Novel substituted (Z)-5-((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-diones and 5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones as potent radio-sensitizing agents

Reddy, Y. Thirupathi; Sekhar, Konjeti R.; Sasi, Nidhish; Reddy, P. Narsimha; Freeman, Michael L.; Crooks, Peter A.

doi:10.1016/j.bmcl.2009.11.082

Cited by 36 publications

(31 citation statements)

References 20 publications

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“…Sekhar and colleagues [129], through affinity-based solid-phase resin capture and liquid chromatography/tandem mass spectrometry (LC/MS-MS), have identified NPM1 as the biological target of YTR107, a potent radiosensitizing compound previously identified [130]. YTR107 ((Z) −5 - ((N-benzyl-1H-indol-3-yl) methylene) pyrimidine-2, 4, 6 (1H, 3H, 5H) trione) (Figure 2I) interferes with DNA damage repair mechanisms and is therefore capable of sensitizing to radiation different tumour cell lines, including HT29 colorectal adenocarcinoma cells, D54 glioblastoma cells, PANC1 pancreatic cancer cells, different breast cancer cell models and NSCLC cell lines (Table 1) [127].…”

Section: Ytr107mentioning

confidence: 99%

Molecules that target nucleophosmin for cancer treatment: an update

et al. 2016

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Nucleophosmin is a highly and ubiquitously expressed protein, mainly localized in nucleoli but able to shuttle between nucleus and cytoplasm. Nucleophosmin plays crucial roles in ribosome maturation and export, centrosome duplication, cell cycle progression, histone assembly and response to a variety of stress stimuli. Much interest in this protein has arisen in the past ten years, since the discovery of heterozygous mutations in the terminal exon of the NPM1 gene, which are the most frequent genetic alteration in acute myeloid leukemia. Nucleophosmin is also frequently overexpressed in solid tumours and, in many cases, its overexpression correlates with mitotic index and metastatization. Therefore it is considered as a promising target for the treatment of both haematologic and solid malignancies. NPM1 targeting molecules may suppress different functions of the protein, interfere with its subcellular localization, with its oligomerization properties or drive its degradation. In the recent years, several such molecules have been described and here we review what is currently known about them, their interaction with nucleophosmin and the mechanistic basis of their toxicity. Collectively, these molecules exemplify a number of different strategies that can be adopted to target nucleophosmin and we summarize them at the end of the review.

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Section: Ytr107mentioning

confidence: 99%

Molecules that target nucleophosmin for cancer treatment: an update

et al. 2016

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“…Barbiturates and thiobarbiturates are medicinally imperative class of heterocyclic compounds, Barbiturates exhibites a wide range of biological activities including antibacterial, hypotensive, tranquilizing [30,31], antioxidants [32], anticonvulsant and anesthetic [33], antiepileptic [34], sedatives and hypnotics [33][34][35], anticancer [36,37], immuno-modulating [37], radio-sensitizing [38] and gelatinase inhibitors [39].…”

mentioning

confidence: 99%

Design and synthesis of new barbituric- and thiobarbituric acid derivatives as potent urease inhibitors: Structure activity relationship and molecular modeling studies

Rauf

Shahzad

Bajda

et al. 2015

Bioorganic & Medicinal Chemistry

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“…17 Knoevenagel condensation of the appropriate 2-methyl- N -benzylindole-3-carboxaldehyde with compounds containing active methylene groups, i.e., barbituric acid ( 6a ) or 2-thiobarbituric acid ( 6b ), under reflux in methanol for 4–6 hr afforded the desired 2-methyl-5-((1-benzyl-1 H -indol-3-yl)methylene)-2-oxo-dihydro- pyrimidine-4,6(1 H ,5 H )-triones 7a–7h , or the 2-methyl-5-((1-benzyl-1 H -indol-3-yl)methylene)-2-thioxo-dihydropyrimidine-4,6(1 H , 5 H )-diones ( 7i–7l ) (Scheme 1) in yields ranging from 83–92% and with purities >99 % by elemental analysis. All the synthesized compounds were characterized by 1 H, 13 C NMR spectrometric analysis and CHN combustion analysis.…”

Section: Resultsmentioning

confidence: 99%

1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: Anti-cancer agents that target nucleophosmin 1 (NPM1)

Penthala

Ketkar

Sekhar

et al. 2015

Bioorganic & Medicinal Chemistry

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In the present study, we have designed and synthesized a series of 1-benzyl-2-methyl-3-indolyl methylene barbituric acid analogues (7a–7h) and 1-benzyl-2-methyl-3-indolylmethylene thiobarbituric acid analogues (7i–7l) as nucleophosmin 1 (NPM1) inhibitors and have evaluated them for their anti-cancer activity against a panel of 60 different human cancer cell lines. Among these analogues 7i, 7j, and 7k demonstrated potent growth inhibitory effects in various cancer cell types with GI50 values < 2 μM. Compound 7k exhibited growth inhibitory effects on a sub-panel of six leukemia cell lines with GI50 values in the range 0.22–0.35 μM. Analogue 7i also exhibited GI50 values < 0.35 μM against three of the leukemia cell lines in the sub-panel. Analogues 7i, 7j, 7k and 7l were also evaluated against the mutant NPM1 expressing OCI-AML3 cell line and compounds 7k and 7l were found to cause dose-dependent apoptosis (AP50 =1.75 μM and 3.3 μM respectively). Compound 7k also exhibited potent growth inhibition against a wide variety of solid tumor cell lines: i.e. A498 renal cancer (GI 50 = 0.19 μM), HOP-92 and NCI-H522 lung cancer (GI50 = 0.25 μM), COLO 205 and HCT-116 colon cancer (GI50 = 0.20 and 0.26 μM, respectively), CNS cancer SF-539 (GI50 = 0.22 μM), melanoma MDA-MB-435 (GI50 = 0.22 μM), and breast cancer HS 578T (GI50 = 0.22 μM) cell lines. Molecular docking studies suggest that compounds 7k and 7l exert their anti-leukemic activity by binding to a pocket in the central channel of the NPM1 pentameric structure. These results indicate that the small molecule inhibitors 7i, 7j, 7k, and 7l could be potentially developed into anti-NPM1 drugs for the treatment of a variety of hematologic malignancies and solid tumors. 2009 Elsevier Ltd. All rights reserved.

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Novel substituted (Z)-5-((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-diones and 5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones as potent radio-sensitizing agents

Cited by 36 publications

References 20 publications

Molecules that target nucleophosmin for cancer treatment: an update

Molecules that target nucleophosmin for cancer treatment: an update

Design and synthesis of new barbituric- and thiobarbituric acid derivatives as potent urease inhibitors: Structure activity relationship and molecular modeling studies

1-Benzyl-2-methyl-3-indolylmethylene barbituric acid derivatives: Anti-cancer agents that target nucleophosmin 1 (NPM1)

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