共查询到20条相似文献,搜索用时 15 毫秒
1.
S. Benzaria G. Gosselin H. Pelicano G. Maury A.-M. Aubertin G. Obert 《Nucleosides, nucleotides & nucleic acids》2013,32(3-5):563-565
Abstract The synthesis, and stability in different media of new PMEA prodrugs, with S-acylthioethyl (SATE) as enzyme-labile phosphonate protecting groups, are described in comparison with the already known Bis(POM)- and Bis(DTE)PMEA. 相似文献
2.
Tichý T Andrei G Dračínský M Holý A Balzarini J Snoeck R Krečmerová M 《Bioorganic & medicinal chemistry》2011,19(11):3527-3539
New Adefovir (PMEA) prodrugs with a pro-moiety consisting of decyl or decyloxyethyl chain bearing hydroxyl function(s), hexaethyleneglycol or a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl unit were prepared starting from the tetrabutylammonium salt of the phosphonate drug and an appropriate alkyl bromide or tosylate. Analogously, two esters of Cidofovir [(S)-HPMPC] bearing a hexaethyleneglycol moiety were prepared. The activity of the prodrugs was evaluated in vitro against different virus families. A loss in the antiviral activities of the hydroxylated decyl or decyloxyethyl esters and hexaethyleneglycol esters of PMEA against human immunodeficiency virus (HIV) and herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (CMV)] occurred in comparison with the parent compound. On the other hand, the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of PMEA showed significant activities against HIV and herpesviruses. (S)-HPMPC prodrugs exhibited anti-cytomegalovirus activities in the same range as the parent drug, whereas the anti-HSV and anti-VZV activities were one- to seven-fold lower than that of Cidofovir. 相似文献
3.
Charlotte Courtens Martijn Risseeuw Guy Caljon Louis Maes Anandi Martin Serge Van Calenbergh 《Bioorganic & medicinal chemistry》2019,27(5):729-747
Fosmidomycin is a natural antibiotic with promising IspC (DXR, 1-deoxy-d-xylulose-5-phosphate reductoisomerase) inhibitory activity. This enzyme catalyzes the first committed step of the non-mevalonate isoprenoid biosynthesis pathway, which is essential in Plasmodium falciparum and Mycobacterium tuberculosis. Mainly as a result of its high polarity, fosmidomycin displays suboptimal pharmacokinetic properties. Furthermore, fosmidomycin is inactive against M. tuberculosis as a result of its inability to penetrate the bacterial cell wall. Temporarily masking the phosphonate moiety as a prodrug has the potential to solve both issues. We report the application of two amino acid based prodrug approaches on a fosmidomycin surrogate. Conversion of the phosphonate moiety into tyrosine-derived esters increases the in vitro activity against asexual blood stages of P. falciparum, while phosphonodiamidate prodrugs display promising antitubercular activities. Selected prodrugs were tested in vivo in a P. berghei malaria mouse model. These results indicate good in vivo antiplasmodial potential. 相似文献
4.
Naproxen (nap) is belonging to Non-steriodal anti-inflammatory drugs (NSAIDs) group of drugs that characterized by their free carboxylic group. The therapeutic activity of nap is usually accompanied by GI untoward side effects. Recently synthesized naproxen amides of some amino acid esters prodrugs to mask the free carboxylic group were reported. Those prodrugs showed a promising colorectal cancer chemopreventive activity. The current study aims to investigate the fate and hydrolysis of the prodrugs kinetically in different pH conditions, simulated gastric and intestinal fluids with pHs of 1.2, 5.5 and 7.4 in vitro at 37 °C. The effect of enzymes on the hydrolysis of prodrugs was also studied through incubation of these prodrugs at 37 °C in human plasma and rat liver homogenates. The pharmacokinetic parameters of selected prodrugs and the liberated nap were studied after oral and intraperitoneal administration in male wistar rats. The results showed the hydrolysis of naproxen amides of amino acid esters to nap through two steps first by degradation of the ester moiety to form the amide of nap with amino acid and the second was through the degradation of the amide link to liberate nap. The two reactions were followed and studied kinetically where K1 and K2 (rate constants of degradation) is reported. The hydrolysis of prodrugs was faster in liver homogenates than in plasma. The relative bioavailability of the liberated nap in vivo was higher in case of prodrug containing ethyl glycinate moiety than that occupied l-valine ethyl ester moiety. Each of nap. prodrugs containing ethyl glycinate and l-valine ethyl ester moieties appears promising in liberating nap, decreasing direct GI side effect and consequently their colorectal cancer chemopreventive activity. 相似文献
5.
