- Purine-benzimidazole hybrids: Synthesis, single crystal determination and in vitro evaluation of antitumor activities
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In an effort to identify novel compounds for the treatment of cancer, a diverse array of potential bioactive hybrid, purine-benzimidazole was synthesized in good yields through nucleophilic substitution at C6 position of purine ring with versatile cyclic amines at C2 position. The structures of newly prepared compounds were confirmed by IR, 1H, 13C NMR, mass spectroscopy and, in case of 19, by single crystal Xray diffraction analysis. The newly synthesized compounds were evaluated against 60 human tumour cell lines at one dose concentration level. Compound 6 exhibited significant growth inhibition and was evaluated as 60 cell panel at five dose concentration levels. Compound 6 proved to be 1.25 fold more active than the positive control 5-FU, with GI50 value of 18.12 μM (MG-MID). Interaction of the compounds with Aurora-A enzyme involved in the process of propagation of cancer, has also been investigated. Compound 6 showed selectivity towards Aurora-A kinase inhibition with IC50 value of 0.0l mM. Molecular docking studies in the active binding site provided theoretical support for the experimental biological data acquired.
- Sharma, Alka,Luxami, Vijay,Paul, Kamaldeep
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Read Online
- Facile and practical synthesis of 2,6-dichloropurine
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A facile and industrially viable process for preparation of 2,6-dichloropurine is reported. The process involves direct chlorination of xanthine with phosphorus oxychloride and a weak nucleophilic organic base, such as amidine, guanidine base, or Proton-Sponge.
- Zeng, Qi,Huang, Bangzhou,Danielsen, Knut,Shukla, Rajesh,Nagy, Thomas
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Read Online
- Design, Synthesis, and Immunological Evaluation of a Multicomponent Construct Based on a Glycotripeptoid Core Comprising B and T Cell Epitopes and a Toll-like Receptor 7 Agonist That Elicits Potent Immune Responses
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We present here for the first time the synthesis and immunological evaluation of a fully synthetic three-component anticancer vaccine candidate that consists of a β-glycotripeptoid core mimicking a cluster of Tn at the surface of tumor cells (B epitope), conjugated to the OVA 323-339 peptide (T-cell epitope) and a Toll-like receptor 7 (TLR7) agonist for potent adjuvanticity. The immunological evaluation of this construct and of precursor components demonstrated the synergistic activity of the components within the conjugate to stimulate innate and adaptive immune cells (DCs, T-helper, and B-cells). Surprisingly, immunization of mice with the tricomponent GalNAc-based construct elicited a low level of anti-Tn IgG but elicited a very high level of antibodies that recognize the TLR7 agonist. This finding could represent a potential vaccine therapeutic approach for the treatment of some autoimmune diseases such as lupus.
- Szekely, Thomas,Roy, Olivier,Dériaud, Edith,Job, Aurélie,Lo-Man, Richard,Leclerc, Claude,Taillefumier, Claude
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supporting information
p. 9568 - 9582
(2018/11/23)
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- SUBSTITUTED BICYCLIC PYRIMIDINE-BASED COMPOUNDS AND COMPOSITIONS AND USES THEREOF
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Novel C-2-substituted bicyclic compounds of Formula I have been prepared and found to be useful as potent inhibitors of hGGPPS by inhibiting geranylgeranylation of proteins and inhibiting the biosynthesis of GGPP. The application is directed to these compounds, to compositions comprising these compounds, and to their use, in particular as medicaments for use in the treatment of cancer and other conditions which are treatable by inhibiting human geranylgeranylation pyrophosphate hGGPPS activity.
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Paragraph 00230; 00231
(2018/08/20)
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- Prolinamides of Aminouracils, Organocatalyst Modifiable by Complementary Modules
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We report the synthesis and evaluation of prolinamide organocatalysts that incorporate aminouracils. The features of these catalysts are enhanced NH acidity of the amide because of the electron-withdrawing nature of the heterocycle, an additional hydrogen-bond donor at the α or β positions of this functional group (using 6-aminouracil or 5,6-diaminouracil respectively), and it can be recovered due to its low solubility and used again without decreasing the enantioselectivity. A unique feature of these systems is the self-assembly capability with complementary modules by Watson–Crick interactions. These supramolecular adducts behave differently from the catalyst alone, some of them have lower performance but others improve the selectivity of the product. Therefore, this approach avoids the synthesis of many catalysts.
