Synthesis of derivatives of NK109, 7-OH Benzo[c]phenanthridine alkaloid, and evaluation of their cytotoxicities and reduction-resistant properties

Nakanishi, Takeshi; Masuda, Akira; Suwa, Masato; Akiyama, Yuji; Hoshino‐Abe, Naoko; Suzuki, Masanobu

doi:10.1016/s0960-894x(00)00467-4

Cited by 103 publications

(47 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To overcome this route of metabolic elimination, NK314 was synthesized by introducing a trimethylene group to N 5 -C 6 of NK109 (ref. 10; Fig. 1A).…”

Section: Introductionmentioning

confidence: 93%

Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials

Guo

Liu

Nishikawa

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

NK314 is a novel synthetic benzo[c]phenanthridine alkaloid that has recently entered clinical trials as an antitumor compound, based on impressive activities in preclinical models. The present investigations were directed at determining the mechanism of action of this agent. NK314 induced significant G 2 cell cycle arrest in several cell lines, independent of p53 status, suggesting the existence of a common mechanism of checkpoint activation. The Chk1-Cdc25C-Cdk1 G 2 checkpoint pathway was activated in response to 100 nmol/L NK314 in ML-1 human acute myeloid leukemia cells. This was associated with the phosphorylation of the histone variant H2AX, an action that was predominant in the G 2 population, suggesting that double-strand DNA breaks caused cells to activate the checkpoint pathway. Double-strand DNA breaks were visualized as chromosomal aberrations when the G 2 checkpoint was abrogated by 7-hydroxystaurosporine. In vitro assays showed that NK314 inhibited the ability of topoisomerase IIA to relax supercoiled DNA and trapped topoisomerase IIA in its cleavage complex intermediate. CEM/VM1 cells, which are resistant to etoposide due to mutations in topoisomerase IIA, were cross-resistant to NK314. However, CEM/C2 cells, which are resistant to camptothecin due to mutations in topoisomerase I, retained sensitivity. These findings support the conclusion that the major mechanism of NK314 is to inhibit topoisomerase IIA, an action that leads to the generation of double-strand DNA breaks, which activate the G 2 DNA damage checkpoint pathway. [Mol Cancer Ther 2007;6(5):1501 -8]

show abstract

“…To overcome this route of metabolic elimination, NK314 was synthesized by introducing a trimethylene group to N 5 -C 6 of NK109 (ref. 10; Fig. 1A).…”

Section: Introductionmentioning

confidence: 93%

Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials

Guo

Liu

Nishikawa

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…Recently, compounds with phenathroline skeleton have been synthesized and biologically evaluated [11][12][13][14][15] as analogues of benzo[c]phenanthridine alkaloids (e.g. nitidine, fagaronine, sanguinarine) that attracted attention due to their interesting biological properties [16][17][18][19] . Compared to 1,10-phenanthroline that has been widely studied both for synthesis and applications, 4,7-phenanthroline received much less interest due to difficulties in its synthesis.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, structure, antimycobacterial and anticancer evaluation of new pyrrolo-phenanthroline derivatives

Matarneh

Mangalagiu

Shova³

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

A study concerning design, synthesis, structure and in vitro antimycobacterial and anticancer evaluation of new fused derivatives with pyrrolo[2,1-c] [4,7]phenanthroline skeleton is described. The strategy adopted for synthesis involves a [3 + 2] dipolar cycloaddition of several in situ generated 4,7-phenanthrolin-4-ium ylides to different substituted alkynes and alkenes. Stereo-and regiochemistry of cycloaddition reactions were discussed. The structure of the new compounds was proven unambiguously, single-crystal X-ray diffraction studies including. The antimycobacterial and anticancer activity of a selection of new synthesized compounds was evaluated against Mycobacterium tuberculosis H37Rv under aerobic conditions and 60 human tumour cell line panel, respectively. Five of the tested compounds possess a moderate antimycobacterial activity, while two of the compounds have a significant antitumor activity against renal cancer and breast cancer.

show abstract

“…No activity was observed when both methylenedioxy moieties in 2 were converted to methoxy groups like 5 (entry 4 in Table 1). 2-(3,4-Dimethoxyphenyl)-6,7-methylenedioxy-1,4-naphthoquinone-1-oxime methyl ether (6) 2-Methoxycarbonyl-3,4-dimethoxyphenyl CH 2 (ϩ) a) Evaluated by methylene blue staining method using HeLa S3 cell. IC 50 (mg/ml) was estimated using Litchfield and Wilcoxon method and the following symbols are used as criteria: (ϩ)ϭϽ0.1 mg/ml; (Ϯ)ϭ0.1-1.0 mg/ml; (Ϫ)ϭϾ1.0 mg/ml.…”

Section: Resultsmentioning

confidence: 99%

“…, R 6 , R 7 ϭOR) bases dependent upon the number of oxygen functions in their molecules. 1) They have been attracted much attention due to their valuable pharmacological activities, [1][2][3] especially the anti-tumor activity of O 4 -type alkaloids such as nitidine 4) (1a), fagaronine 4) (1b), sanguinarine 5) (1c), and NK109 6) (1d).…”

mentioning

confidence: 99%

2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ethers: Their Cytotoxic Activity

Ishikawa

Saito

Kurosawa

et al. 2011

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

Synthesis of derivatives of NK109, 7-OH Benzo[c]phenanthridine alkaloid, and evaluation of their cytotoxicities and reduction-resistant properties

Cited by 103 publications

References 10 publications

Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials

Inhibition of topoisomerase IIα and G2 cell cycle arrest by NK314, a novel benzo[c]phenanthridine currently in clinical trials

Synthesis, structure, antimycobacterial and anticancer evaluation of new pyrrolo-phenanthroline derivatives

2-Aryl-1,4-naphthoquinone-1-oxime Methyl Ethers: Their Cytotoxic Activity

Contact Info

Product

Resources

About