- Design, synthesis and in vitro apoptotic mechanism of novel pyrrolopyrimidine derivatives
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In this work we described the synthesis and evaluation of cytotoxic and apoptotic activity of novel pyrrolopyrimidine derivatives against A549, PC3 and MCF-7 cells. Among the synthesized compounds, 6b, 8a, 9a and 7a, 8b displayed the significant cytotoxic
- Kilic-Kurt, Zühal,Bakar-Ates, Filiz,Aka, Yeliz,Kutuk, Ozgur
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- Novel pyrrolopyrimidine derivatives induce p53-independent apoptosis via the mitochondrial pathway in colon cancer cells
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A series of novel pyrrolopyrimidine urea derivatives were synthesized and evaluated for their anticancer activity against colon cancer cell lines. Compounds showed the remarkable cytotoxic activity on HCT-116 wt cell line. The most potent compound 4c (IC50 = 0.14 μM) induced apoptosis in HCT-116 wt and HCT-116 p53?/? cell lines. Otherwise, treatment of HCT-116 BAX?/?BAK?/? cells with compound 4c didn't lead to activation of apoptosis, suggesting that compound 4c induces apoptotic cell death by activating BAX/BAK-dependent pathway. Moreover, while the compound 4c increase the activation of caspase-3 and caspase-9 levels in HCT-116 wt and HCT-116 p53?/? cells, caspase-3 or caspase-9 activation was not observed in HCT-116 BAX?/?BAK?/? cells. In addition, compound 4c induced mitochondrial apoptosis in cells grown as oncospheroids, which better mimic the in vivo milieu of tumors. 4c treatment also activated JNK along with inhibition of prosurvival kinases such as Akt and ERK 1/2 in HCT-116 wt and HCT-116 p53 ?/? cells as well as in HCT-116 BAX?/?BAK?/? cells. Notably, our results indicated that compound 4c induced mitochondrial apoptosis through activation p53-independent apoptotic signaling pathways.
- Aka, Yeliz,Kilic-Kurt, Zühal,Kutuk, Ozgur
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- Synthesis of Galactosyl-Queuosine and Distribution of Hypermodified Q-Nucleosides in Mouse Tissues
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Queuosine (Q) is a hypermodified RNA nucleoside that is found in tRNAHis, tRNAAsn, tRNATyr, and tRNAAsp. It is located at the wobble position of the tRNA anticodon loop, where it can interact with U as well as C bases located at the respective position of the corresponding mRNA codons. In tRNATyr and tRNAAsp of higher eukaryotes, including humans, the Q base is for yet unknown reasons further modified by the addition of a galactose and a mannose sugar, respectively. The reason for this additional modification, and how the sugar modification is orchestrated with Q formation and insertion, is unknown. Here, we report a total synthesis of the hypermodified nucleoside galactosyl-queuosine (galQ). The availability of the compound enabled us to study the absolute levels of the Q-family nucleosides in six different organs of newborn and adult mice, and also in human cytosolic tRNA. Our synthesis now paves the way to a more detailed analysis of the biological function of the Q-nucleoside family.
- Carell, Thomas,Ensfelder, Timm T.,Heiss, Matthias,Hillmeier, Markus,Kellner, Stefanie,Müller, Markus,Michalakis, Stylianos,Sch?n, Alexander,Scheel, Constanze,Thumbs, Peter,Wagner, Mirko
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supporting information
p. 12352 - 12356
(2020/04/27)
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- Preparation method for catalyzing pyrimidine cyclic hydroxyl chlorination by tetraethylammonium chloride
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The invention discloses a preparation method for catalyzing pyrimidine cyclic hydroxyl chlorination by tetraethylammonium chloride, which comprises the following steps: (1) adding phosphorus oxychloride into a container, adding tetraethylammonium chloride as a catalyst, adding a pyrimidine cyclic hydroxyl compound, and heating to react; (2) preparing an alkali liquor, cooling to 0 DEG C, and slowly dropwise adding an obtained reaction liquid into the alkali liquor for quenching to obtain a target product. The method has the advantages that the provided pyrimidine cyclic hydroxyl chlorination catalysis method is small in environmental pollution, the obtained product is light in color, the catalysis efficiency is high, and the phosphorus oxychloride recovery pressure is small.
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Paragraph 0026-0028
(2020/04/17)
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- Nucleoside heterocycle that binds to both thymidine and cytidine
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This application discloses nucleoside analogs that when incorporated into a oligonucleotide, forms a nucleobase pair with either thymidine or cytidine that are present in a complementary strand at the paired position. These analogs are called “purine bive
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Page/Page column 4; 5
(2018/09/14)
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- 7-to nitrogen-7-halogen-guanine nucleoside synthesis method
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The invention discloses a method for synthesizing 7-denitrification-7-halogen guanosine. The method comprises the following steps: removing a protecting group of a compound of the formula (III) under an alkali condition so as to obtain a compound of the f
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Paragraph 0048; 0049; 0050
(2016/10/08)
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- An improved synthesis approach of the HIV-1 inhibitor RDEA427, a pyrrolo[2,3-d]pyrimidine derivative
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The diarylpyrimidine-like derivative RDEA427 is a highly potent inhibitor against wild-type and a wide range of drug-resistant HIV-1 strains and has attracted much attention. However, the yield of its reported synthesis is too low and the route is less environment-friendly and uneconomic. In order to achieve a short and more economic synthesis of RDEA427, an investigation was carried out. The optimized synthesis approach of RDEA427 was accomplished in an increased overall yield (39%). Moreover, the new route is more environment-friendly and economic. This work will accelerate the drug discovery process.