- Ruíz-Pérez, Karen M.,Quiroz-García, Beatriz,Hernández-Rodríguez, Marcos
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supporting information
p. 5763 - 5772
(2018/11/10)
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- Design, synthesis and evaluation of 4-aminoquinoline-purine hybrids as potential antiplasmodial agents
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A novel series of 4-aminoquinoline-purine hybrids were synthesized and assessed for their antiplasmodial activity against CQ-sensitive and CQ-resistant strains of P. falciparum. It was envisaged that linking of the 4-aminoquinoline pharmacophore (targeting heme-detoxification pathway of malarial parasite) with the purine functionality (targeting plasmodial HG(X)PRT enzyme) will produce a hybrid antiplasmodial agent with increased potency. The synthesized hybrids displayed good antiplasmodial activities against both the sensitive and resistant strains of P. falciparum with up to six-fold better activity (compound 10i, IC50: 0.08?μM) compared to the reference drug CQ (IC50: 0.5?μM) against the resistant strain. The synthesized compounds were also checked for their cytotoxicity towards mammalian cells and with the exception of two compounds out of the twenty synthesized hybrids, all others were non-cytotoxic up to 11.86?μM concentration. Mechanistic heme-binding studies were performed to identify the mechanism of action of the synthesized molecules and good binding interactions were observed. Computational docking studies showed that the most active hybrids dock well within the binding site of HGPRT protein. In silico ADME predictions of the most active hybrids showed that these compounds possess good pharmacokinetic behavior.
- Reddy, P. Linga,Khan, Shabana I.,Ponnan, Prija,Tripathi, Mohit,Rawat, Diwan S.
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p. 675 - 686
(2016/12/14)
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- Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors
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G9a is a histone lysine methyltransferase (HKMT) involved in epigenetic regulation via the installation of histone methylation marks. 6,7-Dimethoxyquinazoline analogues, such as BIX-01294, are established as potent, substrate competitive inhibitors of G9a. With an objective to identify novel chemotypes for substrate competitive inhibitors of G9a, we have designed and synthesised a range of heterocyclic scaffolds, and investigated their ability to inhibit G9a. These studies have led to improved understanding of the key pharmacophoric features of BIX-01294 and the identification of a new core quinoline inhibitory scaffold, which retains excellent potency and high selectivity. Molecular docking was carried out to explain the observed in vitro data. This journal is
- Srimongkolpithak, Nitipol,Sundriyal, Sandeep,Li, Fengling,Vedadi, Masoud,Fuchter, Matthew J.
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p. 1821 - 1828
(2015/01/08)
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- Facile synthesis of 8-azido-6-benzylaminopurine
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Bromination of 6-benzylaminopurine (1) with Br2 in AcOH in the presence of AcONa afforded 6-benzylamino-8-bromopurine (2) in 59% yield. The position of bromination was confirmed by direct transformation of bromide 2 by reaction with NaN3 in dimethyl sulfoxide to 8-azido-6-benzylaminopurine (3) in a yield of 70% and comparison of its properties with the known compound 2-azido-6- benzylaminopurine (11). Compounds 3 and 11 were checked for their biological activity in specific biotests based on the primary cytokinin effects in living plants. Both synthesized compounds displayed effects similar to the typical cytokinin 6-benzylaminopurine (1). Copyright Taylor and Francis Group, LLC.
- Steklov, Mikhail Yu.,Tararov, Vitali I.,Romanov, Georgy A.,Mikhailov, Sergey N.
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experimental part
p. 503 - 511
(2011/12/21)
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- Microwave assisted synthesis of 2,6-substituted aromatic-aminopurine derivatives
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A series of novel 2, 6-diaromatic-aminopurines (6a-6t) have been synthesized from guanine and characterized fully. The effects of different catalysts on the N-alkylation of 2-position of purine ring were discussed.
- Lu, Hong-Fei,Zhang, Liang-Ze,Wu, Ding-Ming,Zhou, Jun-Tao
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scheme or table
p. 1140 - 1144
(2011/11/04)
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- Solvent-free or low-solvent large-scale preparation of chloropyrimidine and analogues
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Chloropyrimidine or other N-containing aromatic heterocyclic analogues can be efficiently prepared from the corresponding hydroxylated precursors under solvent-free or low-solvent conditions with equimolar or less chlorinating reagents. This high-yielding protocol allows successful preparations of multigram and kilogram batches of these important synthetic intermediates.
