- Pyrimidyn-Based Dynamin Inhibitors as Novel Cytotoxic Agents
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Five focused libraries of pyrimidine-based dynamin GTPase inhibitors, in total 69 compounds were synthesised, and their dynamin inhibition and broad-spectrum cytotoxicity examined. Dynamin plays a crucial role in mitosis, and as such inhibition of dynamin was expected to broadly correlate with the observed cytotoxicity. The pyrimidines synthesised ranged from mono-substituted to trisubstituted. The highest levels of dynamin inhibition were noted with di- and tri- substituted pyrimidines, especially those with pendent amino alkyl chains. Short chains and simple heterocyclic rings reduced dynamin activity. There were three levels of dynamin activity noted: 1–10, 10–25 and 25–60 μM. Screening of these compounds in a panel of cancer cell lines: SW480 (colon), HT29 (colon), SMA (spontaneous murine astrocytoma), MCF-7 (breast), BE2-C (glioblastoma), SJ-G2 (neuroblastoma), MIA (pancreas), A2780 (ovarian), A431 (skin), H460 (lung), U87 (glioblastoma) and DU145 (prostate) cell lines reveal a good correlation between the observed dynamin inhibition and the observed cytotoxicity. The most active analogues (31 a,b) developed returned average GI50 values of 1.0 and 0.78 μM across the twelve cell lines examined. These active analogues were: N2-(3-dimethylaminopropyl)-N4-dodecyl-6-methylpyrimidine-2,4-diamine (31 a) and N4-(3-dimethylaminopropyl)-N2-dodecyl-6-methylpyrimidine-2,4-diamine (31 b).
- Odell, Luke R.,Chau, Ngoc,Russell, Cecilia C.,Young, Kelly A.,Gilbert, Jayne,Robinson, Phillip J.,Sakoff, Jennette A.,McCluskey, Adam
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- 2,4-Diamino-6-methylpyrimidines for the potential treatment of Chagas’ disease
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Chagas’ disease, caused by the protozoan parasite Trypanosoma cruzi, affects 8–10 million people across the Latin American population and is responsible for around 12,500 deaths per annum. The current frontline treatments, benznidazole and nifurtimox, are associated with side effects and lack efficacy in the chronic stage of the disease, leading to an urgent need for new treatments. A high throughput screening campaign against the physiologically relevant intracellular form of the parasite identified a series of 2,4-diamino-6-methylpyrimidines. Demonstrating the series did not work through the anti-target TcCYP51, and was generally cytocidal, confirmed its suitability for further development. This study reports the optimisation of selectivity and metabolic stability of the series and identification of a suitable lead for further optimisation.
- Thomas, Michael G.,De Rycker, Manu,Cotillo Torrejon, Ignacio,Thomas, John,Riley, Jennifer,Spinks, Daniel,Read, Kevin D.,Miles, Tim J.,Gilbert, Ian H.,Wyatt, Paul G.
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p. 3025 - 3030
(2018/08/20)
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- Pyrimidine-Based Inhibitors of Dynamin I GTPase Activity: Competitive Inhibition at the Pleckstrin Homology Domain
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The large GTPase dynamin mediates membrane fission during clathrin-mediated endocytosis (CME). The aminopyrimidine compounds were reported to disrupt dynamin localization to the plasma membrane via the PH domain and implicate this mechanism in the inhibition of CME. We have used a computational approach of binding site identification, docking, and interaction energy calculations to design and synthesize a new library of aminopyrimidine analogues targeting site-2 of the pleckstrin homology (PH) domain. The optimized analogues showed low micromolar inhibition against both dynamin I (IC50 = 10.6 ± 1.3 to 1.6 ± 0.3 μM) and CME (IC50(CME) = 65.9 ± 7.7 to 3.7 ± 1.1 mM), which makes this series among the more potent inhibitors of dynamin and CME yet reported. In CME and growth inhibition cell-based assays, the data obtained was consistent with dynamin inhibition. CEREP ExpresS profiling identified off-target effects at the cholecystokinin, dopamine D2, histamine H1 and H2, melanocortin, melatonin, muscarinic M1 and M3, neurokinin, opioid KOP and serotonin receptors.
- Odell, Luke R.,Abdel-Hamid, Mohammed K.,Hill, Timothy A.,Chau, Ngoc,Young, Kelly A.,Deane, Fiona M.,Sakoff, Jennette A.,Andersson, Sofia,Daniel, James A.,Robinson, Phillip J.,McCluskey, Adam
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supporting information
p. 349 - 361
(2017/04/26)
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- TETRAHYDROPYRIDOPYRIMIDINES AND TETRAHYDROPYRIDOPYRIDINES AS INHIBITORS OF HBSAG (HBV SURFACE ANTIGEN) AND HBV DNA PRODUCTION FOR THE TREATMENT OF HEPATITIS B VIRUS INFECTIONS
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The present invention provides tetrahydropyridopyrimidines and tetrahydropyridopyridines having the general formula (I) wherein R1, R2, U, W, X, Y and Z are as described herein, as inhibitors of HBsAg (HBV surface antigen) and HBV DNA production for the treatment and prophylaxis of hepatitis B virus infections.
