19916-73-5Relevant articles and documents
Regioselective alkylation of guanine derivatives in the synthesis of peptide nucleic acid monomers
Dezhenkov,Cheshkov,Prokhorov,Dezhenkova,Shvets,Kirillova, Yu. G.
, p. 1100 - 1106 (2015)
A method for the synthesis of 6-O-benzyl- and 6-O-benzyl-2-N-benzyloxycarbonyl-protected guanine derivatives starting from 2-amino-6-chloropurin is described. A regioselective alkylation of these N(9)-protected guanine derivatives gave the corresponding α-monomers of chiral peptide nucleic acids, the L-glutamic acid derivatives. It was shown that these compound do not inhibit (in the concentrations -1) the topoisomerase I activity.
Synthesis and biological evaluation of new HIV-1 protease inhibitors with purine bases as P2-ligands
Zhu, Mei,Dong, Biao,Zhang, Guo-Ning,Wang, Ju-Xian,Cen, Shan,Wang, Yu-Cheng
supporting information, p. 1541 - 1545 (2019/04/25)
Introducing purine bases to P2-ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitory because of the carbonyl and NH groups promoting the formation of extensive H-bonding interactions. In this work, thirty-three compounds are synthesized and evaluated, among which inhibitors 16a, 16f and 16j containing N-2-(6-substituted-9H-purin-9-yl)acetamide as the P2-ligands along with 4-methoxylphenylsulfonamide as the P2′-ligand, display potent inhibitory effect on the activity of HIV-1 protease with IC50 43 nM, 42 nM and 68 nM in vitro, respectively.
Application of five-membered heterocycle pyrimidine compound
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Paragraph 0077; 0078; 0079; 0080; 0109; 0111; 0112, (2018/09/12)
The invention belongs to the field of medicine and particularly relates to application of a five-membered heterocycle pyrimidine compound with the structural features as shown in formula (I) and the pharmaceutically acceptable salt of the five-membered heterocycle pyrimidine compound serving as nucleotide oxidative damage repairase MTH1 inhibitors. Pharmacological experiment results show that thecompound can evidently inhibit the activity of MTH1 and can be used for preventing and treating clinical diseases related to MTH1.
Effect of O6-substituted guanine analogs on O6-methylguanine DNA-methyltransferase Expression and glioblastoma cells viability
St-Coeur, Patrick-Denis,Cormier, Marc,LeBlanc, Véronique C.,Morin, Pier,Touaibia, Mohamed
, p. 28 - 39 (2017/06/05)
Background: Glioblastoma multiforme (GBM) is often associated with a poor survival prognostic for patients. The main reason seems to be the acquired or inherent resistance to the chemotherapeutic agent used to treat the tumor, temozolomide (TMZ). To this day, the most recognized pathway of resistance is the DNA Direct Repair pathway by the means of the protein O6-methylguanine DNA-methyltransferase (MGMT). Objectives: To design and synthesize a series of MGMT inhibitors that can sensitize GBM cells to TMZ. Methods: Twenty-five O6-alkyl, O6-aryl and O6-substituted-aryl guanine analogs including nine novel compounds were synthesized, characterized, analyzed by molecular docking and tested on the T98G GBM cells viability. Results: Following molecular modeling with MGMT, the newly designed compounds 19, 22, and 24 emerged as the most promising MGMT ligands and displayed modest cytotoxicity. Guanine analog (19), bearing a p-nitrobenzyl moiety, reduced considerably the O6-methylguanine DNA-methyltransferase expression level. When combined with TMZ (1), which is used as first line treatment for brain tumors, compounds 19, 22, and 24 decreased T98G cells?proliferation by 32%, 68% and 50%, respectively. TMZ (1) displayed negligible effect on the proliferation of these cells further supporting the notion that this cell model is resistant to this alkylating agent. Conclusion: Overall, these results notably highlight a group of MGMT inhibitors that warrants further exploration in the development of therapeutic options to circumvent TMZ resistance in brain tumors.
Benzyl guanine derivative, an organic salt compound thereof, a medicine composition, and application thereof
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Paragraph 0052; 0056; 0057; 0061; 0062; 0063; 0064, (2017/09/26)
The invention relates to the field of antitumor medicines and especially relates to a benzyl guanine derivative, an organic salt compound thereof, a medicine composition, and an application thereof. The benzyl guanine derivative is easy to prepare, has good druggability, can inhibit enzyme-catalysis activity of Pin 1 protein, can improve biosynthesis of mature microRNA at cellular and animal levels, and increases the types of antitumor medicines.