- Sun, Zhihua,Wang, Han,Wen, Kun,Li, Ya,Fan, Erkang
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experimental part
p. 4149 - 4153
(2011/07/07)
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- Synthesis of some biologically active halogenopurines
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A series of some biologically active halogenopurines were synthesized from commercially available guanine (1). The reaction of guanine with acetic anhydride yielded 2,9-diacetylguanine (2-1) by acetylation reaction. Further treatment of 2-1 with POCl3 by PEG-2000 phase transfer catalysis furnished the important compound 3a, then 2-amino-6-halogenopurines (3b-d) were obtained through chlorine-exchange halogenations between KX and 3a by TPPB phase transfer catalyst. Further, 2-halogenopurines (2-2a-d, 4-2a-d, 5a-d) were efficiently prepared from 2-amino-6-substituted purines (1, 3a, 4-1) via a diazotization catalyzed by their corresponding CuX, and some new compounds 2-2a, 2-2c, 2-2d, 4-2c, 4-2d, 5b, 5c and 5d have been discovered. The structures of synthesized compounds were mainly established on the basis of their elemental analysis, 1H NMR, as well as their mass spectral data. All the title compounds were screened for their antifungal activities, and some of the compounds showed promising activity.
- Hu, Yu Lin,Liu, Xiang,Lu, Ming,Ge, Qiang,Liu, Xiao Bin
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experimental part
p. 429 - 436
(2010/12/29)
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- N-Alkylation of 2,6-dichloropurine hydrochloride with a variety of alcohols over alumina catalyst
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2,6-Dichloropurine hydrochloride reacts with various types of alcohols using different alumina catalysts and converts into its N-9-alkyl-2-chloro-6- hydroxy-9H-purine products to an extent of 49-74%. The product selectivity depends on the stability of carbocation generated from the alcohol. More stable carbocation formulates both N-7 and N-9-alkyl-2,6-dichloropurine products, whereas the less stable carbocation results in exclusively N-9-alkyl-2-chloro-6- hydroxy-9H-purine. The catalytic activity of alumina prepared using the sol-gel method has larger Brunauer, Emmett, and Teller (BET) surface area and hence shows significantly greater catalytic activity than the commercially available alumina samples. Copyright
- Tumma, Harikrishna,Nagaraju,Reddy, K. Vijayakumar
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scheme or table
p. 1856 - 1866
(2010/07/02)
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- A PROCESS FOR PREPARING 2,6-DICHLOROPURINE
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A process for easily and efficiently preparing 2,6-dichloropurine. In this process 2,6-dichloropurine is obtained in one step diazotization using 2-amino-6-chloropurine as starting material in the presence of chloride or hydrochloric acid.
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- Process for producing 2,6-dihalogenopurine
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A process for conveniently and efficiently preparing a 2,6-halogenopurine using an inexpensive starting material. A process for preparing a 2,6-dihalogenopurine, comprising treating a 2-amino-6-halogenopurine having a protective group at 7th position or 9th position with a diazotizating agent and a halogen source; and a process for preparing a 9-acyl-2-amino-6-halogenopurine, comprising treating a 2-amino-6-halogenopurine with an acylating agent in the presence of a base.
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- METHANOCARBA CYCLOAKYL NUCLEOSIDE ANALOGUES
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The present invention provides novel nucleoside and nucleotide derivatives that are useful agonists or antagonists of P1 or P2 receptors. For example, the present invention provides a compound of formula A-M, wherein A is modified adenine or uracil and M is a constrained cycloalkyl group. The adenine or uracil is bonded to the constrained cycloakyl group. The compounds of the present invention are useful in the treatment or prevention of various diseases including airway diseases (through A 2B, A3, P2Y2 receptors), cancer (through A 3, P2 receptors), cardiac arrhythmias (through A1 receptors) , cardiac ischemia (through A1, A3 receptors), epilepsy (through A1, P2X receptors), and Huntington's Disease (through A2A receptors).
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- PRODUCTION METHOD OF 2,6-DIHALOPURINE
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By reacting the compound of the formula [Ia] or [Ib] with halosilane compound and an agent for diazo reaction, 2,6-dihalopurine of the formula [II] can be produced conveniently in a high yield and can be easily isolated.wherein each symbol is as defined in the specification.
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Page/Page column 11-12
(2008/06/13)
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- Process for preparing 2,6-dichloropurine
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A process for preparing 2,6-dichloropurine including chlorinating 2-amino-6-chloropurine with a chlorine source in the presence of a diazotizating agent.
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- Synthesis and biological activities of C-2, N-9 substituted 6- benzylaminopurine derivatives as cyclin-dependent kinase inhibitor
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In this study, C-2, N-9 substituted 6-benzylaminopurine derivatives were synthesized and their inhibitory effects on cyclin-dependent kinase (CDK2) were evaluated. The effect of substituents at the C-2 and N-9 positions of substituted purine was investigated. Among the compounds tested, compound 7b- iii (6-benzylamino-2-thiomorpholinyl-9-isopropylpurine) was the most active inhibitor (IC50 = 0.9 μM). Compound 7b-iii showed 10-fold higher activity compared to olomoucine and almost the same activity as roscovitine. Results from structure-activity relationship studies should allow the design of more potent and selective CDK inhibitors, which may provide an effective therapy for cancer or other CDK dependent diseases.
