Syntheses of 4-[1-(2-deoxy-β-D-ribofuranosyl)]-derivatives of 2-substituted-5-fluoroaniline: "cytosine replacement" analogs of deoxycytidine for evaluation as anticancer and antihuman immunodeficiency virus (anti-HIV) agents

2000 ◽  
Vol 78 (8) ◽  
pp. 1081-1088
Author(s):  
Zhi-Xian Wang ◽  
Leonard I Wiebe ◽  
Erik De Clercq ◽  
Jan Balzarini ◽  
Edward E Knaus
Keyword(s):  
Anticancer Agent ◽  
Coupling Reaction ◽  
Tumor Cell Lines ◽  
Immunodeficiency Virus ◽  
Sugar Ring ◽  
Type Coupling ◽  
Anti Hiv Agents ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

A group of 4-[1-(2-deoxy-β-D-ribofuranosyl)]-derivatives of 5-fluoroaniline possessing a variety of aryl C-2 substituents (6a R = H, 6b R = F, 6c R = Me) were synthesized. Accordingly, a Heck-type coupling reaction of the 4-iodoaniline derivatives (13a–c) with the bis(tert-butyldimethylsilyl)glycal (11) in the presence of Pd(OAc)2 and Ph3As, followed by removal of the tert-butyldimethylsilyl protection groups using n-Bu4N+F-, yielded the corresponding 4-(β-D-glycero-pentofuran-3-ulos-1-yl)aniline derivatives (14a–c) having a C-3 C=O in the sugar ring. Reduction of the C-3 C=O compounds (14a–c) using NaB(OAc)3H afforded the target 4-[1-(2-deoxy-β-D-ribofuranosyl)]-derivatives of the respective 2-substituted-5-fluoroaniline (6a–c). The deoxycytidine mimic, 3-fluoro-4-[1-(2-deoxy-β-D-ribofuranosyl)]aniline (6a), in which the cytosine ring of deoxycytidine is replaced by a 4-(3-fluoroaniline) ring system, was inactive as an anticancer agent against a variety of tumor cell lines, and as an antihuman immunodeficiency virus (HIV-1, HIV-2) agent. The failure of this unnatural deoxycytidine mimic (6a) to exhibit anticancer-antiviral activity may be due to its inability to undergo phosphorylation by host cell- and virus-induced kinases.Key words: fluoroanilines, deoxycytidine mimics, anticancer-antihuman immunodeficiency virus (HIV) evaluation.

scholarly journals Synthesis and Evaluation of Some Symmetrical Phosphate Dimer Derivatives of 3′-Modified Nucleosides as Potential anti-HIV Agents

1996 ◽  
Vol 7 (6) ◽  
pp. 330-337 ◽  
Author(s):  
C. McGuigan ◽  
H.-W. Tsang ◽  
N. Mahmood ◽  
A. J. Hay
Keyword(s):  
Human Immunodeficiency Virus ◽  
Analytical Data ◽  
Modified Nucleosides ◽  
Nucleoside Analogues ◽  
Immunodeficiency Virus ◽  
Anti Hiv Agents ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

Novel symmetrical nucIeotide-(5′,5′)-dimers of 3′-O-acetylthymidine, 3′-O-methylthymidine, 3′-O-ethylthymidine, 3′-O-n-propylthymidine and 3′-azido-3′-deoxythymidine (AZT) were synthesized as membrane soluble pro-drugs. These were prepared using phosphorodichloridate chemistry and were characterised by spectroscopic and analytical data. In-vitro evaluation of the derivatives in cells acutely infected with the human immunodeficiency virus (HIV-1) demonstrated a range of activities. These derivatives were generally found to display poor inhibition of HIV proliferation. Derivatives containing AZT moieties were found to be potent, but such compounds were less active than the parent nucleoside. The data indicated that the AZT-containing compounds act primarily via the release of the free nucleoside. However, in some cases, the dimers of certain inactive nucleoside analogues were found to be active. In these cases, release of the nucleoside alone cannot account for the activity.

scholarly journals Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors

Acta Naturae ◽  
2013 ◽  
Vol 5 (1) ◽  
pp. 63-72 ◽  
Author(s):  
S. P. Korolev ◽  
O. V. Kondrashina ◽  
D. S. Druzhilovsky ◽  
A. M. Starosotnikov ◽  
M. D. Dutov ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Integrase Inhibitors ◽  
Mechanism Of Inhibition ◽  
Immunodeficiency Virus ◽  
Pharmacokinetic Properties ◽  
Nitro Derivatives ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

