- Invariant and Variable Supramolecular Self-Assembly in 6-Substituted Uracil Derivatives: Insights from X-ray Structures and Quantum Chemical Study
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In this study, three new 6-(arylthio)uracil derivatives, namely, 6-(phenylthio)pyrimidine-2,4(1H,3H)-dione (1), C10H8N2O2S; 6-(p-tolylthio)pyrimidine-2,4(1H,3H)-dione (2), C11H10N2O2S; and 6-(3,5-dimethylphenylthio)pyrimidine-2,4(1H,3H)-dione (3), C12H12N2O2S, have been synthesized. Single-crystal structures of these compounds reveal an invariant molecular tape contains alternate R22(8) synthons formed by N-H···O hydrogen bonds in 1 and 3. This alternate hydrogen-bonded pattern disappeared in 2; instead, a new synthon is generated. The lattice energy calculation suggests that the methyl-substituted derivatives (2 and 3) have high stabilization energy than compound 1. The electrostatic potential map reveals the difference in the accepting tendency of the carbonyl oxygen. The Hirshfeld surface and 2D-fingerprint plots analyses demonstrate that the major intermolecular interactions come from H···O contacts in 1, and these contacts were reduced due to the presence of methyl substitutions in 2 and 3. This reduction is compensated by the increase of the same amount of H···H contacts in these structures. Further, the PIXEL energy and DFT calculations at the M06-2X-D3/cc-pVTZ level of theory were used to characterize the dimeric topology formed in structures of 1-3. The intermolecular interaction energies of dimers calculated by the PIXEL method were compared with the B97D3/def2-TZVP level of approximation. Although these molecules' crystal packing is somewhat different, the energy frameworks show similarities on the respective crystal structure's shortest axis. Furthermore, the nature and strength of various noncovalent interactions such as N-H···O, C-H···O/S/π, π···π, and a chalcogen bond of type C-S···O═C were evaluated using the Bader's quantum theory of atoms-in-molecules framework.
- Abdelbaky, Mohammed S. M.,Al-Wahaibi, Lamya H.,Bysani, Sai Ramya Sree,El-Emam, Ali A.,Garcia-Granda, Santiago,Percino, M. Judith,Tawfik, Samar S.,Thamotharan, Subbiah
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p. 3234 - 3250
(2021/05/29)
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- Pd/PTABS: Catalyst for Room Temperature Amination of Heteroarenes
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A mild and highly efficient catalytic amination procedure for chloroheteroarenes at ambient temperature using the Pd/PTABS catalytic system is reported. The protocol is selective for the amination of chloroheteroarenes using secondary amines such as piperidine, pyrrolidine, and several others. The exceptional mildness of the developed protocol is beneficial for the synthesis of a crucial Buparlisib intermediate as well as the formal synthesis of Alogliptin in competitive yields.
- Murthy Bandaru, Siva Sankar,Bhilare, Shatrughn,Chrysochos, Nicolas,Gayakhe, Vijay,Trentin, Ivan,Schulzke, Carola,Kapdi, Anant R.
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p. 473 - 476
(2018/01/28)
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- Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II
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The recently discovered enzyme tyrosyl-DNA phosphodiesterase 2 (TDP2) has been implicated in the topoisomerase-mediated repair of DNA damage. In the clinical setting, it has been hypothesized that TDP2 may mediate drug resistance to topoisomerase II (topo II) inhibition by etoposide. Therefore, selective pharmacological inhibition of TDP2 is proposed as a novel approach to overcome intrinsic or acquired resistance to topo II-targeted drug therapy. Following a high-throughput screening (HTS) campaign, toxoflavins and deazaflavins were identified as the first reported sub-micromolar and selective inhibitors of this enzyme. Toxoflavin derivatives appeared to exhibit a clear structure-activity relationship (SAR) for TDP2 enzymatic inhibition. However, we observed a key redox liability of this series, and this, alongside early in vitro drug metabolism and pharmacokinetics (DMPK) issues, precluded further exploration. The deazaflavins were developed from a singleton HTS hit. This series showed distinct SAR and did not display redox activity; however low cell permeability proved to be a challenge.
