57181-88-1Relevant academic research and scientific papers
Novel Deazaflavin Analogues Potently Inhibited Tyrosyl DNA Phosphodiesterase 2 (TDP2) and Strongly Sensitized Cancer Cells toward Treatment with Topoisomerase II (TOP2) Poison Etoposide
Kankanala, Jayakanth,Ribeiro, Carlos J. A.,Kiselev, Evgeny,Ravji, Azhar,Williams, Jessica,Xie, Jiashu,Aihara, Hideki,Pommier, Yves,Wang, Zhengqiang
, p. 4669 - 4682 (2019/05/17)
Topoisomerase II (TOP2) poisons as anticancer drugs work by trapping TOP2 cleavage complexes (TOP2cc) to generate DNA damage. Repair of such damage by tyrosyl DNA phosphodiesterase 2 (TDP2) could render cancer cells resistant to TOP2 poisons. Inhibiting TDP2, thus, represents an attractive mechanism-based chemosensitization approach. Currently known TDP2 inhibitors lack cellular potency and/or permeability. We report herein two novel subtypes of the deazaflavin TDP2 inhibitor core. By introducing an additional phenyl ring to the N-10 phenyl ring (subtype 11) or to the N-3 site of the deazaflavin scaffold (subtype 12), we have generated novel analogues with considerably improved biochemical potency and/or permeability. Importantly, many analogues of both subtypes, particularly compounds 11a, 11e, 12a, 12b, and 12h, exhibited much stronger cancer cell sensitizing effect than the best previous analogue 4a toward the treatment with etoposide, suggesting that these analogues could serve as effective cellular probes.
Discovery of anilino-furo[2,3-d]pyrimidine derivatives as dual inhibitors of EGFR/HER2 tyrosine kinase and their anticancer activity
Hossam, Monia,Lasheen, Deena S.,Ismail, Nasser S.M.,Esmat, Ahmed,Mansour, Ahmed M.,Singab, Abdel Nasser B.,Abouzid, Khaled A.M.
, p. 330 - 348 (2017/12/28)
Being responsible for the development of many cancer types, EGFR (Epidermal Growth Factor Receptor) and HER2 (Human Epidermal growth factor Receptor 2) were the focus of this study where a series of novel 4-anilino-furo[2,3-d]pyrimidine derivatives was designed, synthesized and biologically evaluated. Modification of the solvent accessible 5-position side chain greatly affected the in-vitro EGFR/HER2 inhibitory activity. Three derivatives bearing 5-carboxylic acid side chain, namely the 3-chloroanilino derivative (8c), the 3-bromoaniline (8d) and the lapatinib analogue (10) demonstrated the most significant submicromolar EGFR inhibition. Surprisingly, the in-vitro assay of the ester 7h and its acid analogue 10 showed a significant variation of results between the antiproliferative activity against A549 cell line (IC50 0.5 and 21.4 μM) respectively and EGFR inhibitory activity (18% and 100%) respectively, suggesting that 7h might be a prodrug for 10. This assumption was also affirmed by the in-vivo results, where the in-vivo antitumor assessment against EAC (Ehrlich Ascites Carcinoma) solid tumor model revealed that 7h and 8d (10 mg/kg dose) exhibited antitumor activity comparable to that of gefitinib at the same dose, exhibiting TGI% of 67%, 71% and 70%, respectively. This effect could be explained, at least partly, via activation of apoptosis, where 7h and 8d caused more than 2-fold increase of caspase 3 and cytochrome c expression than the control group which is comparable to that of gefitinib-treated group. Finally, 7h was the most effective apoptotic inducer, resulting in a significant elevation in annexin V–FITC-positive apoptotic cells (both early and late apoptosis) by 25 and 79-folds, respectively, compared to control, which is higher than that of gefitinib (22 and 61-folds, respectively).
Discovery of N-(2-aminoethyl)-N-benzyloxyphenyl benzamides: New potent Trypanosoma brucei inhibitors
Buchynskyy, Andriy,Gillespie, J. Robert,Hulverson, Matthew A.,McQueen, Joshua,Creason, Sharon A.,Ranade, Ranae M.,Duster, Nicole A.,Gelb, Michael H.,Buckner, Frederick S.
, p. 1571 - 1584 (2017/02/26)
A phenotypic screen of a compound library for antiparasitic activity on Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), led to the identification of N-(2-aminoethyl)-N-phenyl benzamides as a starting point for hit-to-lead m
Design, synthesis and biological evaluation of salicylamide analogues as epidermal growth factor receptor tyrosine kinase inhibitors
Liu, Yang,Li, Yijing,Liu, Jianzhen,Yang, Limin,Li, Pengzhan,Zhao, Guisen
, p. 314 - 323 (2016/04/04)
Blocking epidermal growth factor receptor (EGFR) has been the hotspot in the field of cancer therapy. Based on the fact that salicylanilides possess well inhibitory activity against EGFR tyrosine kinase, a series of salicylamide analogs bearing 4'-substitution were designed to explore new candidates exhibiting improved efficacy against EGFR. Many of the synthesized compounds inhibited EGFR in the micromolar range, especially compounds 15a and 15b (IC50 = 0.27 μM and 1.1μM, respectively). We report our findings as a basis for further development in salicylamide analogues as EGFR inhibitors.
