Design, Synthesis, and Cytotoxicity of Indolizinoquinoxaline-5,12-dione Derivatives, Novel DNA Topoisomerase IB Inhibitors

Shen, De-Qing; Wu, Ning; Li, Yanping; Wu, Zuping; Zhang, Hongbin; Huang, Zhi‐Shu; Gu, Lian‐Quan; An, Lin‐Kun

doi:10.1071/ch09580

Cited by 7 publications

(2 citation statements)

References 21 publications

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“…Structure activity relationships (SAR) evaluation indicated that the nitrogen atomin the A ring played an important role for cytotoxicity. N,N-syn isomer exhibited higher cytotoxicity and Top1 inhibitory activity than N,N-trans isomer or the corresponding derivatives with two nitrogen atoms in the A ring, such as indolizinophthalazinediones and indolizinoquinoxalinediones [10,11]. This led us to propose that the aminoalkyl side chain enhanced the cytotoxicity and Top1 inhibitory activity of the parent molecule possibly because the cationic side chain under physiological condition could improve cellular uptake and interactions with the Top1-DNA complex [12-15].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of 6-substituted indolizinoquinolinediones as catalytic DNA topoisomerase I inhibitors

Zhang

et al. 2015

European Journal of Medicinal Chemistry

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In our previous work, indolizinoquinolinedione derivative 1 was identified as a Top1 catalytic inhibitor. Herein, a series of 6-substituted indolizinoquinolinedione derivatives were synthesized through modification of the parent compound 1. Top1 cleavage and relaxation assays indicate that none of these novel compounds act as classical Top1 poison, and that the compounds with alkylamino terminus at C-6 side chain, including 8, 11–16, 18–21, 25, 26 and 28–30, are the most potent Top1 catalytic inhibitors. Top1-mediated unwinding assay demonstrated that 14, 22 and 26 were Top1 catalytic inhibitors without Top1-mediated unwinding effect. Moreover, MTT results showed that compounds 26, 28–30 exhibit significant cytotoxicity against human leukemia HL-60 cells, and that compound 26 exerts potent cytotoxicity against A549 lung cancer cells at nanomolar range.

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Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of 6-substituted indolizinoquinolinediones as catalytic DNA topoisomerase I inhibitors

Zhang

et al. 2015

European Journal of Medicinal Chemistry

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“…The MTT assay showed that compound 131 containing pyrazine showed significant inhibitory effects on HCT116, CCRF-CEM, A549, Huh7, and DU-145 cell lines, with IC50 values ranging from 1.61 to 13.15 µM[136].Shen et al designed and synthesized a series of new Indolizinoquinoxalin-5,12-dione derivatives. Compounds 132-134 showed significant inhibitory effects on the growth of four human tumor cell lines (GLC-82, NCI-H460, MCF-7, and MCF-ARD), with IC50 values ranging from 0.20 to 16.46 µM[137].Devi et al synthesized a series of new anthraquinone-based copper (II) complexes. Nuclear targeting complex 135 showed significant cytotoxicity to cancer cells in visible…”

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Natural Products–Pyrazine Hybrids: A Review of Developments in Medicinal Chemistry

Chen,

Guo,

Quan

et al. 2023

Molecules

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Pyrazine is a six-membered heterocyclic ring containing nitrogen, and many of its derivatives are biologically active compounds. References have been downloaded through Web of Science, PubMed, Science Direct, and SciFinder Scholar. The structure, biological activity, and mechanism of natural product derivatives containing pyrazine fragments reported from 2000 to September 2023 were reviewed. Publications reporting only the chemistry of pyrazine derivatives are beyond the scope of this review and have not been included. The results of research work show that pyrazine-modified natural product derivatives have a wide range of biological activities, including anti-inflammatory, anticancer, antibacterial, antiparasitic, and antioxidant activities. Many of these derivatives exhibit stronger pharmacodynamic activity and less toxicity than their parent compounds. This review has a certain reference value for the development of heterocyclic compounds, especially pyrazine natural product derivatives.

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Switching Futile para‐Quinone to Efficient Reactive Oxygen Species Generator: Ubiquitin‐Specific Protease‐2 Inhibition, Electrocatalysis, and Quantification

et al. 2017

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Understanding the correlation between structural features of small-molecule drugs and their mode of action is a fascinating topic and crucial for the drug-discovery process. However, in many cases, knowledge of the exact parameters that dictate the mode of action is still lacking. Following a large screening for ubiquitin specific protease 2 (USP2) inhibition, an effective para-quinone-based inhibitor with an unclear mode of action was identified. To gain a deeper understanding of the mechanism of inhibition, a set of para-quinones were prepared and studied for USP2 inhibition, electrocatalysis, and reactive oxygen species (ROS) quantification. The excellent correlation obtained from the above-mentioned studies disclosed a distinct pattern of "N-C=O-N" in the bicyclic para-quinones to be a crucial factor for ROS generation, and demonstrated that minor changes in such a skeleton drastically altered the ROS-generating ability. The knowledge acquired herein would serve as an important guideline for future medicinal chemistry optimization of related structures to select the preferred mode of action.

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Design, Synthesis, and Cytotoxicity of Indolizinoquinoxaline-5,12-dione Derivatives, Novel DNA Topoisomerase IB Inhibitors

Cited by 7 publications

References 21 publications

Synthesis and biological evaluation of 6-substituted indolizinoquinolinediones as catalytic DNA topoisomerase I inhibitors

Synthesis and biological evaluation of 6-substituted indolizinoquinolinediones as catalytic DNA topoisomerase I inhibitors

Natural Products–Pyrazine Hybrids: A Review of Developments in Medicinal Chemistry

Switching Futile para‐Quinone to Efficient Reactive Oxygen Species Generator: Ubiquitin‐Specific Protease‐2 Inhibition, Electrocatalysis, and Quantification

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