Human immunodeficiency virus type 1 integrase is one of the most attractive targets for the development of anti-HIV-1 inhibitors. The capacity of a series of 2,1,3-benzoxadiazoles (benzofurazans) and their N-oxides (benzofuroxans) selected using the PASS software to inhibit the catalytic activity of HIV-1 integrase was studied in the present work. Only the nitro-derivatives of these compounds were found to display inhibitory activity. The study of the mechanism of inhibition by nitro-benzofurazans/benzofuroxans showed that they impede the substrate DNA binding at the integrase active site. These inhibitors were also active against integrase mutants resistant to raltegravir, which is the first HIV-1 integrase inhibitor approved for clinical use. The comparison of computer-aided estimations of the pharmacodynamic and pharmacokinetic properties of the compounds studied and raltegravir led us to conclude that these compounds show promise and need to be further studied as potential HIV-1 integrase inhibitors.

Synthesis and Antiviral Activity of 1,3-Disubstituted Uracils against HIV-1 and HCMV

2003 ◽  
Vol 14 (5) ◽  
pp. 271-279 ◽  
Author(s):  
Tokumi Maruyama ◽  
Shigetada Kozai ◽  
Tetsuo Yamasaki ◽  
Myriam Witvrouw ◽  
Christophe Pannecouque ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Human Cytomegalovirus ◽  
Therapeutic Agents ◽  
Reverse Transcriptase Inhibitors ◽  
Uracil Derivatives ◽  
Immunodeficiency Virus ◽  
Anti Hiv Agents ◽  
Anti Hiv ◽  
Hiv 1

The development of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) is an efficient strategy for finding new therapeutic agents against human immunodeficiency virus (HIV). A large number of 6-substituted uracil derivatives have been prepared in order to explore new NNRTIs. However, there are few approaches to anti-HIV agents from 1,3-disubstituted uracil derivatives. Therefore, we tried to prepare several 1,3-disubstituted uracils, which were easily obtainable from uracil by preparation under alkali and Mitsunobu conditions, and examined their antiviral activity against HIV-1 and human cytomegalovirus (HCMV). We found that 1-benzyl-3-(3,5-dimethylbenzyl)uracil and 1-cyanomethyl-3-(3,5-dimethylbenzyl)-4-thiouracil showed powerful inhibition against HCMV and HIV-1, respectively.

scholarly journals Antihuman Immunodeficiency Virus Type 1 (HIV-1) Activity of Rare Earth Metal Complexes of 4-Hydroxycoumarins in Cell Culture

2006 ◽  
Vol 2006 ◽  
pp. 1-7 ◽  
Author(s):  
Ilia Manolov ◽  
Sevda Raleva ◽  
Petya Genova ◽  
Alexey Savov ◽  
Liliana Froloshka ◽  
...  
Keyword(s):  
Viral Replication ◽  
Earth Metal ◽  
H Nmr ◽  
Immunodeficiency Virus ◽  
Physicochemical Methods ◽  
Anti Hiv Agents ◽  
First Time ◽  
Anti Hiv ◽  
Hiv 1

The cerium Ce(III), lanthanum La(III), and neodymium Nd(III) complexes with 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one (warfarin) (W) and 3,3′-benzylidenebis[4-hydroxycoumarin] (1) were synthesized and studied for the first time for cytotoxicity (on MT-2 cells) and as anti-HIV agents under acute and chronic infection. The complexes were characterized by different physicochemical methods: mass spectrometry, ¹H NMR, ¹³C NMR, and IR spectroscopy. The spectra of the complexes were interpreted on the basis of comparison with the spectrum of the free ligands. Anti-HIV effect of the complexes/ligands was measured in MT-2 cells by microtiter infection assay. Detection of endogenous reverse transcriptase (RT) activity and RT processivity by PCR indicative for proviral DNA synthesis demonstrated that anti-HIV activity has not been linked to early stages of viral replication. No effect on late steps of viral replication has been found using cells chronically producing HIV-1LAIvirus. La(W) demonstrated anti-HIV activity (IC50=21.4μM) close to maximal nontoxic concentration. Nd(W), Ce(1), and Nd(1) demonstrated limited anti-HIV potency, so none of the complexes seems appropriate to be used in clinic. Further targeting of HIV-1 inhibition by La(W) is under progress.

scholarly journals Small-Molecule Anti-HIV-1 Agents Based on HIV-1 Capsid Proteins