Bis[(para-methoxy)benzyl] phosphonate prodrugs with improved stability and enhanced cell penetration
Dang Q Liu Y Rydzewski RM Brown BS Robinson E van Poelje PD Colby TJ Erion MD 《Bioorganic & medicinal chemistry letters》2007,17(12):3412-3416
A series of substituted bis[(para-methoxy)benzyl] (bisPMB) esters of 1-naphthalenemethylphosphonate (NMPA) were synthesized and evaluated as phosphonate prodrugs. BisPMB NMPA esters (4b and 4c) with significantly improved aqueous stability were identified that also resulted in increased intracellular levels of NMPA following prodrug incubation with primary rat hepatocytes. 相似文献
6.
Kazmierski WM Bevans P Furfine E Spaltenstein A Yang H 《Bioorganic & medicinal chemistry letters》2003,13(15):2523-2526
We have developed a new approach to prodrugs, which utilizes a pH-induced intramolecular O-->N migration of an acyloxy group in carbonate moiety to a free amino moiety at neutral pH. This method is exemplified by facile rearrangement of highly water-soluble prodrug 3 to carbamate 4, a close analogue of HIV-1 protease inhibitor Amprenavir. The O-->N acyloxy migration is unprecedented in the context of prodrugs and it enables a high atom economy due to recycling of the 'pro' moiety. 相似文献
7.
Elworthy TR Dunn JP Hogg JH Lam G Saito YD Silva TM Stefanidis D Woroniecki W Zhornisky E Zhou AS Klumpp K 《Bioorganic & medicinal chemistry letters》2008,18(24):6344-6347
The N-2 position of pyridazinone 1, a potent HIV-1 NNRTI that has limited aqueous solubility, was derivatized into a series of hydroxymethyl esters and carbonates as well as one phosphate. The derivatives served as prodrugs to effectively deliver 1 to rat plasma upon oral treatment at 50 mpk. Increases of 4.3- to 8.6-fold in 24-hour exposure of 1 (over that of parent) were observed while the prodrugs and the hydroxymethyl adduct 2 were undetectable. 相似文献
8.
Q Dang B S Brown P D van Poelje T J Colby M D Erion 《Bioorganic & medicinal chemistry letters》1999,9(11):1505-1510
A new prodrug approach for intracellular delivery of phosphonates was developed via the synthesis of 3-phthalidyl esters of 1-naphthalenemethylphosphonate. This approach is advantageous over the traditional acyloxymethyl phosphonate prodrugs, because these prodrugs do not generate formaldehyde and have improved plasma half-lives. 相似文献
9.
A Q Siddiqui C McGuigan C Ballatore O Wedgwood E De Clercq J Balzarini 《Bioorganic & medicinal chemistry letters》1999,9(17):2555-2560
Simple mono-derivatisation of the aryl moiety of some phosphoramidate pronucleotide derivatives of d4A and ddA served to increase the lipophilicity of these membrane-soluble prodrugs. A concomitant and significant enhancement of potency against HIV-1 and HIV-2 in vitro was observed for the ddA- and d4A-based prodrugs compared to the original underivatised prodrugs. 相似文献
10.
Novel 5'-norcarbocyclic adenine and guanine phosphonic acid analogues with 6',6'-difluorine moiety were designed and synthesized from commercially available epichlorohydrin 5. A regioselective Mitsunobu reaction successfully proceeded from an allylic functional group 16b at low reaction temperature in polar cosolvent to give purine phosphonate analogues 17 and 24, respectively. The purine nucleoside phosphonate and phosphonic acid analogues were subjected to antiviral screening against HIV-1. Adenine analogue 21 and its SATE prodrug 29 show significant anti-HIV activity in MT-4 cell lines. 相似文献
11.