- Raoof, Ali,Depledge, Paul,Hamilton, Niall M.,Hamilton, Nicola S.,Hitchin, James R.,Hopkins, Gemma V.,Jordan, Allan M.,Maguire, Laura A.,McGonagle, Alison E.,Mould, Daniel P.,Rushbrooke, Mathew,Small, Helen F.,Smith, Kate M.,Thomson, Graeme J.,Turlais, Fabrice,Waddell, Ian D.,Waszkowycz, Bohdan,Watson, Amanda J.,Ogilvie, Donald J.
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p. 6352 - 6370
(2013/09/23)
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- 5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2
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Based on previous reports of certain 5-deazaflavin derivatives being capable of activating the tumour suppressor p53 in cancer cells through inhibition of the p53-specific ubiquitin E3 ligase HDM2, we have conducted an structure-activity relationship (SAR) analysis through systematic modification of the 5-deazaflavin template. This analysis shows that HDM2-inhibitory activity depends on a combination of factors. The most active compounds (e.g., 15) contain a trifluoromethyl or chloro substituent at the deazaflavin C9 position and this activity depends to a large extent on the presence of at least one additional halogen or methyl substituent of the phenyl group at N10. Our SAR results, in combination with the HDM2 RING domain receptor recognition model we present, form the basis for the design of drug-like and potent activators of p53 for potential cancer therapy.
- Dickens, Michael P.,Roxburgh, Patricia,Hock, Andreas,Mezna, Mokdad,Kellam, Barrie,Vousden, Karen H.,Fischer, Peter M.
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p. 6868 - 6877
(2013/11/06)
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- Synthesis and biological evaluation of novel pyrimido[4,5-b]quinoline-2,4- dione derivatives as MDM2 ubiquitin ligase inhibitors
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A series of pyrimido[4,5-b]quinoline-2,4-dione derivatives was synthesized and evaluated for their cytotoxic activities in vitro against five human cancer cell lines. Selected compounds were tested for their MDM2 E3 ligase inhibitory activities and p53-MDM2 binding inhibitory activities. Among tested compounds, four sulfur-containing compounds (4-7) displayed enhanced cytotoxic activities and better MDM2 E3 ligase inhibitoty activities in comparison with that of HLI98c. Three compounds (4-6) showed better p53-MDM2 binding inhibitory potency with IC50 values ranging from 1.3 μM to 9.0 μM.
- Dou, Xiaoxue,Li, Xin,Tao, Liu,Hu, Chunqi,Zhang, Lei,He, Qiaojun,Yang, Bo,Hu, Yongzhou
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p. 581 - 587
(2013/07/28)
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- Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors
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New analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) were synthesized and evaluated for their in vitro activities against HIV-1 in MT-4 cell cultures. Chemical diversity was introduced in 4 of the six positions of the core and the influence of each substituent was studied. This library was built on the basis of a rational diversity analysis with the objective of maximizing diversity and thus, the activity range with a minimum number of synthesized compounds. Among them, 2{1,2,3,1} and 2{1,2,3,4} exhibited the most potent anti-HIV-1 activities (EC50 = 0.015 μg/mL; 0.046 μM, SI >1667) and (EC50 = 0.025 μg/mL; 0.086 μM, SI >1000), respectively, which were about 71-fold and 38-fold more active than the reference compound HEPT (EC50 = 1.01 μg/mL; 3.27 μM, SI >25).
- Puig-De-La-Bellacasa, Raimon,Gimenez, Laura,Pettersson, Sofia,Pascual, Rosalia,Gonzalo, Encarna,Este, Jose A.,Clotet, Bonaventura,Borrell, Jose I.,Teixido, Jordi
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experimental part
p. 159 - 174
(2012/09/05)
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- Microwave-assisted synthesis of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5, 7(1H,6H)-dione libraries: Derivatives of toxoflavin
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The parallel synthesis of a library of toxoflavin derivatives is described. The microwave-assisted approach involves the de novo generation of the heterocyclic scaffold and allows for facile introduction of a variety of fragments.
