- Influence of 4′-Substitution on the Activity of Gemcitabine and Its ProTide against VZV and SARS-CoV-2
-
In addition to its therapeutic value as a chemotherapy drug, gemcitabine is of ongoing interest to the scientific community for its broad-spectrum antiviral activity. Herein the synthesis of 4′-methoxy- and 4′-fluoro-substituted gemcitabine analogues along with their phosphoramidate prodrugs is described. Among these derivatives, 4′-fluorogemcitabine proved to be active against varicella zoster virus (VZV, TK+ strain) with an EC50 of 0.042 μM and produced significant cytotoxicity (CC50 = 0.11 μM). Upon derivatization of this trifluoro nucleoside as its prodrug, decreased anti-VZV activity was observed, but with a concomitantly improved selectivity index (SI = 36). When this prodrug was tested against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), its antiviral activity (EC50 = 0.73 μM) was comparable to or slightly lower than its cytotoxic concentration in measurements of cell growth and cell morphology, respectively.
- Zheng, Zihua,Groaz, Elisabetta,Snoeck, Robert,De Jonghe, Steven,Herdewijn, Piet,Andrei, Graciela
-
supporting information
p. 88 - 92
(2020/12/21)
-
- Generation of Stable Isopentenyl Monophosphate Aryloxy Triester Phosphoramidates as Activators of Vγ9Vδ2 T Cells
-
Aryloxy triester phosphoramidate prodrugs of the monophosphate derivatives of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) were synthesized as lipophilic derivatives that can improve cell uptake. Despite the structural similarity of IPP and DMAPP, it was noted that their phosphoramidate prodrugs exhibited distinct stability profiles in aqueous environments, which we show is due to the position of the allyl bond in the backbones of the IPP and DMAPP monophosphates. As the IPP monophosphate aryloxy triester phosphoramidates showed favorable stability, they were subsequently investigated for their ability to activate Vγ9/Vδ2 T cells and they showed promising activation of this subset of T cells. Together, these findings represent the first report of IPP and DMAPP monophosphate prodrugs and the ability of IPP aryloxy triester phosphoramidate prodrugs to activate Vγ9/Vδ2 T cells highlighting their potential as possible immunotherapeutics.
- Xu, Qin,Taher, Taher E.,Ashby, Elizabeth,Sharif, Maria,Willcox, Benjamin E.,Mehellou, Youcef
-
p. 2375 - 2380
(2021/05/26)
-
- 2,4,7-SUBSTITUTED-7-DEAZA-2'-DEOXY-2'-FLUOROARABINOSYL NUCLEOSIDE AND NUCLEOTIDE PRO-DRUGS AND USES THEREOF
-
The present disclosure is concerned with 2,4,7-substituted-7-deaza-2'-deoxy-2'- fluoroarabinosyl nucleoside and nucleotide prodrugs that are capable of inhibiting viral infections and methods of treating viral infections such as, for example, human immunodeficiency virus (HIV), human papillomavirus (HPV), herpes simplex virus (HSV), human cytomegalovirus (HCMV), chicken pox, infectious mononucleosis, mumps, measles, rubella, shingles, ebola, viral gastroenteritis, viral hepatitis, viral meningitis, human metapneumovirus, human parainfluenza virus type 1, parainfluenza virus type 2, parainfluenza virus type 3, respiratory syncytial virus, viral pneumonia, Chikungunya virus (CHIKV), Venezuelan equine encephalitis (VEEV), dengue (DENV), influenza, West Nile virus (WNV), zika (ZIKV), 229E, NL63, OC43, HKU1, Middle East respiratory syndrome coronavirus (MERS-CoV), severe acute respiratory syndrome coronavirus (SARS-CoV), and severe acute respiratory syndrome coronavirus disease 2019 (SARS-CoV-2), using these compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
- -
-
Paragraph 00352; 00355
(2020/12/30)
-
- Radiosynthesis of [18F]-labelled pro-nucleotides (ProtIDes)
-
Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of P
- Cavaliere, Alessandra,Probst, Katrin C.,Paisey, Stephen J.,Marshall, Christopher,Dheere, Abdul K.H.,Aigbirhio, Franklin,McGuigan, Christopher,Westwell, Andrew D.
