- Prodrug compound and application ofprodrug compound in treatment of cancer
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The present invention provides a compound indicated by a formula (I), pharmaceutically acceptable salts or esters thereof, a pharmaceutical composition of the compound, and application of the compoundand the pharmaceutical composition in the inhibition or regulation of the activity of tyrosine kinase and treating disease symptoms or symptoms including cancer mediated by tyrosine kinase.
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Paragraph 0160-0161
(2021/03/06)
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- PRODRUGS OF THE TYROSINE KINASE INHIBITOR FOR TREATING CANCER
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There are provided compounds of Formula (I), and pharmaceutically acceptable salts and esters thereof, and pharmaceutical compositions thereof, useful for inhibition or modulation of the activity of tyrosine kinases and treatment of disease states or conditions mediated by tyrosine kinases, including cancers. (I)
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Paragraph 00121-00122
(2021/03/05)
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- A convenient solid phase approach to obtain lipophilic 5′-phosphoramidate derivatives of DNA and RNA oligonucleotides
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This paper explores the potential of a modified phosphotriester approach to the synthesis of 5′-phosphoramidate derivatives of DNA and RNA oligonucleotides. The modification of 5′-deprotected support-bound oligonucleotides is done in two steps: i) conversion of the 5′-OH group of an oligonucleotide into an activated phosphodiester, and ii) treatment of the activated phosphodiester with an aminocompound. The approach is efficient and compatible with conventional solid phase oligonucleotide synthesis. It can be used for the conjugation of therapeutically relevant oligonucleotides with functional moieties or carrier constructions, which are to be removed after endocytosis.
- Dovydenko, Ilya S.,Kupryushkin, Maxim S.,Pyshnyi, Dmitrii V.,Apartsin, Evgeny K.
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p. 102 - 111
(2018/02/16)
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- Emtricitabine phosphonate compound
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The invention belongs to the field of synthesis of organic compounds and medicine and relates to an emtricitabine phosphonate compound, a preparation method thereof, a medicinal compound containing the compound and application of the compound in antiviral drugs for treatment. A provided phosphonate compound of a nucleoside analog has equivalent or superior stability in human plasma, artificial gastric juice and artificial intestinal juice under comparison with emtricitabine and can remarkably reduce the quantity of hepatitis B viruses in animal bodies; compared with emtricitabine, the compoundhas obviously higher anti-HBV activity, excellent liver targeting and smaller toxic and side effects and is a therapeutic agent with a clinical application prospect for HIV and HBV.
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Paragraph 0055; 0057; 0058; 0059; 0060
(2018/07/30)
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- SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF
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Disclosed herein are nucleosides, nucleotide analogs, methods of synthesizing nucleotide analogs and methods of treating diseases and/or conditions such as a Filoviridae virus infection with one or more nucleosides and/or nucleotide analogs.
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Paragraph 0699; 0705; 0706; 0709
(2016/03/11)
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- Synthesis and biological evaluation of LNA phosphoramidates
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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
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- Activation of p16 gene silenced by DNA methylation in cancer cells by phosphoramidate derivatives of 2′-deoxyzebularine
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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.
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experimental part
p. 7593 - 7601
(2009/12/07)
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- Antiviral phosphoramidates
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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,
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Page/Page column 18; 38
(2008/06/13)
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- Application of phosphoramidate ProTide technology significantly improves antiviral potency of carbocyclic adenosine derivatives
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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
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p. 7215 - 7226
(2007/10/03)
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- Anti-cancer ProTides: Tuning the activity of BVDU phosphoramidates related to thymectacin
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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
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p. 3219 - 3227
(2007/10/03)
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- CHEMICAL COMPOUNDS
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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 19; 103-104
(2010/02/10)
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- Anti-proliferative and anti-leukemic activity of DDE46 (compound WHI-07), a novel bromomethoxylated arylphosphate derivative of zidovudine, and related compounds: Studies using human acute lymphoblastic leukemia cells and the zebrafish model
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The anti-proliferative effects of a novel bromomethoxylated arylphosphate derivative of zidovudine (compound DDE46, CAS 213982-96-8) were first examined in a zebra fish embryo model. DDE46 blocked the cell division at the 2-cell stage of the embryonic development followed by total cell fusion. DDE46 also inhibited the proliferation of the leukemic cell lines NALM-6 and MOLT-3. DDE46 enhanced the activity of the pro-apoptotic enzymes Caspase-3, Caspase-6, Caspase-8, and Caspase-9 leading to the apoptotic death of the leukemic cell line Jurkat. These results justify the further development of this agent as a new anti-leukemic drug candidate. ECV · Editio Cantor Verlag, Aulendorf (Germany).