- Todorovic, Nick,Giacomelli, Andrew,Hassell, John A.,Frampton, Christopher S.,Capretta, Alfredo
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experimental part
p. 6037 - 6040
(2010/11/21)
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- PROCESS FOR STRAIGHTENING KERATIN FIBRES WITH A HEATING MEANS AND DENATURING AGENTS
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The invention relates to a process for straightening keratin fibres, comprising: (i) a step in which a straightening composition containing at least two denaturing agents is applied to the keratin fibres, (ii) a step in which the temperature of the keratin fibres is raised, using a heating means, to a temperature of between 110 and 250° C.
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- Efficient synthesis of novel 6-Phenylthio-2,4-disubstituted pyrimidines
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6-Phenylthio-2,4-disubstituted pyrimidines were prepared in five steps starting from barbituric acid. Reaction of barbituric acid with POCl3 in presence of N, N-dimethylaniline furnishes the 2,4,6-trichloropyrimidine, which on reaction with aq. NaOH under reflux yielded the 6-chlorouracil. Reaction of 6-chlorouracil with thiophenol under basic condition furnishes the 6-phenylthiouracil, which on chlorination using excess POCl3 under reflux yielded the key synthon, 6-phenylthio-2,4-dichloropyrimidine. Aromatic nucleophilic substitution reaction of 6-phenylthio-2,4-dichloropyrimidine with a oxygen nucleophile like sodium benzylate and nitrogen nucleophiles like heterocyclic primary amines, aliphatic primary amines and substituted aromatic primary amines furnished the target compounds, 6-phenylthio-2,4-disubstituted pyrimidines respectively in 40-80% yield.
- Goudgaon,Ch, Upendar Reddy
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body text
p. 443 - 448
(2010/03/04)
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- Synthesis and electrochemical properties of structurally modified flavin compounds
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Four structurally modified flavin compounds have been synthesized and characterized for their redox potential by chemical reduction with sodium dithionite. Besides the previously reported 1- and 5-deazariboflavin, a 7,8-didemethyl derivative and an 8-isopropylriboflavin have been obtained. The synthesis of these compounds started in all cases from appropriately substituted anilines that were condensed with the ribityl chain, followed by completion of the annealed three-ring structure. The didemethyl- and the isopropyl compounds gave absorption maxima similar to riboflavin (436 and 448 nm, respectively), whereas 1-deazariboflavin showed a bathochromically shifted absorption (λmax = 537 nm), and that of 5-deazariboflavin was hypsochromically shifted (λmax = 400 nm). The midpoint potentials (E0′) of the four modified flavin compounds were determined by potentiometric titration, using riboflavin as a reference compound. Both alkyl-modified flavins showed slightly less negative midpoint potentials, whereas both deaza compounds had more negative midpoint values compared to the reference compound. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Mansurova, Madina,Koay, Melissa S.,Gaertner, Wolfgang
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supporting information; experimental part
p. 5401 - 5406
(2009/05/07)
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- Synthesis, biological active molecular design, and molecular docking study of novel deazaflavin-cholestane hybrid compounds
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Novel deazaflavin-cholestane hybrid compounds, 3′,8′-disubstituted-5′-deazacholest-2,4-dieno[2,3-g]pteridine-2′,4′(3′H,8′H)-diones, have been synthesized by condensation reaction between 6-(monosubstituted amino)-pyrimidin-2,4(1H,3H)-diones and 2-hydroxymethylenecholest-4-en-3-one in presence of p-toluenesulfonic acid monohydrate and diphenyl ether. The antitumor activities against human tumor cell lines (CCRF-HSB-2 and KB cells) have been investigated in vitro, and many of these compounds showed promising antitumor activities. Furthermore, molecular docking study using LigandFit within the software package Discovery Studio 1.7 was done for lead optimization of these compounds as potential PTK inhibitors. In general, all of the synthesized steroid-hybrid compounds showed good binding affinities into PTK (PDB code: 1t46).
- Shrestha, Ajaya R.,Shindo, Takashi,Ashida, Noriyuki,Nagamatsu, Tomohisa
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body text
p. 8685 - 8696
(2009/04/11)
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- Synthesis of 5-deazaflavin derivatives and their activation of p53 in cells
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A family of 5-deazaflavin derivatives has been synthesised using a two-step convergent strategy. The biological activity of these compounds was evaluated in cells, by assessing their ability to stabilize and activate p53. These compounds may act as low molecular weight inhibitors of the E3 activity of HMD2 in tumours that retain wild-type p53. Importantly, we have demonstrated that the nitro group present in all three of the original lead compounds [1-3 (HL198C-E)] is not essential for observation of this biological activity.