-
-
- Aryloxy Triester Phosphoramidates as Phosphoserine Prodrugs: A Proof of Concept Study
-
The specific targeting of protein-protein interactions by phosphoserine-containing small molecules has been scarce due to the dephosphorylation of phosphoserine and its charged nature at physiological pH, which hinder its uptake into cells. To address these issues, we herein report the synthesis of phosphoserine aryloxy triester phosphoramidates as phosphoserine prodrugs that are enzymatically metabolized to release phosphoserine. This phosphoserine-masking approach was applied to a phosphoserine-containing inhibitor of 14-3-3 dimerization, and the generated prodrugs exhibited improved pharmacological activity. Collectively, this provided a proof of concept that the masking of phosphoserine with biocleavable aryloxy triester phosphoramidate masking groups is a viable intracellular delivery system for phosphoserine-containing molecules. Ultimately, this will facilitate the discovery of phosphoserine-containing small-molecule therapeutics.
- Dhiani, Binar A.,James, Edward,Kadri, Hachemi,Lambourne, Olivia A.,Mehellou, Youcef,Miccoli, Ageo,Thornton, Peter J.
-
supporting information
(2020/03/30)
-
- Phosphoramidate derivative of nucleoside compound and application thereof
-
The invention belongs to the technical field of medicines, and relates to a phosphoramidate derivative of a nucleoside compound and application thereof, and a pharmaceutical composition containing thecompound. The phosphoramidate derivative can be used as
- -
-
Paragraph 0207; 0209-0211
(2020/12/30)
-
- Phosphoramidate derivatives of nucleoside compounds and uses of derivatives
-
The invention belongs to the technical field of medicines, and relates to phosphoramidate derivatives of nucleoside compounds, uses of the phosphoramidate derivatives, and a pharmaceutical compositioncontaining the compounds. The derivatives and pharmaceu
- -
-
Paragraph 0020; 0222-0224
(2020/12/14)
-
- Nucleoside phosphate/amide derivative and medical application thereof
-
The invention relates to a nucleoside phosphate/amide derivative shown in the formula I and isomers, nontoxic pharmaceutically acceptable salts and solvates thereof. The formula I is shown in the description. In the formula I, Nu represents nucleoside res
- -
-
Paragraph 0032; 0033; 0036; 0037
(2019/01/23)
-
- NOVEL SMALL MOLECULE DRUG CONJUGATES OF GEMCITABINE DERIVATIVES
-
Disclosed are compounds having formula (I) or a pharmaceutically acceptable salt, ester, amide, solvate, or stereoisomer thereof, wherein L, Y1, Y2, Y3, Y4, Y5, Z1, Z2, Z3, Z4, Z5, Z6, and Effector are each as defined in the specification; compositions thereof; uses thereof; and methods of use thereof.
- -
-
Page/Page column 88
(2019/08/26)
-
- 4'-THIO-NUCLEOTIDE AND -NUCLEOSIDE PRODRUGS FOR THE TREATMENT OF CANCER
-
The present disclosure is concerned with 4'-thio nucleotide and nucleoside compounds for the treatment of various cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
- -
-
Paragraph 00423
(2019/11/12)
-
- Synthesis and Biological Evaluation of (E)-4-Hydroxy-3-methylbut-2-enyl Phosphate (HMBP) Aryloxy Triester Phosphoramidate Prodrugs as Activators of Vγ9/Vδ2 T-Cell Immune Responses
-
The aryloxy triester phosphoramidate prodrug approach has been used with success in drug discovery. Herein, we describe the first application of this prodrug technology to the monophosphate derivative of the phosphoantigen HMBPP and one of its analogues. Some of these prodrugs exhibited specific and potent activation of Vγ9/Vδ2 T-cells, which were then able to lyse bladder cancer cells in vitro. This work highlights the promise of this prodrug technology in the discovery of novel immunotherapeutics.