- Oh, Chang-Hyun,Lee, Su-Chul,Lee, Ki-Soo,Woo, Eun-Rhan,Hong, Chang Yong,Yang, Boem-Seok,Baek, Dae Jin,Cho, Jung-Hyuck
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p. 187 - 190
(2007/10/03)
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- Studies on Nucleosides: Part XIII - Synthesis and Antiviral Activity of Acyclic Analogues of Spongosine
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6-Amino-9--2-methoxypurine (9), 6-amino-2-ethoxy-9-purine (10) and 6-amino-9-(2-hydroxyethoxymethyl)-2-methoxypurine (17) have been synthesized.Condensation of 2,6-dichloropurine (4) with 2-O-chloromethyl-1,3-di-O-benzylglycerol (5) furnishes the protected acyclic nucleosides 8 (yield 50percent) and 7 (yield 7percent).Amination of 7 and 8 affords 6 and 13 respectively.Treatment of 13 with sodium methoxide and ethoxide gives 11 and 12 respectively.Deblocking of 11 and 12 with Pd-C/H2 finally produces 9 and 10 respectively.Condensation of 4 with 1-O-benzyl-2-O-chloromethylethanediol gives 19 (yield 55percent) and 15 (yield 5percent).Amination of 19 affords 18 which on treatment with sodium methoxide furnishes 16.Deblocking of 16 with Pd-C/H2 gives 17.Compounds 9, 10, 11, 13 and 17 in combination with interferon inducer, mycoviral ds RNA, exhibit 16, 0, 16, 40 and 40percent enhancement of protection respectively against the semliki forest virus in Swiss albino mice.
- Singh, P. K.,Saluja, Sunita,Pratap, Ram,George, C. X.,Bhakuni, D. S.
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p. 823 - 827
(2007/10/02)
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- Syntheses of 2,6,9-Trisubstituted Purines and Their Antiviral Activity
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2-Chloro- and 2-alkoxy-6-aminoalkyl-9-(2-tetrahydropyranyl)-9H-purines (3-14), 2-alkylthio-9-(tetrahydropyranyl) adenines (15-17), and 2-alkylthio-9-tetrahydropyranyl-8-azaadenines (18-20) have been synthesized.Compounds (2 to 14) have been screened against Ranikhet disease virus.Of the compounds tested 2, 3, 11 and 13 exhibit above 75percent inhibition against RDV.
- Bhakuni, D. S.,Gupta, P. K.,Chowdhury, B. L.
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p. 1286 - 1288
(2007/10/02)
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- Syntheses of 9-β-D-Ribofuranosylpurine (Nebularine) and Its Analogues
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9-β-D-Ribofuranosylpurine (nebularine) (9) has been synthesized by two methods. (i) 2,6-Dichloro-2',3',5'-tri-O-benzoyl-9-β-D-ribofuranosylpurine (7) on dehalogenation followed by debenzoylation using methanolic ammonia affords nebularine (9). (ii) 6-Chloro-2',3',5'-tri-O-acetyl-9-β-D-ribofuranosylpurine (18) on dehalogenation followed by deacetylation yields 9.Nebularine analogues , 9-β-D-xylofuranosylpurine (12) and 9-α-L-rhamnopyranosylpurine (15) have also been synthesized from 2,6-dichloro-2',3',5'-tri-O-acetyl-9-β-D-xylofuranosylpurine (10) and 2,6-dichloro-2',3',4'-tri-O-benzoyl-9-α-L-rhamnopyranosylpurine (13).Dehalogenation of 10 and 13 followed by deacetylation and debenzoylation with methanolic ammonia affords 12 and 15 respectively.
- Gupta, P. K.,Bhakuni, D. S.
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p. 534 - 537
(2007/10/02)
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- Synthesis of 2-Methoxy-9-α-L-rhamnopyranosyladenine
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2-Methoxy-9-α-L-rhamnopyranosyladenine (8) has been synthesized by two methods: (i) 2,6-dichloro-2,3',4'-tri-O-benzoyl-9-α-L-rhamnopyranosylpurine (5) on amination followed by debenzoylation using methanolic ammonia gives 6-amino-2-chloro-9-α-L-rhamnopyranosylpurine (6) which on treatment with sodium methoxide in methanol under reflux yields 8 (20 percent). (ii) 5 is refluxed with sodium methoxide in methanol to give 2,6-dimethoxy-9-α-L-rhamnopyranosylpurine (7) which on amination with methanolic ammonia yields 8 (18.6 percent).
- Saxena, N. K.,Gupta, P. K.,Bhakuni, D. S.
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p. 332 - 334
(2007/10/02)
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