- Wilson, Jennifer M.,Henderson, Graham,Black, Fiona,Sutherland, Andrew,Ludwig, Robert L.,Vousden, Karen H.,Robins, David J.
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- FUSED PYRIMIDINE DERIVATIVE
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The present invention provides a fused pyrimidine derivative having an insulin secretion stimulating activity represented by Formula (I): {wherein R1 represents a hydrogen atom, lower alkyl, or the like; n represents an integer of 0 to 3; and X1 and X2 may be the same or different and each represents a hydrogen atom, lower alkyl, or the like; and formula (II): represents formula (III): [wherein X--Y--Z represents R2C=CR3-NR4 (wherein R2, R3 and R4 may be the same or different and each represents a hydrogen atom, lower alkyl, or the like)]}, or a pharmaceutically acceptable salt thereof.
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Page/Page column 13
(2010/11/08)
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- Syntheses, π-stacking interactions and base-pairings of uracil pyridinium salts and uracilyl betaines with nucleobases
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Reaction of 6-chlorouracil with 4-(dimethylamino)pyridine, 4-methylpyridine, and pyridin-4-yl-morpholine yielded pyridinium-substituted uracils as chlorides which were converted into pyridinium uracilates by deprotonation. These heterocyclic mesomeric betaines are cross-conjugated and thus possess separate cationic (pyridinium) and anionic (uracilate) moieties. Calculations and X-ray single crystal analyses were performed in order to characterize these systems and to compare the salts with the betaines. 1H NMR experiments in D2O proved π-interactions between the uracilyl betaines and adenine, adenosine, as well as adeninium. No π-stacking interactions were detected between the betaines and guanosine. The acidic N8-H group of the uracil pyridinium salts caused acid-base reactions which were observed in parallel to π-stacking interactions. Self-complementarity of the modified uracils was detected by 1H NMR experiments in DMSO-d6 and electrospray ionisation mass spectrometry (ESIMS). Ab initio calculations predicted base-pairings of the modified uracils with adeninium, cytosine, and guanine. Several geometries of hydrogen-bonded associates were calculated. Hoogsteen pairings between the uracil-4- (dimethylamino)pyridinium salt and adeninium, as well as associates between the corresponding betaine plus cytosine, and the betaine plus guanine were calculated, and the most stable conformations were determined. In the ESI mass spectra, prominent peaks of associates between the modified uracils and adeninium, cytosine, cytidine, guanosine and d(CpGp) were detected. The Royal Society of Chemistry 2006.
- Schmidt, Andreas,Lindner, Anika,Nieger, Martin,Ruiz-Delgado, Maria Del Carmen,Ramirez, Francisco Javier
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p. 3056 - 3066
(2008/02/11)
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- Synthesis and enzymatic evaluation of pyridinium-substituted uracil derivatives as novel inhibitors of thymidine phosphorylase.
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A series of water soluble N(1)- and C(6)-substituted uracil pyridinium compounds were prepared as potential inhibitors of thymidine phosphorylase (TP). The C(6)-uracil substituted derivatives were the most active. 1-[(5-Chloro-2,4-dihydroxypyrimidin-6-yl)methyl]pyridinium chloride, was identified as the best inhibitor being 5-fold more potent than the known inhibitor, 6-amino-5-bromouracil.
- Murray, Paul E,McNally, Virginia A,Lockyer, Stacey D,Williams, Kaye J,Stratford, Ian J,Jaffar, Mohammed,Freeman, Sally
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p. 525 - 530
(2007/10/03)
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- Mechanism of formation of 6-chlorouracil ammonium complexes
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Hydrolytically stable hydroxyalkylammonium complexes of 6-chlorouracil, in which the uracil N1 proton participates in the coordination bond, were prepared by ion exchange.