- Davey, Martin S.,Malde, Roshni,Mykura, Rory C.,Baker, Alfie T.,Taher, Taher E.,Le Duff, Cécile S.,Willcox, Benjamin E.,Mehellou, Youcef
-
p. 2111 - 2117
(2018/03/21)
-
- SYNTHESIS OF 3'-DEOXYADENOSINE-5'-0-[PHENYL(BENZYLOXY-L-ALANINYL)]PHOSPHATE (NUC-7738)
-
The present invention generally relates to a novel process for the preparation of 3'-deoxyadenosine derivatives,and particularly NUC-7738 (3'-deoxyadenosine-5'-O-[phenyl(benzyloxy-L-alaninyl)] phosphate) an anticancer ProTide of deoxyadenosine.
- -
-
Page/Page column 25; 26; 28; 29
(2019/01/07)
-
- Kinetin Riboside and Its ProTides Activate the Parkinson’s Disease Associated PTEN-Induced Putative Kinase 1 (PINK1) Independent of Mitochondrial Depolarization
-
Since loss of function mutations of PINK1 lead to early onset Parkinson’s disease, there has been growing interest in the discovery of small molecules that amplify the kinase activity of PINK1. We herein report the design, synthesis, serum stability, and hydrolysis of four kinetin riboside ProTides. These ProTides, along with kinetin riboside, activated PINK1 in cells independent of mitochondrial depolarization. This highlights the potential of modified nucleosides and their phosphate prodrugs as treatments for neurodegenerative diseases.
- Osgerby, Laura,Lai, Yu-Chiang,Thornton, Peter J.,Amalfitano, Joseph,Le Duff, Cécile S.,Jabeen, Iqra,Kadri, Hachemi,Miccoli, Ageo,Tucker, James H. R.,Muqit, Miratul M. K.,Mehellou, Youcef
-
p. 3518 - 3524
(2017/05/05)
-
- Kinase-independent phosphoramidate S1P1receptor agonist benzyl ether derivatives
-
Previously published S1P receptor modulator benzyl ether derivatives have shown potential as being viable therapeutics for the treatment of neurodegenerative diseases, however, two of the most S1P1-selective compounds are reported as being poorly phosphorylated by kinases in vivo. Phosphoramidates of BED compounds (2a, 2b) were synthesised with the aim of producing kinase-independent S1P receptor modulators. Carboxypeptidase, human serum and cell lysate processing experiments were conducted. ProTide BED analogues were found to have an acceptable level of stability in acidic and basic conditions and in vitro metabolic processing experiments showed that they are processed to the desired pharmacologically active monophosphate. The research describes the development of an entirely novel family of therapeutic agents.
- James, Edward,Pertusati, Fabrizio,Brancale, Andrea,McGuigan, Chris
-
supporting information
p. 1371 - 1378
(2017/03/08)
-
- Nucleoside analogs of the phosphate prodrug and its application
-
The invention provides a phosphate prodrug of a nucleoside analog as shown in the general formula I as well as all possible isomers and medicinal salts of the phosphate prodrug. The invention also provides an application of the compound to preparation of drugs for preventing and treating tumor diseases or virus related diseases.
- -
-
Paragraph 0086; 0087; 0092; 0093; 0094
(2017/08/25)
-
- DIASTEREOSELECTIVE SYNTHESIS OF PHOSPHATE DERIVATIVES AND OF THE GEMCITABINE PRODRUG NUC-1031
-
The present invention provides a method for the preparation of intermediates useful in the synthesis of gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate. It also provides a method of preparing gemcitabine-[phenyl-benzoxy-L-alaninyl)]-phosphate.
- -
-
Page/Page column 22; 23; 34; 35
(2017/07/06)
-
- THIONUCLEOSIDE DERIVATIVE OR SALT THEREOF, AND PHARMACEUTICAL COMPOSITION
-
Disclosed are a compound and a pharmaceutical composition that exhibit an excellent drug efficacy against a tumor, in particular a tumor which has acquired resistance to gemcitabine. Specifically, provided is a thionucleoside derivative represented by General Formula [1] (in the formula, R1 represents a hydroxyl group which may be protected, a C1-20 alkoxy group which may be substituted, or the like; R2 represents a C1-20 alkoxy group which may be substituted, a C3-8 cycloalkoxy group which may be substituted, or the like; and R3 represents a hydrogen atom or the like); or a salt thereof. Further, provided is a pharmaceutical composition containing such a thionucleoside derivative or a salt thereof.