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 208
Author(s):  
Takuya Kobayakawa ◽  
Masaru Yokoyama ◽  
Kohei Tsuji ◽  
Masayuki Fujino ◽  
Masaki Kurakami ◽  
...  
Keyword(s):  
Small Molecule ◽  
Hydrophobic Interactions ◽  
Future Design ◽  
Sar Studies ◽  
Immunodeficiency Virus ◽  
Conical Structure ◽  
Anti Hiv Agents ◽  
Anti Hiv ◽  
Hiv 1

The capsid of human immunodeficiency virus type 1 (HIV-1) is a shell that encloses viral RNA and is highly conserved among many strains of the virus. It forms a conical structure by assembling oligomers of capsid (CA) proteins. CA dysfunction is expected to be an important target of suppression of HIV-1 replication, and it is important to understand a new mechanism that could lead to the CA dysfunction. A drug targeting CA however, has not been developed to date. Hydrophobic interactions between two CA molecules via Trp184/Met185 in CA were recently reported to be important for stabilization of the multimeric structure of CA. In the present study, a small molecule designed by in silico screening as a dipeptide mimic of Trp184 and Met185 in the interaction site, was synthesized and its significant anti-HIV-1 activity was confirmed. Structure activity relationship (SAR) studies of its derivatives were performed and provided results that are expected to be useful in the future design and development of novel anti-HIV agents targeting CA.

scholarly journals Identification of Specific Determinants of Human APOBEC3F, APOBEC3C, and APOBEC3DE and African Green Monkey APOBEC3F That Interact with HIV-1 Vif

2010 ◽  
Vol 84 (24) ◽  
pp. 12599-12608 ◽  
Author(s):  
Jessica L. Smith ◽  
Vinay K. Pathak
Keyword(s):  
Amino Acids ◽  
Mutational Analysis ◽  
Proteasomal Degradation ◽  
African Green Monkey ◽  
Host Proteins ◽  
Immunodeficiency Virus ◽  
Green Monkey ◽  
Anti Hiv Agents ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Human APOBEC3F (hA3F) and human APOBEC3G (hA3G) are potent anti-human immunodeficiency virus (anti-HIV) host factors that suppress viral replication by hypermutating the viral genome, inhibiting reverse transcription, and hindering integration. To overcome hA3F and hA3G, HIV-1 encodes Vif, which binds and targets these host proteins for proteasomal degradation. Previously, we reported that the hA3F-Vif interactions that lead to hA3F degradation are located in the region comprising amino acids 283 to 300. We have now performed mutational analysis of this region and found that the 289EFLARH294 amino acids contribute to hA3F-Vif binding and are critical for A3F's sensitivity to Vif. Mutants in which E289 is mutated significantly increase hA3F's ability to inhibit viral infectivity in the presence of Vif, and coimmunoprecipitation assays show that binding of Vif to the E289K mutant is decreased. We examined the role of the EFLARH sequence in other A3 proteins, including human A3C (hA3C), human A3DE (hA3DE), African green monkey A3F (agmA3F), and rhesus macaque A3F (rhA3F). hA3C, hA3DE, and agmA3F were all susceptible to degradation induced by HIV-1 Vif, while rhA3F was not. Mutagenesis of the glutamate in the EFLARH sites of hA3C, hA3DE, and agmA3F decreases the susceptibilities of these proteins to Vif-induced degradation. Together, these results indicate that the EFLARH region in hA3F, hA3C, hA3DE, and agmA3F interacts with HIV-1 Vif and that this interaction plays a role in the Vif-mediated proteasomal degradation of these A3 proteins. These studies identify a conserved region in 3 of 7 human A3 proteins that is critical for degradation mediated by HIV-1 Vif and provide structural insights into the hA3F-Vif interactions that could facilitate the development of a novel class of anti-HIV agents.

scholarly journals Unique Anti-Human Immunodeficiency Virus Activities of the Nonnucleoside Reverse Transcriptase Inhibitors Calanolide A, Costatolide, and Dihydrocostatolide

1999 ◽  
Vol 43 (8) ◽  
pp. 1827-1834 ◽  
Author(s):  
Robert W. Buckheit ◽  
E. Lucile White ◽  
Valerie Fliakas-Boltz ◽  
Julie Russell ◽  
Tracy L. Stup ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Reverse Transcriptase ◽  
Resistant Virus ◽  
Immunodeficiency Virus ◽  
Anti Hiv Agents ◽  
Anti Hiv ◽  
Virus Strains ◽  
Hiv 1 ◽  
Calanolide A