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Page/Page column 274; 275
(2016/11/21)
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- Pyrimidine-based antagonists of h-MCH-R1 derived from ATC0175: In vitro profiling and in vivo evaluation
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A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1 in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series, but no improvement in brain partitioning was noted. One example from this series was shown to inhibit food intake and decrease body weight in a chronic study. However no clear correlation between the pharmacodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1.
- Semple, Graeme,Tran, Thuy-Anh,Kramer, Bryan,Hsu, Debbie,Han, Sangdon,Choi, Juyi,Vallar, Pureza,Casper, Martin D.,Zou, Ning,Hauser, Erin K.,Thomsen, William,Whelan, Kevin,Sengupta, Dipanjan,Morgan, Michael,Sekiguchi, Yoshinori,Kanuma, Kosuke,Chaki, Shigeyuki,Grottick, Andrew J.
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supporting information; experimental part
p. 6166 - 6171
(2010/06/19)
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- PYRIMIDINE DERIVATIVES AND METHODS OF TREATMENT RELATED TO THE USE THEREOF
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The present invention encompasses novel substituted pyrimidine compounds of Formula (I): which act as MCH receptor antagonists. These compounds are useful in pharmaceutical compositions whose use includes prophylaxis or treatment of improving memory function, sleeping and arousal, anxiety, depression, mood disorders, seizure, obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, binge eating disorders including bulimia, anorexia, mental disorders including manic depression, schizophrenia, delirium, dementia, stress, cognitive disorders, attention deficit disorder, substance abuse disorders and dyskinesias including Parkinson’s disease, epilepsy, and addiction.
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Page/Page column 137; 138
(2008/06/13)
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- QUINOLINE, TETRAHYDROQUINOLINE AND PYRIMIDINE DERIVATIVES AS MCH ANTAGONIST
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The present invention relates to compounds of the Formula (I) wherein Q is: which act as MCH receptor antagonists. These compositions are useful in pharmaceutical compositions whose use includes prophylaxis or treatment of improving memory function, sleeping and arousal, anxiety, depression, mood disorders, seizure, obesity, diabetes, appetite and eating disorders, cardiovascular disease, hypertension, dyslipidemia, myocardial infarction, binge eating disorders including bulimia, anorexia, mental disorders including manic depression, schizophrenia, delirium, dementia, stress, cognitive disorders, attention deficit disorder, substance abuse disorders and dyskinesias including Parkinson's disease, epilepsy, and addiction.
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Page/Page column 301
(2010/02/08)
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- Study on the preparation of heteroaryl substituted enamines. A simple synthesis of heteroaryl substituted acetaldoximes from enamines
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A comparative study of the reactivity of methyl groups towards N,N-dimethylformamide dimethyl acetal and tert-butoxybis(dimethylamino)methane was carried out on methyl substituted six-membered nitrogen containing heterocycles 1 to give enamines 2, which were easily transformed to oximes by treating with hydroxylamine hydrochloride in methanol. Most of them were isolated as (E,Z)-oximes of heteroarylacetaldehyde (11), but 5-(1,2,4-triazinyl) substituted derivatives as (E,Z)-oximes of 2,5-dihydro-1,2,4-triazin-(Z)-5-ylideneacetaldehyde (11t, 11u, and 12). Oximes were finally transformed to the corresponding acetonitriles 16 and 3-(dimethylamino)acrylonitriles 17.
- ?opar, Anton,Stanovnik, Branko,Ti?ler, Miha
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p. 465 - 474
(2007/10/03)
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- Pyri(mi)dyl-oxy-and -thio-benzoic acid derivatives useful as herbicides and plant growth regulants
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New pyri(mi)dyl-oxy- or -thio-benzoic acid derivatives of the formula STR1 are taught which have herbicidal and plant growth regulating activity. In the formula Z can be Ch or N, X is oxygen or sulphur, A is oxygen, sulphur, a radical R5 --N=or a radical R6 O--N=and B is oxygen, sulphur, a radical STR2 with the proviso that at least one of the radicals R1, R2 or R3 represents alkyl or a part of a 3- to 6-membered fused carbocyclic ring.
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- (1)H and (13)C Dinamic Nuclear Magnetic Resonance Study of Hindered Internal Rotation in (N,N-Dimethylamino)pyrimidines
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The free energies of activation ΔG for hindered rotation around the C-N exocyclic bond in a series of 2- and 4-(N,N-dimethylamino)pyrimidines have been determined by (1)H and (13)C n.m.r. lineshape analysis.Good linear correlations have been obtained between the coupling constant (1)J(C,H) for the dimethylamino group and the ΔG parameter.Such correlations have been used to estimate ΔG values of symmetrical or unsymmetrical pyrimidines for which an experimental determination of this thermodynamic parameter is either impossible or extremely difficult.In addition, substituent effects on the barrier heights indicate that: (i) the difference between the ΔG4 and ΔG2 values decreases with increasing electron-withdrawing power of the substituent, and (ii) substituent effects are larger through a ring nitrogen than through a ring carbon atom.Correlation of the ΔG values with Hammett constants is discussed.
- Riand, Jacques,Chenon, Marie-Therese,Lumbroso-Bader, Nicole
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p. 1551 - 1558
(2007/10/02)
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