4270-27-3Relevant academic research and scientific papers
Invariant and Variable Supramolecular Self-Assembly in 6-Substituted Uracil Derivatives: Insights from X-ray Structures and Quantum Chemical Study
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
, p. 3234 - 3250 (2021/05/29)
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.
Pd/PTABS: Catalyst for Room Temperature Amination of Heteroarenes
Murthy Bandaru, Siva Sankar,Bhilare, Shatrughn,Chrysochos, Nicolas,Gayakhe, Vijay,Trentin, Ivan,Schulzke, Carola,Kapdi, Anant R.
supporting information, p. 473 - 476 (2018/01/28)
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.
Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II
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.
, p. 6352 - 6370 (2013/09/23)
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.
5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2
Dickens, Michael P.,Roxburgh, Patricia,Hock, Andreas,Mezna, Mokdad,Kellam, Barrie,Vousden, Karen H.,Fischer, Peter M.
, p. 6868 - 6877 (2013/11/06)
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.
Synthesis and biological evaluation of novel pyrimido[4,5-b]quinoline-2,4- dione derivatives as MDM2 ubiquitin ligase inhibitors
Dou, Xiaoxue,Li, Xin,Tao, Liu,Hu, Chunqi,Zhang, Lei,He, Qiaojun,Yang, Bo,Hu, Yongzhou
, p. 581 - 587 (2013/07/28)
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.
Diverse combinatorial design, synthesis and in vitro evaluation of new HEPT analogues as potential non-nucleoside HIV-1 reverse transcription inhibitors
Puig-De-La-Bellacasa, Raimon,Gimenez, Laura,Pettersson, Sofia,Pascual, Rosalia,Gonzalo, Encarna,Este, Jose A.,Clotet, Bonaventura,Borrell, Jose I.,Teixido, Jordi
experimental part, p. 159 - 174 (2012/09/05)
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).
Microwave-assisted synthesis of 3-aryl-pyrimido[5,4-e][1,2,4]triazine-5, 7(1H,6H)-dione libraries: Derivatives of toxoflavin
Todorovic, Nick,Giacomelli, Andrew,Hassell, John A.,Frampton, Christopher S.,Capretta, Alfredo
experimental part, p. 6037 - 6040 (2010/11/21)
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.
PROCESS FOR STRAIGHTENING KERATIN FIBRES WITH A HEATING MEANS AND DENATURING AGENTS
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, (2010/03/02)
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.
Efficient synthesis of novel 6-Phenylthio-2,4-disubstituted pyrimidines
Goudgaon,Ch, Upendar Reddy
body text, p. 443 - 448 (2010/03/04)
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.
Synthesis and electrochemical properties of structurally modified flavin compounds
Mansurova, Madina,Koay, Melissa S.,Gaertner, Wolfgang
supporting information; experimental part, p. 5401 - 5406 (2009/05/07)
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.