- -
-
Paragraph 0582-0584
(2017/12/27)
-
- ProTides of BVdU as potential anticancer agents upon efficient intracellular delivery of their activated metabolites
-
Nucleosides represent a major chemotherapeutic class for treating cancer, however their limitations in terms of cellular uptake, nucleoside kinase-mediated activation and catabolism are well-documented. The monophosphate pro-nucleotides known as ProTides represents a powerful strategy for bypassing the dependence on active transport and nucleoside kinase-mediated activation. Herein, we report the structural tuning of BVdU ProTides. Forty six phosphoramidates were prepared and biologically evaluated against three different cancer cell lines; murine leukemia (L1210), human CD4+T-lymphocyte (CEM) and human cervical carcinoma (HeLa). Twenty-fold potency enhancement compared to BVdU was achieved against L1210 cells. Interestingly, a number of ProTides showed low micromolar activity against CEM and HeLa cells compared to the inactive parent BVdU. The ProTides showed poor, if any measurable toxicity to non-tumourigenic human lung fibroblast cell cultures. Separation of four pairs of the diastereoisomeric mixtures and comparison of their spectral properties, biological activities and enzymatic activation rate is reported.
- Kandil, Sahar,Balzarini, Jan,Rat, Stephanie,Brancale, Andrea,Westwell, Andrew D.,McGuigan, Christopher
-
p. 5618 - 5623
(2016/11/29)
-
- Facile synthesis of the NNRTI microbicide MC-1220 and synthesis of its phosphoramidate prodrugs
-
A facile and novel synthetic route to MC-1220 was achieved by condensation of 4,6-dichloro-N,N-5-trimethylpyrimidin-2-amine (1) with the sodium salt of 2,6-difluorophenylacetonitrile, followed by methylation and strong acidic hydrolysis. The prodrugs of M
- Loksha, Yasser M.,Pedersen, Erik B.,La Colla, Paolo,Loddo, Roberta
-
p. 940 - 946
(2016/01/15)
-
- PROCESS FOR THE PREPARATION OF GEMCITABINE-[PHENYL(BENZOXY-L-ALANINYL)] PHOSPHATE
-
The present invention provides a process for the preparation of gemcitabine-[phenyl(benzoxy-L-alaninyl)] phosphate of Formula I in high yield and purity.
- -
-
Page/Page column 16-17
(2016/02/26)
-
- Application of ProTide technology to gemcitabine: A successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development
-
Gemcitabine is a nucleoside analogue commonly used in cancer therapy but with limited efficacy due to a high susceptibility to cancer cell resistance. The addition of a phosphoramidate motif to the gemcitabine can protect it against many of the key cancer resistance mechanisms. We have synthesized a series of gemcitabine phosphoramidate prodrugs and screened for cytostatic activity in a range of different tumor cell lines. Among the synthesized compounds, one in particular (NUC-1031, 6f) was shown to be potent in vitro. Importantly, compared with gemcitabine, 6f activation was significantly less dependent on deoxycytidine kinase and on nucleoside transporters, and it was resistant to cytidine deaminase-mediated degradation. Moreover, 6f showed a significant reduction in tumor volumes in vivo in pancreatic cancer xenografts. The ProTide 6f is now in clinical development with encouraging efficacy signals in a Phase I/II study, which strongly supports the ProTide approach to generate promising new anticancer agents.