- Benyumov, Alexey O.,Venkatachalam, Taracad K.,Grigoriants, Olga O.,Vassilev, Alexei O.,Tibbles, Heather E.,Downs, Suzanne,Dumez, Darin,Uckun, Fatih M.
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p. 114 - 122
(2007/10/03)
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- Syntheses and spectral characterization of 2-aryloxy - 5,5′- bis(bromomethyl)-1,3,2P-dioxaphosphorinane 2-oxides
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2-Aryloxy-5,5′-bis(bromomethyl)-1,3,2-dioxaphosphorinane 2-oxides 3 have been synthesized by the reaction of 2,2′-bis(bromomethyl)-1,3- propanediol 1 with various arvlphosphorodichloridates 2a-h in the presence of triethylamine in dry tetrahydrofuran at room temperatuure. Their 1H, 13C, 31P NMR and mass spectral data are discussed.
- Stephen Babu,Anasuyamma,Venugopal,Naga Raju,Suresh Reddy
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p. 1248 - 1251
(2007/10/03)
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- L-2',3'-dideoxy nucleoside analogs as anti-hepatitis B (HBV) and anti-HIV agents
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The present invention relates to the surprising discovery that certain dideoxynucleoside analogs which contain a dideoxy ribofuranosyl moiety having an L-configuration (as opposed to the naturally occurring D-configuration) exhibit unexpected activity against Hepatitis B virus (HBV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds according to the present invention exhibit primary utility as agents for inhibiting the growth or replication of HBV, HIV and other retroviruses, most preferably HBV. The compound 1-(2,3-dideoxy-beta-L-ribofuranosyl)-5-fluorocytosine is shown to be a potent anti-HIV agent with low toxicity to host cells.
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- Method for treating HBV infections with L-2',3'-didehydro-dideoxy-5-fluorocytidine
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The present invention relates to the surprising discovery that certain dideoxynucleoside analogs which contain a dideoxy ribofuranosyl moiety having an L-configuration (as opposed to the naturally occurring D- configuration) exhibit unexpected activity against Hepatitis B virus (HBV). In particular, the compounds according to the present invention show potent inhibition of the replication of the virus in combination with very low toxicity to the host cells (i.e., animal or human tissue). Compounds according to the present invention exhibit primary utility as agents for inhibiting the growth or replication of HBV, HIV and other retroviruses, most preferably HBV.
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- Synthesis of potential UDP-glucuronosyltransferase inhibitors containing a diphosphate function
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The synthesis of potential inhibitors of UDP-glucuronosyltransferase, in which the β-phosphate moiety of uridine 5'-diphosphate is linked to phenolic or alcoholic hydroxyl groups, is described.Key intermediates in the formation of the diphosphate function are S-(4-methylphenyl) 2-cyanoethyl phosphorothioate triesters which, after conversion into the corresponding S-(4-methylphenyl) phosphorothioate diesters, react with phosphate monoesters, in the presence of iodine, to give the target molecules.
- Noort, D.,Marel, G. A. van der,Gen, A. van der,Mulder, G. J.,Boom, J. H. van
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- A SIMPLIFIED STRATEGY FOR THE SYNTHESIS OF DIDEOXYRIBONUCLEOTIDE BLOCKS
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The rapid synthesis of dideoxyribonucleotide blocks in 60-85percent isolated yields has been achieved by combining the phosphorylation and condensation steps in a sequential reaction series which also allows the recovery of unreacted nucleotides.
- Sadana, K. L.,Hruska, F. E.,Loewen, P. C.
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p. 3367 - 3370
(2007/10/02)
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