- Synthesis of 2,6-diamino-substituted purine derivatives and evaluation of cell cycle arrest in breast and colorectal cancer cells
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Reversine is a potent antitumor 2,6-diamino-substituted purine acting as an Aurora kinases inhibitor and interfering with cancer cell cycle progression. In this study we describe three reversine-related molecules, designed by docking calculation, that present structural modifications in the diamino units at positions 2 and 6. We investigated the conformations of the most stable prototropic tautomers of one of these molecules, the N6-cyclohexyl-N6-methyl-N2-phenyl-7H-purine-2,6-diamine (3), by Density Functional Theory (DFT) calculation in the gas phase, water and chloroform, the last solvent considered to give insights into the detection of broad signals in NMR analysis. In all cases the HN(9) tautomer resulted more stable than the HN(7) form, but the most stable conformations changed in different solvents. Molecules 1-3 were evaluated on MCF-7 breast and HCT116 colorectal cancer cell lines showing that, while being less cytotoxic than reversine, they still caused cell cycle arrest in G2/M phase and polyploidy. Unlike reversine, which produced a pronounced cell cycle arrest in G2/M phase in all the cell lines used, similar concentrations of 1-3 were effective only in cells where p53 was deleted or down-regulated. Therefore, our findings support a potential selective role of these structurally simplified, reversine-related molecules in p53-defective cancer cells.
- Bosco, Bartolomeo,Defant, Andrea,Messina, Andrea,Incitti, Tania,Sighel, Denise,Bozza, Angela,Ciribilli, Yari,Inga, Alberto,Casarosa, Simona,Mancini, Ines
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Read Online
- Medicinal Chemistry Optimization of a Diaminopurine Chemotype: Toward a Lead for Trypanosoma brucei Inhibitors
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Human African trypanosomiasis (HAT), or sleeping sickness, is caused by the protozoan parasite Trypanosoma brucei and transmitted through the bite of infected tsetse flies. The disease is considered fatal if left untreated. To identify new chemotypes against Trypanosoma brucei, previously we identified 797 potent kinase-targeting inhibitors grouped into 59 clusters plus 53 singleton compounds with at least 100-fold selectivity over HepG2 cells. From this set of hits, a cluster of diaminopurine-derived compounds was identified. Herein, we report our medicinal chemistry investigation involving the exploration of structure-activity and structure-property relationships around one of the high-throughput screening (HTS) hits, N2-(thiophen-3-yl)-N6-(2,2,2-trifluoroethyl)-9H-purine-2,6-diamine (1, NEU-1106). This work led to the identification of a potent lead compound (4aa, NEU-4854) with improved in vitro absorption, distribution, metabolism, and excretion (ADME) properties, which was progressed into proof-of-concept translation of in vitro antiparasitic activity to in vivo efficacy.
- Singh, Baljinder,Diaz-Gonzalez, Rosario,Ceballos-Perez, Gloria,Rojas-Barros, Domingo I.,Gunaganti, Naresh,Gillingwater, Kirsten,Martinez-Martinez, Maria Santos,Manzano, Pilar,Navarro, Miguel,Pollastri, Michael P.
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p. 9912 - 9927
(2020/10/19)
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- Design, synthesis and biological evaluation of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent Kinase2 (CDK2) dual inhibitors against malignant cancer
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In the current study, we have designed and synthesized a series of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent kinase2 (CDK2) dual inhibitors by integrating purine-based pharmacophore into the recognition cap group of CS055. The representative compound 14d with excellent antiproliferative activities towards five solid cancer cells, showed potent inhibitory activities against HDAC1, HDAC2 and CDK2 with IC50 values of 70.7 nM, 23.1 nM and 0.80 μM, respectively. Besides, compound 14d could effectively block the cell cycle in the G2/M phase and induce apoptosis, which might be related to increasing intracellular ROS levels. Importantly, compound 14d exhibited desirable pharmacokinetic (PK) properties with the intraperitoneal bioavailability of 50.8percent in ICR mice, and potent in vivo antitumor activity in the HCT116 xenograft model. Therefore, compound 14d could be considered as a promising lead compound for the development of multitargeting anticancer agents.
- Cheng, Chunhui,Ullah, Sadeeq,Yuan, Qipeng,Yun, Fan
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- HETEROCYCLIC HYDROXAMIC ACIDS AS PROTEIN DEACETYLASE INHIBITORS AND DUAL PROTEIN DEACETYLASE-PROTEIN KINASE INHIBITORS AND METHODS OF USE THEREOF
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The present invention relates to novel hydroxamic acids which are specific histone deacetylase (HDAC) inhibitors and/or TTK/Mpsl kinase inhibitors, including pharmaceutically acceptable salts thereof, which are useful for modulating HDAC and/or TTK/Mpsl k
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Paragraph 00147; 00148
(2016/04/26)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE
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This application discloses compounds according to generic Formula (I) wherein all variables are defined as described herein, which inhibit BTK. The compounds disclosed herein are useful to modulate the activity of BTK and treat diseases associated with ex
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Page/Page column 37
(2014/09/29)
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- Lead optimization of purine based orally bioavailable Mps1 (TTK) inhibitors
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Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.