- Huang, Boshi,Liu, Xinhao,Li, Wanzhuo,Chen, Zihui,Kang, Dongwei,Zhan, Peng,Liu, Xinyong
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- Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design
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Current treatment of toxoplasmosis targets the parasite’s folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and human DHFR. Computational analysis of biochemical differences between Toxoplasma gondii and human DHFR enabled the design of inhibitors with both improved potency and selectivity. The approach described herein yielded TRC-19, a promising lead with an IC50 of 9 nM and 89-fold selectivity in favor of Toxoplasma gondii DHFR, as well as crystallographic data to substantiate in silico methodology. Overall, 50% of synthesized in silico designs met hit threshold criteria of IC50 2-fold selectivity favoring Toxoplasma gondii, further demonstrating the efficiency of our structure-based drug design approach.
- Welsch, Matthew E.,Zhou, Jian,Gao, Yueqiang,Yan, Yunqing,Porter, Gene,Agnihotri, Gautam,Li, Yingjie,Lu, Henry,Chen, Zhongguo,Thomas, Stephen B.
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supporting information
p. 1124 - 1129
(2016/12/16)
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- IRAK INHIBITORS AND USES THEREOF
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The present invention provides furano- and pyrrolo- pyrimidine and pyridine compounds, compositions thereof, and methods of using the same.
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Paragraph 00252; 00255; 00256
(2014/02/15)
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- Synthesis and evaluation against hepatitis C virus of 7-deaza analogues of 2′-C-methyl-6-O-methyl guanosine nucleoside and l-Alanine ester phosphoramidates
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7-Deazapurines are known to possess broad antiviral activity, however the 2′-C-methylguanosine analogue displays poor cell permeation and limited phosphorylation, thus is not an efficient inhibitor of hepatitis C virus (HCV) replication. We previously rep
- Bourdin, Claire,McGuigan, Christopher,Brancale, Andrea,Chamberlain, Stanley,Vernachio, John,Hutchins, Jeff,Gorovits, Elena,Kolykhalov, Alexander,Muhammad, Jerry,Patti, Joseph,Henson, Geoffrey,Bleiman, Blair,Bryant, K. Dawn,Ganguly, Babita,Hunley, Damound,Obikhod, Aleksandr,Walters, C. Robin,Wang, Jin,Ramamurty, Changalvala V.S.,Battina, Srinivas K.,Srivinas Rao
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supporting information
p. 2260 - 2264
(2013/04/23)
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- N4-(3-bromophenyl)-7-(substituted benzyl) pyrrolo[2,3-d] pyrimidines as potent multiple receptor tyrosine kinase inhibitors: Design, synthesis, and in vivo evaluation
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With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized eleven N4-(3-bromophenyl)-7- (substitutedbenzyl) pyrrolo[2,3-d]pyrimidines 9a-19
- Gangjee, Aleem,Zaware, Nilesh,Raghavan, Sudhir,Yang, Jie,Thorpe, Jessica E.,Ihnat, Michael A.
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experimental part
p. 2444 - 2454
(2012/05/05)
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- PYRROLOPYRIMIDINES AS FAK AND ALK INHIBITERS FOR TREATMENT OF CANCERS AND OTHER DISEASES
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Disclosed are compounds which inhibit the activity of focal adhesion kinase (FAK) and anaplastic lymphoma kinase (ALK), compositions containing the compounds, and methods of treating diseases during which FAK and ALK are expressed. The diseases are, for example, cancers.
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Page/Page column 60
(2012/04/23)
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- NOVEL COMPOUNDS AS RESPIRATORY STIMULANTS FOR TREATMENT OF BREATHING CONTROL DISORDERS OR DISEASES
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The present invention includes compositions that are useful in the treatment of breathing control diseases or disorders in a subject in need thereof. The present invention also includes a method of treating a respiratory disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the invention, The present invention further includes a method of preventing destabilization or stabilizing breathing rhythm in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation of the invention.
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Page/Page column 126; 127
(2012/06/16)
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- THERAPEUTIC AGENTS
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The invention provides a compound of formula (I): wherein R1, and W have any of the values defined in the application; or a salt thereof. The compounds and salts thereof have beneficial therapeutic properties (e.g. immunosuppressant properties).