- Erkin,Krutikov,Lavrent'ev
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p. 1946 - 1948
(2007/10/03)
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- Model systems for flavoenzyme activity: One- and two-electron reduction of flavins in aprotic hydrophobic environments
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The processes occurring during the electrochemically irreversible reduction of flavins in aprotic organic medium have been the cause of considerable controversy. To provide insight into these events we have investigated the reduction of flavins alkylated at N(3). We have demonstrated that the reversible reduction of N(3)-methylated flavin can be converted to the irreversible reduction observed with unalkylated flavins through addition of the weak external proton donor phthalimide. Proton transfer to the flavin radical anion generated at the electrode leads to partial formation of the neutral flavin radical, which is instantaneously further reduced to the fully reduced flavin anion. This mirrors the reduction of unalkylated flavins, where the proton source is the imide proton at N(3) of fully oxidized flavin in bulk solution. Simultaneous electrochemistry and EPR experiments confirm the disappearance of electrogenerated flavin radical anion both methylated and non-methylated at N(3), upon addition of phthalimide. UV/vis spectroelectrochemistry likewise confirmed the generation of the radical anion in the absence of proton donors and fully reduced flavin in the presence of proton donors.
- Niemz, Angelika,Imbriglio, Jason,Rotello, Vincent M.
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p. 887 - 892
(2007/10/03)
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- SYNTHESIS AND X-RAY ANALYSIS OF 1-BENZYL-6-CHLOROURACIL
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1-Benzyl-6-chlorouracil (3) was prepared by benzylation of 6-chlorouracil (2) which was obtained by alkaline hydrolysis of 2,4,6-trichloropyrimidine (1).
- Ishikawa, Ichiro,Itoh, Tsuneo,Melik-Ohanjanian, Raphael G.,Takayanagi, Hiroaki,Mizuno, Yoshihisa,et al.
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p. 1641 - 1646
(2007/10/02)
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- Process for producing 2,4,5,6-tetrachloropyrimidine by way of 5,6-dichloro-2,4-dihydroxypyrimidine which was produced from the corresponding 5,6-dichloro-2,4-di(trihalomethyl)-pyrimidine and a process for producing 2,4-dihydroxypyrimidine derivatives
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2,4-Dihydroxypyrimidines of the formula STR1 with the substituent meanings given in the description, are obtained by reacting pyrimidines of the formula STR2 with the substituent meanings given in the description, with aqueous alkalis at elevated temperature. 2,4,5,6-Tetrachloropyrimidine is obtained from the dihydroxypyrimidines by reaction with agents which replace hydroxyl by chlorine.
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- Reactions of 4a-Peroxides and 4a-Pseudobases of N10- and N5-Phenethylflavins
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A number of N5,N10-dialkylisoalloxazines have been synthesized in which either the N5 or the N10 substituent is a meta-substituted phenethyl group.Some of these compounds have been subjected to experiments in order to determine whether an intramolecular transfer of oxygen can occur between the flavin and the phenethyl group (a model of monooxygenase).When in the 1,5-dihydro reduced state, N5-alkyl-substituted isoalloxazines react with molecular oxygen to dive 4a-hydroperoxy derivatives.The hydroperoxides of the N5-ethyl-N10-phenethylflavins provide 4a-pseudobases on spontaneous decomposition.These in turn undergo ring contraction in base to yield 10a-spirohydantoins (Scheme V).The structure of 10a-spirohydantoin (28b) is as established by X-ray crystallographic technique.Spontaneous decomposition of 4a-hydroperoxides is not accompanied by intramolecular oxygen transfer to the phenethyl substituent groups at N10 or N5 (eq.4) 10a-Spirohydantoins may also be obtained by base treatment of 4a-pseudobases that have been prepared separately from the oxidized isoalloxazine (i.e., flavinium cation). 4a-(Allylperoxy)flavin derivatives, obtained by addition of alkyl peroxides to flavinium cations, undergo both spontaneous and photochemocal conversion to 10a-spirohydantoin.These findings are discissed in therms of proposals which have been made for the mechanism of action of flavoenzyme monooxygenases.
- Iwata, Masaki,Bruice, Thomas C.,Carrell, H. L.,Glusker, Jenny P,
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p. 5036 - 5044
(2007/10/02)
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