic HBG derivatives were devoid of inhibitory activity however several of the tricyclic PCV derivatives showed promising antiviral activity, in particular 9g (R?=?4-MeO-C6H4) displayed good inhibitory activity (HSV-1 EC50 1.5?μM, HSV-2 EC50 0.8?μM) and retained inhibitory activity in HSV-1 TK? cells (EC50 0.8?μM). Computational docking experiments supported the biological data observed and this preliminary study provides useful data for further development of tricyclic acyclic nucleoside derivatives with improved lipophilicity and retention of activity in HSV-1 TK deficient strains. Also, the new tricyclic derivatives were evaluated against a broad range of other DNA and RNA viruses, but were found to be inactive at subtoxic concentrations. In addition, weak to moderate cytostatic effect was observed for the new compounds. 相似文献
17.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(6):773-778
The CHCl3-soluble fraction of the whole plant of Duranta repens showed anti-plasmodial activity against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum, with IC50 values of 8.5?±?0.9 and 10.2?±?1.5?μg/mL, respectively. From this fraction, two new flavonoid glycosides, 7-O-α-d-glucopyranosyl-3,4′-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (1) and 7-O-α-d-glucopyranosyl(6′′′-p-hydroxcinnamoyl)-3,4′-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (2), along with five known flavonoids, 3,7,4′-trihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6-dimethoxyflavone (3), 3,7-dihydroxy-3′-(4-hydroxy-3-methylbutyl)-5,6,4′-trimethoxyflavone (4), 5,7-dihydroxy-3′-(2-hydroxy-3-methyl-3-butenyl)-3,6,4′-trimethoxyflavone (5), 3,7-dihydroxy-3′-(2-hydroxy-3-methyl-3-buten-yl)-5,6,4′-trimethoxyflavone (6), and 7-O-α-d-glucopyranosyl-3,5-dihydroxy-3′-(4′′-acetoxy-3′′-methylbutyl)-6,4′-dimethoxyflavone (7), have been isolated as anti-plasmodial principles. Their structures were deduced by spectroscopic analysis including 1D and 2D NMR techniques. The compounds (1–7) showed potent anti-plasmodial activities against D6 and W2 strains of Plasmodium falciparum, with IC50 values in the range of 5.2–13.5?μM and 5.9–13.1?μM, respectively. 相似文献
18.
Hamid Tanzadehpanah Massoud Saidijam Jamshidkhan Chamani Hanie Mahaki 《Journal of biomolecular structure & dynamics》2013,31(14):3803-3818
Bioactive peptides have been defined as specific protein fragments that have numerous biological activities. The aim of this study was to introduce three multifunctional peptides. Hence, we used rabbit lung angiotensin converting enzyme (ACE) inhibitor peptide AFKDEDTEEVPFR to prepare two analogous peptides KDEDTEEVP and KDEDTEEVH. ACE inhibitory, antioxidant, and antimicrobial activities of three synthetic peptides were investigated. Among the three peptides, KDEDTEEVP exhibited the highest ACE inhibitory activity with IC50 value of 69.63 ± 2.51 μM. Furthermore, the results of fluorescence spectroscopy and molecular modeling showed that KDEDTEEVP had more affinity to ACE than other peptides. The peptide of KDEDTEEVH showed the strongest antioxidant scavenging capacity on DPPH radicals (EC50 = 135 ± 9.62 μM), hydroxyl radicals (EC50 = 144 ± 8.73 μM), and ABTS radicals (EC50 = 62 ± 4.52%). Moreover, it showed the highest activity in iron-chelating test (EC50 = 226 ± 14.13 μM) and could also effectively inhibit the peroxidation of linoleic acid. The antimicrobial activity results showed that KDEDTEEVH had higher efficiency against Gram-positive than Gram-negative bacteria with MIC values of higher than 205 ± 10.75 μM. Although there was not a direct correlation between ACE inhibitor and antioxidant activity for analogous peptides, both analogous peptides exhibited more efficiency than the mother peptide. Thus, they can be considered as multifunctional peptides and would be beneficial ingredient to be used in food and drug industry. 相似文献
19.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(2):302-310
A series of novel L-isoserine derivatives were synthesised and evaluated for their ability to inhibit aminopeptidase N (APN)/CD13. In our preliminary biological results, some of these compounds possessed a potent inhibitory activity against the APN. Within this series, compound 14b not only showed similar enzyme inhibition (IC50 of 12.2?μM) compared with the positive control bestatin (half maximal inhibitory concentration (IC50) of 7.3?μM), but also had a potent antiproliferative activity against human cancer cell lines cells. 相似文献
20.
Zhao Wang Zhao Yu Dongwei Kang Jian Zhang Ye Tian Dirk Daelemans Erik De Clercq Christophe Pannecouque Peng Zhan Xinyong Liu 《Bioorganic & medicinal chemistry》2019,27(3):447-456
A novel series of acetamide-substituted derivatives and two prodrugs of doravirine were designed and synthesized as potent HIV-1 NNRTIs by employing the structure-based drug design strategy. In MT-4 cell-based assays using the MTT method, it was found that most of the new compounds exhibited moderate to excellent inhibitory potency against the wild-type (WT) HIV-1 strain with a minimum EC50 value of 54.8?nM. Among them, the two most potent compounds 8i (EC50?=?59.5?nM) and 8k (EC50?=?54.8?nM) displayed robust activity against WT HIV-1 with double-digit nanomolar EC50 values, being superior to lamivudine (3TC, EC50?=?12.8?μM) and comparable to doravirine (EC50?=?13?nM). Besides, 8i and 8k shown moderate activity against the double RT mutant (K103N?+?Y181C) HIV-1 RES056 strain. The HIV-1 RT inhibition assay further validated the binding target. Molecular simulation of the representative compounds was employed to provide insight on their structure-activity relationships (SARs) and direct future design efforts. Finally, the aqueous solubility and chemical stability of the prodrugs 9 and 10 were investigated in detail. 相似文献