- Kumar, D. Vijay,Hoarau, Christophe,Bursavich, Matthew,Slattum, Paul,Gerrish, David,Yager, Kraig,Saunders, Michael,Shenderovich, Mark,Roth, Bruce L.,McKinnon, Rena,Chan, Ashley,Cimbora, Daniel M.,Bradford, Chad,Reeves, Leslie,Patton, Scott,Papac, Damon I.,Williams, Brandi L.,Carlson, Robert O.
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scheme or table
p. 4377 - 4385
(2012/08/07)
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- Synthesis and screening of 2,6-diamino-substituted purine derivatives as potential cardiomyogenesis inducing agents
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The synthesis of 2,6-diamino-substituted purines is reported starting from 2,6-dichloropurine via two subsequent selective nucleophilic substitution reactions. The first substitution takes place selectively in 6-, the second in 2-position. The compounds w
- Koley, Moumita,K?nig, Xaver,Hilber, Karlheinz,Schnürch, Michael,Stanetty, Peter,Mihovilovic, Marko D.
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experimental part
p. 45 - 61
(2011/06/18)
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- COMPOUNDS AND THERAPEUTIC USES THEREOF
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The invention relates to compounds, pharmaceutical compositions, and uses thereof, including therapeutic uses thereof, such as methods useful for treating cancer.
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Page/Page column 98
(2010/11/03)
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- PURINYL DERIVATIVES AND THEIR USE AS POTASSIUM CHANNEL MODULATORS
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This invention relates to novel purinyl derivatives and their use as potassium channel modulating agents. Moreover the invention is directed to pharmaceutical compositions useful for the treatment or alleviation of diseases or disorders associated with the activity of potassium channels.
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Page/Page column 33
(2008/12/04)
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- Development of potent purine-derived nitrile inhibitors of the trypanosomal protease TbcatB
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Human African trypanosomiasis (HAT), a major health concern in sub-Saharan Africa, is caused by the protozoan parasite Trypanosoma brucei. Recent studies have shown that a cathepsin B like protease, TbcatB, is essential to the survival of T. brucei in vit
- Mallari, Jeremy P.,Shelat, Anang A.,Obrien, Terri,Caffrey, Conor R.,Kosinski, Aaron,Connelly, Michele,Harbut, Michael,Greenbaum, Doron,McKerrow, James H.,Guy, R. Kiplin
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p. 545 - 552
(2008/09/18)
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- Microwave-assisted regioselective synthesis of acyclic nucleosides through an alkylating reaction with 2-oxa-1,4-butanediol diacetate
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An efficient and green procedure for the synthesis of purine acyclic nucleosides through microwave-assisted, alkylation of various purine nucleobases with 2-oxa-1,4-butanediol diacetate in the absence of solvent and catalyst is described. The advantages of using this method include its environmental friendliness, simple manipulation, short reaction time, high regioselectivity, and good yields.
- Qu, Guirong,Han, Suhui,Zhang, Zhiguang,Geng, Mingwei,Xue, Feng
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p. 819 - 824
(2007/10/03)
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- A practical synthesis of 2-arylamino-6-alkylaminopurines from 2,6-dichloropurine
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A practical synthesis of N-[4-(6-cyclobutylamino-9H-purin-2-ylamino)- phenyl]-N-methyl acetamide (QAB205, 5a), an anti-asthmatic agent, is described from 2,6-dichloropurine (1) by base-assisted substitution of the 6-chloro substituent with cyclobutylamine
- Ciszewski, Lech,Waykole, Liladhar,Prashad, Mahavir,Repic, Oljan
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p. 799 - 802
(2012/12/22)
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- HETEREOARYL NITRILE DERIVATIVES
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The invention provides compounds of Formula (I) or a pharmaceutically acceptable salt or ester thereof wherein the symbols have meaning as defined, which are inhibitors of cathepsin K and find use pharmaceutically for treatment of diseases and medical con
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- Novel purine nitrile derived inhibitors of the cysteine protease cathepsin K
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Starting from the high-throughput screening hit 1a, novel cathepsin K inhibitors have been developed based on a purine scaffold. High-resolution X-ray structures of several derivatives have revealed the binding mode of these unique cysteine protease inhib
- Altmann, Eva,Cowan-Jacob, Sandra W.,Missbach, Martin
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p. 5833 - 5836
(2007/10/03)
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- Determination of 2-chloro-2'-deoxyadenosine (antileukemic agent) and related compounds by electrochemical method
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Electrochemical method for determination of 2-chloro-2'-deoxyadenosine and related compounds modified in exocyclic 6-NH2 group is described. Electrochemical detection of investigated compounds, based on the electrooxidation process of the adenine moiety, has been performed in aqueous solutions, in the pH range 2-9, on a glassy carbon electrode.
- Bojarska,Kazimierczuk
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p. 1073 - 1074
(2007/10/03)
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- Solution-phase synthesis of 2,6,9-trisubstituted purines
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A simple three-step method for the solution-phase combinatorial synthesis of 2,6,9-trisubstituted purines from 2,6-dichloropurine is described. The synthesis exploits the use of resin capture to remove excess reagent used in the final step.
- Fiorini, Maria T.,Abell, Chris
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p. 1827 - 1830
(2007/10/03)
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