Kevin B. Daniel Jody L. Major Jourden Kimberly E. Negoescu Seth M. Cohen 《Journal of biological inorganic chemistry》2011,16(2):313-323
This study details the development of matrix metalloproteinase inhibitor prodrugs (proMMPi) that are activated in the presence
of reactive-oxygen species (ROS). Conventional matrix metalloproteinase inhibitors (MMPi) utilize a zinc-binding group (ZBG)
that chelates to the catalytic zinc(II) ion of matrix metalloproteinases (MMPs) to inhibit their activity. To create ROS-sensitive
prodrugs, sulfonate esters were used as a protecting group for the ZBG to block their metal binding ability. Surprisingly,
these sulfonate esters were found to be cleaved by H2O2 only when the ZBG contained an N-oxide donor atom moiety. Sulfonate ester derivatives of full-length MMPi based on these ROS-triggerable systems were synthesized.
It was found that proMMPi with sulfonate ester protecting groups showed relatively high rates of cleavage in the presence
of H2O2 to release the active MMPi. In vitro MMP inhibition studies confirmed a significant increase in inhibitory activity of proMMPi
upon addition of H2O2, demonstrating the use of sulfonate esters to act as cleavable triggers for ROS-activated prodrugs. 相似文献
12.
Azéma L Lherbet C Baudoin C Blonski C 《Bioorganic & medicinal chemistry letters》2006,16(13):3440-3443
A series of four prodrugs directed against Trypanosoma brucei aldolase bearing various transient enzyme-labile phosphate protecting groups was developed. Herein, we describe the synthesis and evaluation of cell permeation of these prodrugs. The oxymethyl derivative was the most efficient prodrug with a good recovering of the free drug (IC(50)=20 microM) and without any measurable cytotoxicity. 相似文献
13.
Elisa Pileggi Michaela Serpi Graciela Andrei Dominique Schols Robert Snoeck Fabrizio Pertusati 《Bioorganic & medicinal chemistry》2018,26(12):3596-3609
The importance of phosphonoamidate prodrugs (ProTides) of acyclic nucleoside phosphonate (ANPs) is highlighted by the approval of Tenofovir Alafenamide Fumarate for the treatment of HIV and HBV infections. In the present paper we are reporting an expedient, one-pot, two-steps synthesis of allyl phosphonoamidates and diamidates that offers a time saving strategy when compared to literature methods. The use of these substrates in the cross metathesis reactions with alkenyl functionalised thymine and uracil nucleobases is reported. ANPs prodrugs synthesized via this methodology were evaluated for their antiviral activities against DNA and RNA viruses. It is anticipated that the use of 5,6,7,8-tetrahydro-1-napthyl as aryloxy moiety is capable to confer antiviral activity among a series of otherwise inactive uracil ProTides. 相似文献
14.
《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):147-158
Abstractα -Aminoalkylphosphonate di(chlorophenyl) esters and (α -aminoalkyl)phenylphosphinate phenylesters have been tested as irreversible inhibitors of human neutrophil elastase, porcine pancreatic elastase and chymotrypsin, serine proteases important in biochemical processes. Peptidyl derivatives of diphenyl (α -aminoalkyl) phosphonates have previously been shown to be potent and specific inhibitors of serine proteases at low concentrations. Addition of a halogen to the phenoxy group of the inhibitors should make the leaving group more electrophilic, and thus more reactive. Peptide phosphonate inhibitors with chlorine in the meta- or para- positions of the phenoxy ester moiety were synthesized and shown to be potent inhibitors of elastase. Tripeptide phosphonates are more potent inhibitors than dipeptide phosphonates, however, addition of the halogen did not increase the inhibitory potency of these phosphonates with elastase compared to the non-halogenated phosphonates. In the case of chymotrypsin, the halogenated phenoxy esters were more reactive, possibly due to an alternate binding mode. The novel (α -aminoalkyl)phenylphosphinate phenylesters were poor inhibitors of serine proteases. 相似文献
15.
This article describes a very simple route for synthesizing novel lipophilic phosphonate bis(t-bu-SATE) prodrugs of acyclic cyclopentenylated nucleosides such as adenine 17 and cytosine 18. The key intermediate 6 was constructed via a ring-closing metathesis of compound 5, which could be readily prepared from diethylmalonate 4. The chemical stability of the bis(SATE) derivatives was tested at neutral (pH = 7.2) and slightly acid (milli-Q water, pH = 5.5) pH. The synthesized compounds were evaluated as potential antiviral agents against HIV-1 virus. 相似文献
16.