DERIVATIVES OF PHENYL (THIO) UREA DEOXYTHYMIDINE AND USE THEREOF AS ANTIMALARIALS
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Page/Page column 22, (2013/03/26)
Deoxythymidine derivatives according to formula (I) are disclosed. wherein: X may be O or S; and R1, R2, R3, R4 and R5 may each be independently selected from H, halo, C1-C6 alkyl, C1-C6 haloalkyl, nitro, phenyl, heteroaryl, substituted heteroaryl wherein the substituents may be C1-C6 alkyl or C1-C6 haloalkyl, benzyl, -CH2OAr, -OR6 and six-membered ring heterocyclic groups containing 1 or more O and/or N heteroatoms wherein any N heteroatom may be C1-C6 alkyl-substituted; and R6 may be selected from C1-C6 alkyl, phenyl, six-membered ring heterocyclic groups containing at least one O heteroatom, benzyl and substituted benzyl wherein the substituents may be halo, C1-C6 alkyl or C1-C6 alkoxy; R7 may be H or C1-C6 alkyl; and the stereochemistry of the bond depicted as ? is either α or β. Such derivatives have shown good inhibitory activity against malaria-causing parasites, e.g. Plasmodium falciparum, but have shown low levels of toxicity to human cells.
Synthesis and evaluation of α-thymidine analogues as novel antimalarials
Cui, Huaqing,Carrero-Lérida, Juana,Silva, Ana P. G.,Whittingham, Jean L.,Brannigan, James A.,Ruiz-Pérez, Luis M.,Read, Kevin D.,Wilson, Keith S.,González-Pacanowska, Dolores,Gilbert, Ian H.
, p. 10948 - 10957 (2013/03/13)
Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea- α-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this
Synthesis of a new series of aminomethylated 5-nitro-1H-benzo [d] imidazoles, 6-nitrobenzo [d] oxazol-2(3H)-ones and 4-nitroisoindoline-1,3-diones as antileishmanial and antimicrobial agents
Rastogi, Nisheeth,Kant, Padam,Sethi, Rakesh,Shukla, Sarveshwar,Harrison, Darwin Anil
, p. 149 - 152 (2013/09/23)
4-(Chlorobenzyloxy) anilines were incorporated into 5-nitro-1H-benzo [d] imidazole, 6-nitrobenzo [d] oxazol-2(3H)-one and 4-nitroisoindoline-1,3-dione in the presence of 40% aq formaldehyde to furnish a new series of 5-nitro-1-(4-chlorobenzyloxy)-anilinomethyl-1 H-benzo [d] imidazoles /6-nitro-3-(4-(chlorobenzyloxy)-anilinomethyl)-benzo [d] oxazol-2(3H)-ones and 4-nitro-2-(4-chlorobenzyloxy)-anilinomethyl) isoindoline-1,3-diones (11-25). The structures of the compounds were established by means of elemental analysis and spectral data (IR & PMR). Compounds were screened for their antileishmanial and antimicrobial potential.
5-(Aminomethyl)-3-aryl-2-oxazolidinones. A novel class of mechanism-sased inactivators of monoamine oxidase B
Gates, Kent S.,Silverman, Richard B.
, p. 9364 - 9372 (2007/10/02)
The mechanism of inactivation of monoamine oxidase (MAO) by 5-(aminomethyl)-3-aryl-2-oxazolidinones has been investigated. (R)- and (S)-3-[4-[(3-chlorophenyl)methoxy]phenyl]-5-[(methylamino)methyl]-2- oxazolidinone (1) exhibit all of the properties of a mechanism-based inactivator. Several other analogues of 1 also inactivate MAO. Inactivation of MAO by (R)- and (S)-[methoxy-3H]-1 and by [methoxy- 3H]-3-(4-methoxyphenyl)-5-[(methylamino)methyl]-2-oxazolidinone (15, R = 3H) led to incorporation of 1.0, 1.2, and 2.1 equiv of tritium per enzyme molecule after denaturation, indicating that a covalent bond between the oxazolidinones and MAO is formed. The partition ratios, determined from the amount of radioactive non-amines generated per tritium incorporated into the enzyme, were 17.6 and 10.9 for the R and S isomers, respectively. Inactivation of MAO by (R)- and (S)-[carboxy-14C]-1 resulted in release of 4.5 and 3.0 equiv of 14CO2, respectively. However, in addition to the loss of 14CO2 there also was incorporation of 1.5 and 1.0 equiv of 14C, respectively, into the enzyme after denaturation. The flavin spectrum indicated that the flavin was reduced after inactivation, but upon denaturation the spectrum returned to that of the oxidized form, suggesting that attachment is to an amino acid residue, not to the flavin. 5-(Aminomethyl)-3-(4-cyanophenyl)-2-oxazolidinone inactivates MAO at a rate comparable to or faster than does the corresponding 4-methoxyphenyl analogue, suggesting that there is little or no electronic effect of ring substitution on the rate of inactivation. All of these results support an inactivation mechanism that involves one-electron oxidation of the amine to the amine radical cation, followed by proton removal to give the α radical, which can partition among three pathways (Scheme V): radical combination with an active-site amino acid residue radical to give inactive enzyme, decomposition of the oxazolidinone ring with loss of CO2, and second electron transfer to give the corresponding aldehyde product.