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Page/Page column 55-56
(2010/04/03)
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- Synthesis of the transfer-RNA nucleoside queuosine by using a chiral allyl azide intermediate
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Chilled out: Chiral allyl azides are rarely used in natural product synthesis because of their tendency to undergo a [3.3] sigmatropic rearrangement (see scheme, top). In allylic cyclopentenyl azides, this rearrangement can be suppressed at just 0°C, enabling a short convergent synthesis of the hypermodified transfer-RNA nucleoside queuosine. (Chemical Equation Presented).
- Klepper, Florian,Jahn, Eva-Maria,Hickmann, Volker,Carell, Thomas
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p. 2325 - 2327
(2008/03/11)
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- DIARYL-PURINE, AZAPURINES AND -DEAZAPURINES AS NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS FOR TREATMENT OF HIV
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This application concerns certain 2-phenylamino-6-aryl amino-, 6-aryloxy-, and 6- arylthio- purines, -azapurines and -deazapurines. These compounds are non-nucleoside reverse transcriptase inhibitors and have potential as anti-HIV treatment.
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Page/Page column 12; 13; 14
(2008/06/13)
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- Acyclic Nucleoside Analogs. II. Acyclic Analogs of Guanosine, 7-Deazaguanosine, and 7-Deazaadenosine with a cis-Hydroxypentene Fragment
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Condensations of 5-acetoxy-1-bromo-2-pentene with 2-amino-6-chloropurine, 4-chloropyrrolopyrimidine, and 2-amino-4-chloropyrrolopyrimidine sodium salts gave acyclic analogs of guanosine, 7-deazaguanosine, and 7-deazaadenosine.The subsequent deprotection with 0.1 N NaOH or methanol saturated with ammonium yielded the desired nucleoside analogs containing a cis-hydroxypentene fragment and either natural or modified heterocycle. - Keywords: nucleosides; acyclic analogs; pyrrolopyrimidines.
- Tsytovich, A. V.,Shamshin, D. V.,Burkovskii, V. B.,Shvets, V. I.
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p. 756 - 761
(2007/10/03)
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- THE SYNTHESIS OF N-PYRIMIDIN-5-YL)ETHYL>BENZOYL>-L-GLUTAMIC ACIDS AS ANTINEOPLASTIC AGENTS
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A series of N-pyrimidin-5-yl)ethyl>benzoyl>-L-glutamic acids were synthesized.In this current synthesis, compound 2-amino-4-chloro-pyrrolopyrimidine (4) was selected as an important precursor for the preparation of key intermediates such as 5b, 10b, 15a and 15b.These highly functionalized pyrrolopyrimidines were then later coupled with either 4-ethynylbenzoylglutamate or 4-iodobenzoylglutamate in a palladium catalyzed Heck reaction and thus provided the basic skeleton of the targeted molecules.The availability ofthe chlorine atom at the 4-position of the pyrrolopyrimidine nucleus has allowed us to introduce different substituents at this position efficiently.By this approach, we were able to prepare a variety of 4-substituted pyrrolopyrimidine based folate antagonists (2a-2g) which are closely related to the novel thymidylate synthase inhibitor LY231514.In vitro analysis has demonstrated that some of these agents are highly cytotoxic against human leukemic cells (CCRF-CEM) in culture.
- Shih, Chuan,Gossett, L. S.
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p. 825 - 841
(2007/10/02)
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- 2-Amino-2'-deoxytubercidin and Related Pyrrolopyrimidinyl 2'-Deoxyribofuranosides
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Phase-transfer glycosylation of 2-amino-4-chloro-7H-pyrrolopyrimidine (4a) with 1-chloro-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranose (7) yields in a regio- and diastereoselective reaction the crystalline condensation product 5a.Nucleophilic disp
- Seela, Frank,Steker, Herbert,Driller, Hansjuergen,Bindig, Uwe
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- Queuine Analogues. Their Synthesis and Inhibition of Growth of Mouse L5178Y Cells in Vitro
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A variety of analogues of queuine (7--7-deazaguanine), i.e., those with 7-N-substituted aminomethyl side chains and those in which the oxygen function at the 6 position of the 7-deazaguanine ring was
- Akimoto, Hiroshi,Nomura, Hiroaki,Yoshida, Mitsuzi,Shindo-Okada, Nobuko,Hoshi, Akio,Nishimura, Susumu
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p. 1749 - 1753
(2007/10/02)
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- Thiodeazapurine derivatives
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7-Deazapurine derivatives of the formula: STR1 wherein R1 is hydrogen atom or an acyl group and R4 and R5 each is a hydrogen atom or a hydrocarbon residue which may optionally have one or more substituents or R4
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- Synthesis of Acyclo-7-deazaguanosine by Regiospecific Phase-Transfer Alkylation of 2-Amino-4-methoxy-7H-pyrrolopyrimidine
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Acyclo-7-deazaguanosine (2), a structural analogue of the antiviral highly active acycloguanosine (1), has been synthesized.Regiospecificity of the electrophilic attack was shown by phase-transfer methylation of 2-amino-4-methoxy-7H-pyrrolopyrimidi
- Seela, Frank,Kehne, Andreas,Winkeler, Heinz-Dieter
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p. 137 - 146
(2007/10/02)
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