- Slusarczyk, Magdalena,Lopez, Monica Huerta,Balzarini, Jan,Mason, Malcolm,Jiang, Wen G.,Blagden, Sarah,Thompson, Emely,Ghazaly, Essam,McGuigan, Christopher
-
supporting information
p. 1531 - 1542
(2014/03/21)
-
- Synthesis and Biological Evaluation of Purine 2′-Fluoro-2′-deoxyriboside ProTides as Anti-influenza Virus Agents
-
2′-Fluoro-2′-deoxyguanosine has been reported to have potent anti-influenza virus activity invitro and invivo. Herein we describe the synthesis and biological evaluation of 6-modified 2′-fluoro-2′-deoxyguanosine analogues and their corresponding phosphora
- Meneghesso, Silvia,Vanderlinden, Evelien,Brancale, Andrea,Balzarini, Jan,Naesens, Lieve,Mcguigan, Christopher
-
supporting information
p. 415 - 425
(2013/08/25)
-
- Synthesis and biological evaluation of pyrimidine nucleoside monophosphate prodrugs targeted against influenza virus
-
Uridine-based nucleoside analogues have often been found to have relatively poor antiviral activity. Enzymatic assays, evaluating inhibition of influenza virus RNA polymerase, revealed that some uridine triphosphate derivatives displayed inhibitory activity on UTP incorporation into viral RNA. Here we report the synthesis, antiviral activity and enzymatic evaluation of novel ProTides designed to deliver the activated (monophosphorylated) uridine analogues inside the influenza virus-infected cells. After evaluation of the activation profile we identified two ProTides with moderate antiviral activity in MDCK cells (23a, EC99=49±38μM and 23b, EC99≥81μM) while the corresponding nucleoside analogue (2'-fluoro-2'-deoxyuridine) was inactive. Thus, at least in these cases the poor antiviral activity of the uridine analogues may be ascribed to poor phosphorylation.
- Meneghesso, Silvia,Vanderlinden, Evelien,Stevaert, Annelies,McGuigan, Christopher,Balzarini, Jan,Naesens, Lieve
-
experimental part
p. 35 - 43
(2012/07/28)
-
- Design, synthesis and biological evaluation of 2′-deoxy-2′, 2′-difluoro-5-halouridine phosphoramidate ProTides
-
We report the synthesis of a series of novel 2′-deoxy-2′, 2′-difluoro-5-halouridines and their corresponding phosphoramidate ProTides. All compounds were evaluated for antiviral activity and for cellular toxicity. Interestingly, 2′-deoxy-2′,2′-difluoro-5-iodo- and -5-bromo-uridines showed selective activity against feline herpes virus replication in cell culture due to a specific recognition (activation) by the virus-encoded thymidine kinase.
- Quintiliani, Maurizio,Persoons, Leentje,Solaroli, Nicola,Karlsson, Anna,Andrei, Graciela,Snoeck, Robert,Balzarini, Jan,McGuigan, Christopher
-
experimental part
p. 4338 - 4345
(2011/09/12)
-
- Synthesis and antiviral evaluation of α-l-2′- deoxythreofuranosyl nucleosides
-
The synthesis of a series of α-l-2′-deoxythreofuranosyl nucleosides featuring the nucleobases A, T, C and U is described in seven steps from 1,2-O-isopropyledene-α-l-threose, involving a Vorbru?ggen coupling and a Barton-McCombie deoxygenation protocol as the key steps. All analogues, including a phosphoramidate nucleoside phosphate prodrug of the T analogue, were evaluated against a broad panel of different viruses but found inactive, while also lacking notable cellular toxicity. The thymidine analogue showed inhibition to mitochondrial thymidine kinase-2 (TK-2), herpes simplex virus type 1 (HSV-1) TK, varicella-zoster virus (VZV) TK and Mycobacterium tuberculosis thymidylate kinase.
- Toti, Kiran S.,Derudas, Marco,McGuigan, Christopher,Balzarini, Jan,Van Calenbergh, Serge
-
experimental part
p. 3704 - 3713
(2011/11/07)
-
- The application of phosphoramidate protide technology to acyclovir confers anti-HIV inhibition
-
Recently, it has been reported that phosphorylated acyclovir (ACV) inhibits human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in a cell-free system. To deliver phosphorylated ACV inside cells, we designed ACV monophosphorylated derivatives using ProTide technology. We found that the L-alanine derived ProTides show anti-HIV activity at noncytotoxic concentrations; ester and aryl variation was tolerated. ACV ProTides with other amino acids, other than L-phenylalanine, showed no detectable activity against HIV in cell culture. The inhibitory activity of the prodrugs against herpes simplex virus (HSV) types -1 and -2 and thymidine kinase-deficient HSV-1 revealed different structure-activity relationships but was again consistent with successful nucleoside kinase bypass. Enzymatic and molecular modeling studies have been performed in order to better understand the antiviral behavior of these compounds. ProTides showing diminished carboxypeptidase lability translated to poor anti-HIV agents and vice versa, so the assay became predictive.