Design, synthesis, biophysical and primer extension studies of novel acyclic butyl nucleic acid (BuNA)
Kumar, Vipin,Gore, Kiran R.,Pradeepkumar,Kesavan, Venkitasamy
, p. 5853 - 5865 (2013/09/12)
A novel nucleic acid analogue called acyclic (S)-butyl nucleic acid (BuNA) composed of an acyclic backbone containing a phosphodiester linkage and bearing natural nucleobases was synthesized. Next, (S)-BuNA nucleotides were incorporated in DNA strands and their effect on duplex stability and changes in structural conformation were investigated. Circular dichroism (CD), UV-melting and non-denatured gel electrophoresis (native PAGE) studies revealed that (S)-BuNA is capable of making duplexes with its complementary strands and integration of (S)-BuNA nucleotides into DNA duplex does not alter the B-type-helical structure of the duplex. Furthermore, (S)-BuNA oligonucleotides and (S)-BuNA substituted DNA strands were studied as primer extensions by DNA polymerases. This study revealed that the acyclic scaffold is tolerated by enzymes and is therefore to some extent biocompatible.
6-Oxo and 6-thio purine analogs as antimycobacterial agents
Pathak, Ashish K.,Pathak, Vibha,Seitz, Lainne E.,Suling, William J.,Reynolds, Robert C.
, p. 1685 - 1695 (2013/05/09)
6-Oxo and 6-thio analogs of purine were prepared based on the initial activity screening of a small, diverse purine library against Mycobacterium tuberculosis (Mtb). Certain 6-oxo and 6-thio-substituted purine analogs described herein showed moderate to good inhibitory activity. N 9-substitution apparently enhances the anti-mycobacterial activity in the purine series described herein. Several 2-amino and 2-chloro purine analogs were also synthesized that showed moderate inhibitory activity against Mtb.
Design and synthesis of nucleoproline amino acids for the straightforward preparation of chiral and conformationally constrained nucleopeptides
Kramer, Rolf A.,Bleicher, Konrad H.,Wennemers, Helma
, p. 2621 - 2634 (2013/03/13)
A straightforward synthesis of orthogonally protected nucleoproline (Nup) amino acids and their coupling to oligomers are described. A key step is the attachment of alkynylated nucleobases to Fmoc-protected 4-azidoproline (Fmoc-Azp-OH) by a Cu-catalyzed 1,3-dipolar cycloaddition ('click reaction'). The developed protocol allows preparation of the nucleoprolines in scales of >30g. Solid-phase peptide synthesis proved to be straightforward with these Nup amino acids. The resulting oligonucleoproline peptides adopt defined helices, are very well H2O soluble, and show comparable cell-penetrating properties as recently reported α-nucleoalanine peptides. Copyright
4-nitrobenzyloxycarbonyl derivatives of O 6-benzylguanine as hypoxia-activated prodrug inhibitors of O 6-alkylguanine-DNA alkyltransferase (AGT), which produces resistance to agents targeting the o -6 position of DNA guanine
Zhu, Rui,Liu, Mao-Chin,Luo, Mei-Zhen,Penketh, Philip G.,Baumann, Raymond P.,Shyam, Krishnamurthy,Sartorelli, Alan C.
, p. 7720 - 7728 (2012/01/13)
A series of 4-nitrobenzyloxycarbonyl prodrug derivatives of O 6-benzylguanine (O6-BG), conceived as prodrugs of O 6-BG, an inhibitor of the resistance protein O6- alkylguanine-DNA alkyltransferase (AGT), were synthesized and evaluated for their ability to undergo bioreductive activation by reductase enzymes under oxygen deficiency. Three agents of this class, 4-nitrobenzyl (6-(benzyloxy)-9H-purin-2-yl)carbamate (1) and its monomethyl (2) and gem-dimethyl analogues (3), were tested for activation by reductase enzyme systems under oxygen deficient conditions. Compound 3, the most water-soluble of these agents, gave the highest yield of O6-BG following reduction of the nitro group trigger. Compound 3 was also evaluated for its ability to sensitize 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl] hydrazine (laromustine)-resistant DU145 human prostate carcinoma cells, which express high levels of AGT, to the cytotoxic effects of this agent under normoxic and oxygen deficient conditions. While 3 had little or no effect on laromustine cytotoxicity under aerobic conditions, significant enhancement occurred under oxygen deficiency, providing evidence for the preferential release of the AGT inhibitor O6-BG under hypoxia.
Synthesis and biological activities of O6-alkylguanine derivatives
Hu, Yu Lin,Ge, Qiang,Lu, Ming,Lu, Hong Fei
, p. 425 - 432 (2012/01/13)
The synthesis of some biologically active O6-alkylguanine derivatives was achieved by alkoxylation of 2-amino-6-chloropurine with sodium alkoxides in polar aprotic solvent (DMSO) conditions. The starting material 2-amino-6-chloropurine was prepared by chlorination of 2,9-diacetylguanine (obtained from acetylation of commercially available guanine) by PEG-2000 phase transfer catalysis. The structures of the products were deduced from elemental analysis and spectral data (IR, 1H NMR, and mass spectra). All the title compounds were screened for their antifungal activities, and some of the compounds showed promising activities.