ABSTRACT (+)-Calanolide A (NSC 650886) has previously been reported to be a unique and specific nonnucleoside inhibitor of the reverse transcriptase (RT) of human immunodeficiency virus (HIV) type 1 (HIV-1) (M. J. Currens et al., J. Pharmacol. Exp. Ther., 279:645–651, 1996). Two isomers of calanolide A, (−)-calanolide B (NSC 661122; costatolide) and (−)-dihydrocalanolide B (NSC 661123; dihydrocostatolide), possess antiviral properties similar to those of calanolide A. Each of these three compounds possesses the phenotypic properties ascribed to the pharmacologic class of nonnucleoside RT inhibitors (NNRTIs). The calanolide analogs, however, exhibit 10-fold enhanced antiviral activity against drug-resistant viruses that bear the most prevalent NNRTI resistance that is engendered by amino acid change Y181C in the RT. Further enhancement of activity is observed with RTs that possess the Y181C change together with mutations that yield resistance to AZT. In addition, enzymatic inhibition assays have demonstrated that the compounds inhibit RT through a mechanism that affects both the Km for dTTP and theV max, i.e., mixed-type inhibition. In fresh human cells, costatolide and dihydrocostatolide are highly effective inhibitors of low-passage clinical virus strains, including those representative of the various HIV-1 clade strains, syncytium-inducing and non-syncytium-inducing isolates, and T-tropic and monocyte-tropic isolates. Similar to calanolide A, decreased activities of the two isomers were observed against viruses and RTs with amino acid changes at residues L100, K103, T139, and Y188 in the RT, although costatolide exhibited a smaller loss of activity against many of these NNRTI-resistant isolates. Comparison of cross-resistance data obtained with a panel of NNRTI-resistant virus strains suggests that each of the three stereoisomers may interact differently with the RT, despite their high degree of structural similarity. Selection of viruses resistant to each of the three compounds in a variety of cell lines yielded viruses with T139I, L100I, Y188H, or L187F amino acid changes in the RT. Similarly, a variety of resistant virus strains with different amino acid changes were selected in cell culture when the calanolide analogs were used in combination with other active anti-HIV agents, including nucleoside and nonnucleoside RT and protease inhibitors. In assays with combinations of anti-HIV agents, costatolide exhibited synergy with these anti-HIV agents. The calanolide isomers represent a novel and distinct subgroup of the NNRTI family, and these data suggest that a compound of the calanolide A series, such as costatolide, should be evaluated further for therapeutic use in combination with other anti-HIV agents.

scholarly journals 3,4-Dihydro-2-Alkoxy-6-Benzyl-4-Oxopyrimidines (DABOs): A New Class of Specific Inhibitors of Human Immunodeficiency Virus Type 1

1993 ◽  
Vol 4 (6) ◽  
pp. 361-368 ◽  
Author(s):  
M. Artico ◽  
S. Massa ◽  
A. Mai ◽  
M. E. Marongiu ◽  
G. Piras ◽  
...  
Keyword(s):  
Methoxy Group ◽  
New Class ◽  
Immunodeficiency Virus ◽  
Alkoxy Groups ◽  
Anti Hiv Agents ◽  
Hydrolysis Of ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Specific Inhibitors

A series of novel 3,4-dihydro-6-benzyl-4-oxopyrimidines substituted at both the C-5 and the C-2 positions were synthesized as potential anti-HIV agents. Preparation of the title compounds was achieved by condensation of O-methylisourea with methyl 2-alkyl-4-phenylacetylacetate and subsequent displacement of the methoxy group by reaction with a series of linear, ramified and cyclic alkoxy groups containing from three to six carbon units. Methyl 2-alkyl-4-phenylacetylacetates were prepared by alkylation of methyl 4-phenylacetylacetate, which was obtained starting from Meldrum's acid and phenacetyl chloride. Acid hydrolysis of 3,4-dihydro-6-benzyl-2-methoxy-4-oxopyrimidines furnished the corresponding 1,2,3,4-tetrahydro-6-benzyl-2,4-dioxopyrimidines. In acutely infected MT-4 cells, compounds 3e, 3o, 3q and 3r showed an anti-HIV-1 activity as potent and/or selective as HEPT and ddl. Unlike HEPT, the replacement of a methyl for an hydrogen atom at position C-5 of 3,4-dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) did not abolish the antiviral activity, as well as the substitution of the C-5 methyl for an ethyl group did not increase the potency. However, similarly to HEPT and its derivatives, DABOs targeted the HIV-1 reverse transcriptase and neither inhibited the multiplication of HIV-2 in acutely infected MT-4 cells, nor that of HIV-1 in chronically infected H9/IIIB cells.

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