- Derudas, Marco,Carta, Davide,Brancale, Andrea,Vanpouille, Christophe,Lisco, Andrea,Margolis, Leonid,Balzarini, Jan,McGuigan, Christopher
-
supporting information; experimental part
p. 5520 - 5530
(2010/02/28)
-
- Synthesis and biological evaluation of LNA phosphoramidates
-
The synthesis of LNA phosphoramidates is presented. The LNA phosphoramidates were evaluated for their ability to inhibit cell proliferation of the human prostate cancer cell line 15PC3. A number of the LNA phosphoramidates showed cell proliferation inhibition determined by the MTS assay. Copyright Taylor & Francis Group, LLC.
- Jensen, Jacob,Sjogren, Gitte,Hansen, Jens Bo,Rosenbohm, Christoph,Koch, Troels
-
-
- Activation of p16 gene silenced by DNA methylation in cancer cells by phosphoramidate derivatives of 2′-deoxyzebularine
-
We report herein the application of the phosphoramidate ProTide technology to improve the metabolism of the DNA methytransferase inhibitor, zebularine (Z). Zebularine is a riboside that must undergo a complex metabolic transformation before reaching the critical 2′-deoxyzebularine 5′-triphosphate (dZTP). Because 2′-deoxyzebularine (dZ) is not phosphorylated and therefore inactive, the ProTide strategy was employed to bypass the lack of phosphorylation of dZ and the inefficient reduction of zebularine 5′-diphosphate by ribonucleotide-diphosphate reductase required for zebularine. Several compounds were identified as more potent inhibitors of DNA methylation and stronger inducers of p16 tumor suppressor gene than zebularine. However, their activity was dependent on the administration of thymidine to overcome the potent inhibition of thymidylate synthase (TS) and deoxycytidine monophosphate (dCMP) deaminase by dZMP, which deprives cells of essential levels of thymidine. Intriguingly, the activity of the ProTides was cell line-dependent, and activation of p16 was manifest only in Cf-Pac-1 pancreatic ductal adenocarcinoma cells.
- Yoo, Christine B.,Valente, Rocco,Congiatu, Costantino,Gavazza, Federica,Angel, Annette,Siddiqui, Maqbool A.,Jones, Peter A.,McGuigan, Christopher,Marquez, Victor E.
-
experimental part
p. 7593 - 7601
(2009/12/07)
-
- Antiviral phosphoramidates
-
The invention provides novel nucleoside compounds of formula I wherein R1, R2a, R2b, R3, R4, R5, R6, R8a, R9 and R10 are as defined herein which are useful for the treatment of Hepatitis C Virus (HCV) mediated diseases. The invention further provides methods for treatment or prophylaxis of HCV mediated diseases with compounds of formula I and pharmaceutical compositions comprising these compounds,
- -
-
Page/Page column 34
(2008/06/13)
-
- Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
-
We report the application of phosphoramidate pronucleotide (ProTide) technology to the antiviral agent carbocyclic L-d4A (L-Cd4A). The phenyl methyl alaninyl parent ProTide of L-Cd4A was prepared by Grignard-mediated phosphorochloridate reaction and resulted in a compound with significantly improved anti-HIV (2600-fold) and HBV activity. We describe modifications of the aryl, ester, and amino acid regions of the ProTide and how these changes affect antiviral activity and metabolic stability. Separate and distinct SARs were noted for HIV and HBV. Additionally, ProTides were prepared from the D-nucleoside D-Cd4A and the dideoxy analogues L-CddA and D-CddA. These compounds showed more modest potency improvements over the parent drug. In conclusion, the ProTide approach is highly successful when applied to L-Cd4A with potency improvements in vitro as high as 9000-fold against HIV. With a view to preclinical candidate selection we carried out metabolic stability studies using cynomolgus monkey liver and intestinal S9 fractions.