Hamada Y Matsumoto H Yamaguchi S Kimura T Hayashi Y Kiso Y 《Bioorganic & medicinal chemistry》2004,12(1):159-170
To improve the low water-solubility of HIV protease inhibitors, we synthesized water-soluble prodrugs of KNI-727, a potent small-sized dipeptide-type HIV-1 protease inhibitor consisting of an Apns-Dmt core (Apns; allophenylnorstatine, Dmt; (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid) as inhibitory machinery. These prodrugs contained an O-acyl peptidomimetic structure with an ionized amino group leading to an increase in water-solubility, and were designed to regenerate the corresponding parent drugs based on the O-->N intramolecular acyl migration reaction via a five-membered ring intermediate at the alpha-hydroxy-beta-amino acid residue, that is Apns. The synthetic prodrug 3a improved the water-solubility (13 mg/mL) more than 8000-fold in comparison with the parent compound, which is the practically acceptable value as water-soluble drug. Furthermore, to understand the structural effects of the O-acyl moiety on the migration rate, we evaluated several phenylacetyl-type and benzoyl-type prodrugs. These prodrugs were stable as an HCl salt and in a strongly acidic solution corresponding to gastric juice (pH 2.0), and could be converted to the parent compounds promptly under aqueous conditions from slightly acidic to basic pH at 37 degrees C. 相似文献
17.
Hamada Y Matsumoto H Kimura T Hayashi Y Kiso Y 《Bioorganic & medicinal chemistry letters》2003,13(16):2727-2730
To improve the low water-solubility of HIV-1 protease inhibitors KNI-272, -279 and -727, we previously reported the water-soluble prodrugs of these inhibitors based on O-->N intramolecular acyl migration reaction. These prodrugs were rapidly converted to the corresponding parent drugs under physiological conditions. To understand the steric and electrostatic effects of O-acyl moiety on the migration rate, we examined several types of prodrug. A remarkably slow migration was observed in the benzoyl-type prodrugs, and Hammett plot of migration rate constants of p-substituted benzoyl-type prodrugs gave a linear free energy relationship. 相似文献
18.
Mourier N Camplo M Della Bruna GS Pellacini F Ungheri D Chermann JC Kraus JL 《Nucleosides, nucleotides & nucleic acids》2000,19(7):1057-1091
A series of anti-HIV prodrugs possessing various polyaminated side arms have been developed. The incorporation of a N-Boc protected monoamine or diamine side arm into the backbone of the 2',3'-dideoxy-3'-thiacytidine 1 (BCH-189) provided an increase in antiviral potency, which could be several orders magnitude greater than the parent drug (1) depending on the cell culture systems used (MT-4 or MDMs). Twenty six 2',3'-dideoxy-3'-thiacytidine prodrugs which differ from each other by the length, the nature of the 5'-O function and the 5'-O or/and N-4 position on the nucleoside moiety were synthesized. Among this new series of prodrugs, several congeners (12c and 12a) were found to inhibit HIV-1 replication in cell culture with 50% effective concentrations EC50 of 10 and 50 nM respectively, in MT-4 cells. Compound 12c was found more active on infected MDMs cells with 50% effective concentration of 0.01 nM. The synthesis and the antiviral properties of these compounds are discussed. 相似文献
19.
20.
Yuzeng Liang Ashoke Sharon Jason P. Grier Kimberly L. Rapp Raymond F. Schinazi Chung K. Chu 《Bioorganic & medicinal chemistry》2009,17(3):1404-1409
A series of (?)-β-d-(2R,4R)-dioxolane-thymine-5′-O-aliphatic acid esters as well as amino acid esters were synthesized as prodrugs of (?)-β-d-(2R,4R)-dioxolane-thymine (DOT). The compounds were evaluated for anti-HIV activity against HIV-1LAI in human peripheral blood mononuclear (PBM) cells as well as for their cytotoxicity in PBM, CEM and Vero cells. Improved anti-HIV potency in vitro was observed for the compound 2–4 (5′-O-aliphatic acid esters) without increase in cytotoxicity in comparison to the parent drug. Chemical and enzymatic hydrolysis of the prodrugs was also studied, in which the prodrugs exhibited good chemical stability with the half-lives from 3 h to 54 h at pH 2.0 and 7.4 phosphate buffer. However, the prodrugs were relatively labile to porcine esterase with the half-lives from 12.3 to 48.0 min. 相似文献