Design, synthesis and preliminary bioactivity studies of imidazolidine-2,4-dione derivatives as Bcl-2 inhibitors

Wang, Gang; Wang, Yutao; Wang, Lei; Han, Leiqiang; Hou, Xuben; Fu, Huansheng; Fang, Hao

doi:10.1016/j.bmc.2015.10.023

Cited by 20 publications

(20 citation statements)

References 19 publications

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“…The second one describes the CDI activation of N-terminal moieties of dipeptides followed by cyclization (Scheme 1, method B). The disclosed methodology is a valid eco-friendly alternative (replacing the use of triphosgene) 46 to prepare 5-benzyl-3-(methyloxycarbonyl)benzyl hydantoin 2e (Table 2, entry 5), which the corresponding carboxylic acid is an antiparasite agent, inhibitor of dihydro-orodotase dehydrogenase from Clostridium (Zymobacterium) oroticum. 6,7 The Journal of Organic Chemistry Article ■ RESULTS AND DISCUSSION Synthesis of 3-Substituted Alkoxycarbonyl Hydantoins from Unsymmetrical Ureas of Amino Esters (Method A).…”

Section: ■ Introductionmentioning

confidence: 99%

Mechanochemical Preparation of 3,5-Disubstituted Hydantoins from Dipeptides and Unsymmetrical Ureas of Amino Acid Derivatives

et al. 2016

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5-Substituted-3-(alkoxycarbonyl)alkyl-hydantoin derivatives were prepared by mechanochemistry from amino esters or dipeptides, via a 1,1'-carbonyldiimidazole-mediated one-pot/two-step cyclization reaction involving amino acid unsymmetrical urea A and carboxy-imidazolyl-dipeptide ester B intermediates. Comparative experiments in solution were also performed. The successful preparation of an antibacterial agent precursor was also investigated.

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Section: ■ Introductionmentioning

confidence: 99%

Mechanochemical Preparation of 3,5-Disubstituted Hydantoins from Dipeptides and Unsymmetrical Ureas of Amino Acid Derivatives

et al. 2016

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“…One other hit, 609515, also possesses reasonable physicochemical properties (logP = 2.31, topological polar surface area = 87.7) and even showed a trend toward selectively inhibiting BRCA1 mutated cells versus cells with restored BRCA1 activity ( Fig 2B ). In addition to inhibiting ssDNA binding to RAD52, compounds possessing the benzylhydantoin chemical scaffold of 609515 are known to be inhibitors of Bcl-2 [ 24 ] and dihydroorotate dehydrogenase [ 25 ], two other potential anti-cancer mechanisms. This hit might represent a starting point for a multi-mechanism antineoplastic hit to lead project.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection

et al. 2016

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It has been reported that inhibition of RAD52 either by specific shRNA or a small peptide aptamer induced synthetic lethality in tumor cell lines carrying BRCA1 and BRCA2 inactivating mutations. Molecular docking was used to screen two chemical libraries: 1) 1,217 FDA approved drugs, and 2) 139,735 drug-like compounds to identify candidates for interacting with DNA binding domain of human RAD52. Thirty six lead candidate compounds were identified that were predicted to interfere with RAD52 –DNA binding. Further biological testing confirmed that 9 of 36 candidate compounds were able to inhibit the binding of RAD52 to single-stranded DNA in vitro. Based on molecular binding combined with functional assays, we propose a model in which the active compounds bind to a critical “hotspot” in RAD52 DNA binding domain 1. In addition, one of the 9 active compounds, adenosine 5’-monophosphate (A5MP), and also its mimic 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) 5’ phosphate (ZMP) inhibited RAD52 activity in vivo and exerted synthetic lethality against BRCA1 and BRCA2–mutated carcinomas. These data suggest that active, inhibitory RAD52 binding compounds could be further refined for efficacy and safety to develop drugs inducing synthetic lethality in tumors displaying deficiencies in BRCA1/2-mediated homologous recombination.

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“…A series of studies was introduced to discover that hydantoin derivatives, important heterocyclic compounds, act as antioxidant agents (Gus'kov et al, 2004). Moreover, Imidazolidine-2,4 dione derivatives are specific biologically active compounds and act as antiproliferative agents (Reddy et al, 2010), hypoglycemic, aldose reductase inhibitor agents (Iqbal et al, 2015) and Bcl-2 inhibitors (Wang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives and their biological evaluation as analgesic, antipyretic and anti-inflammatory agents

El-Sharkawy

Albratty

Alhazmi

2018

Braz. J. Pharm. Sci.

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Pyrimidine derivative 3 was afforded through the reaction of compound (1) with 5-ureidohydantion (2). Product 3 underwent a cyclization to produce fused pyrimidine derivative 7, although the latter product 7 was synthesized through one step via the reaction of compound (1) with 5-ureidohydantion (2) using another catalyst. Compound 3 was oriented to react with cyclic ketones 8a,b in the presence of elemental sulfur, salicylaldehyde (10), aryldiazonium chlorides 12a,b and ω-bromo-4-methoxy-acetophenone ( 14), which afforded, fused thiophene derivatives 9a,b, coumarin derivative 11, arylhdrazono derivatives 13a,b and 4-methoxyphenyl butenyl derivative 15, respectively. The latter product 15 was reacted with either potassium cyanide (16a) or potassium thiocyanide (16b) to form cyano and thiocyano derivatives 17a,b, respectively. Compound 17a underwent further cyclization to afford pyridopyrimidine derivative 19. Compound 15 was reacted with either hydrazine (20a) or phenylhydrazine (20b) to produce hydrazo derivatives 21a,b and these products were cyclize to produce pyrrole derivatives 23a,b. Finally, 5-ureidohydantion (2) was reacted with compounds 24a,b,c to afford pyrimidine derivatives 25a,b,c. The structures of the synthesized compounds were confirmed using IR, 1 H NMR, 13 C NMR and mass spectrometry techniques. Compounds 11 and 19 have promising as analgesic and antipyretic activities.

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Design, synthesis and preliminary bioactivity studies of imidazolidine-2,4-dione derivatives as Bcl-2 inhibitors

Cited by 20 publications

References 19 publications

Mechanochemical Preparation of 3,5-Disubstituted Hydantoins from Dipeptides and Unsymmetrical Ureas of Amino Acid Derivatives

Mechanochemical Preparation of 3,5-Disubstituted Hydantoins from Dipeptides and Unsymmetrical Ureas of Amino Acid Derivatives

Identification of a Small Molecule Inhibitor of RAD52 by Structure-Based Selection

Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives and their biological evaluation as analgesic, antipyretic and anti-inflammatory agents

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