- McGuigan, Christopher,Hassan-Abdallah, Alshaimaa,Srinivasan, Sheila,Wang, Yikang,Siddiqui, Adam,Daluge, Susan M.,Gudmundsson, Kristjan S.,Zhou, Huiqiang,McLean, Ed W.,Peckham, Jennifer P.,Burnette, Thimysta C.,Marr, Harry,Hazen, Richard,Condreay, Lynn D.,Johnson, Lance,Balzarini, Jan
-
p. 7215 - 7226
(2007/10/03)
-
- Phosphoramidate and phosphate prodrugs of (-)-β-D-(2R,4R)-dioxolane- thymine: Synthesis, anti-HIV activity and stability studies
-
A series of phosphoramidate and phosphate prodrugs of DOT were synthesized via dichlorophosphate or H-phosphonate chemistry and evaluated for their anti-HIV activity against LAI M184V mutants in PBM cells as well as for their cytotoxicity. The antiviral and cytotoxic profiles of the prodrugs were compared with that of the parent compound (DOT), and it was found that four aryl phosphoramidates 5, 18, 20, and 26 showed a significant enhancement (8- to 12-fold) in anti-HIV activity without cytotoxicity. Chemical stability of these prodrugs was evaluated in phosphate buffer at pH values of biological relevance (i.e., pH 2.0 and 7.4). Enzymatic hydrolysis was also studied in esterase or lipase in buffer solution. Chemical stability studies indicate that the phosphoramidates have good chemical stability at pH 2.0 and at pH 7.4 phosphate buffer. Phosphoramidate prodrugs were hydrolyzed in vitro by esterase or lipase and found to be better substrates for lipases than for esterases. 1,3-Diol cyclic phosphates showed potent anti-HIV activity without increasing the cytotoxicity compared with that of DOT and have good chemical and enzymatic stability. Long-chain lipid phosphates, although showed potent anti-HIV activity, exhibited increased cytotoxicity.
- Liang, Yuzeng,Narayanasamy, Janarthanan,Schinazi, Raymond F.,Chu, Chung K.
-
p. 2178 - 2189
(2007/10/03)
-
- CHEMICAL COMPOUNDS
-
Phosphoramidate derivatives of nucleotides and their use in the treatment of cancer are described. The base moieties of, for example, each of deoxyuridine, cytarabine, gemcitabine and citidine may be substituted at the 5-position. The phosphoramidate moiety has attached to the P atom an aryl-O moiety and an α-amino acid moiety. The α-amino acid moiety may correspond to or be derived from either a naturally occurring or a non-naturally occurring amino acid.
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-
Page/Page column 74
(2010/02/10)
-
- Anti-cancer ProTides: Tuning the activity of BVDU phosphoramidates related to thymectacin
-
Based on our wide ranging knowledge of phosphoramidate ProTides as anti-viral agents we have tuned the lead anti-cancer agent thymectacin in the ester and amino acid regions and revealed a substantial enhancement in in vitro potency versus colon and prostate cancer cell lines. Twelve analogues have been reported, with yields of 29-78%. The compounds are fully characterised and data clearly reveal the presence of two phosphate diastereoisomers, as expected, in roughly equi-molar proportions. The compounds were evaluated in tissue culture versus three different tumour cell lines, using thymectacin as the control. It is notable that minor structural modification of the parent phenyl methoxyalaninyl structure of thymectacin leads to significant enhancements in potency. In particular, replacement of the methyl ester moiety in the lead by a benzyl ester gave a 175-fold boost in potency versus colon cancer HT115. This derivative emerges as a low micromolar inhibitor of HT115 cells and a new lead for further optimisation.
- McGuigan, Christopher,Thiery, Jean-Christophe,Daverio, Felice,Jiang, Wen G.,Davies, Gaynor,Mason, Malcolm
-
p. 3219 - 3227
(2007/10/03)
-