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

2010 ◽  
Vol 63 (7) ◽  
pp. 1116 ◽  
Author(s):  
De-Qing Shen ◽  
Ning Wu ◽  
Yan-Ping Li ◽  
Zu-Ping Wu ◽  
Hong-Bin Zhang ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Carcinoma Cell ◽  
Large Cell ◽  
Cancer Drug ◽  
Significant Activity ◽  
Dna Topoisomerase ◽  
Design Synthesis ◽  
Cell Lung Carcinoma ◽  
Heterocyclization Reaction ◽  
Topoisomerase Ib

A series of new indolizinoquinoxaline-5,12-dione derivatives were designed and synthesized via a heterocyclization reaction of 6,7-dichloroquinoxaline-5,8-dione with active methylene reagents and pyridine derivatives. The synthesized compounds exhibited significant activity to inhibit the growth of four human tumour cell lines, including lung adenocarcinoma cell, large-cell lung carcinoma cell, breast carcinoma cell, and ardriamycin-resistant breast carcinoma cell at micromolar range. These compounds were also investigated for their inhibition to DNA topoisomerase IB activity. The results indicated that the indolizinoquinoxaline-5,12-dione structure might be a potential pharmacophore in anti-cancer drug design.

Design, Synthesis and Antiplasmodial Evaluation of Sulfoximine-triazole Hybrids as Potential Antimalarial Prototypes

2019 ◽  
Vol 15 (6) ◽  
pp. 685-692 ◽  
Author(s):  
Tommy F. Mabasa ◽  
Babatunde Awe ◽  
Dustin Laming ◽  
Henok H. Kinfe
Keyword(s):  
Alkyl Substituent ◽  
Antimalarial Drugs ◽  
Significant Activity ◽  
Design Synthesis ◽  
Antimalarial Agents ◽  
Falciparum Strain ◽  
Physiological Properties ◽  
Resistant Strains ◽  
Cytotoxicity Activities ◽  
Drug Resistant Strains

Background:Malaria, caused by the deadly Plasmodium falciparum strain, claims the lives of millions of people annually. The emergence of drug-resistant strains of P. falciparum to the artemisinin-based combination therapy (ACT), the last line of defense against malaria, is worrisome and urges for the development of new chemo-types with a new mode of action. In the search of new antimalarial agents, hybrids of triazoles and other known antimalarial drugs have been reported to possess better activity than either of the parent compounds administered individually. Despite their better activity, no hybrid antimalarial drugs have been developed so far.Objective:In the hope of developing new antimalarial prototypes, we propose the design, synthesis and antimalarial evaluation of novel sulfoximine-triazole hybrids owing to their interesting biological and physiological properties.Methods:The sulfoximine part of the hybrid will be synthesized via imidation of the corresponding sulfoxide. Propargylation of the NH moiety of the sulfoximine followed by copper-catalyzed click chemistry with benzyl azide was envisaged to provide the target sulfoximine-triazole hybrids.Results:Five novel sulfoximine-triazole hybrids possessing various substituents on the sulfoximine moiety have been successfully synthesized and evaluated for their antiplasmodial and cytotoxicity activities. The results revealed that the co-presence of the sulfoximine and triazole moieties along with a lipophilic alkyl substituent on the sulfur atom impart significant activity.Conclusion:Sulfoximine-triazole hybrids could be used as a prototype for the synthesis of new derivatives with better antiplasmodial activities.

scholarly journals In Vitro and In Silico Characterization of an Antimalarial Compound with Antitumor Activity Targeting Human DNA Topoisomerase IB

2021 ◽  
Vol 22 (14) ◽  
pp. 7455
Author(s):  
Bini Chhetri Soren ◽  
Jagadish Babu Dasari ◽  
Alessio Ottaviani ◽  
Beatrice Messina ◽  
Giada Andreotti ◽  
...  
Keyword(s):  
Enzyme Reaction ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Topoisomerase Ib ◽  
Topological State ◽  
Cleavage Step ◽  
Dynamics Simulations ◽  
In Silico Characterization ◽  
Dna Complex

Human DNA topoisomerase IB controls the topological state of supercoiled DNA through a complex catalytic cycle that consists of cleavage and religation reactions, allowing the progression of fundamental DNA metabolism. The catalytic steps of human DNA topoisomerase IB were analyzed in the presence of a drug, obtained by the open-access drug bank Medicines for Malaria Venture. The experiments indicate that the compound strongly and irreversibly inhibits the cleavage step of the enzyme reaction and reduces the cell viability of three different cancer cell lines. Molecular docking and molecular dynamics simulations suggest that the drug binds to the human DNA topoisomerase IB-DNA complex sitting inside the catalytic site of the enzyme, providing a molecular explanation for the cleavage-inhibition effect. For all these reasons, the aforementioned drug could be a possible lead compound for the development of an efficient anti-tumor molecule targeting human DNA topoisomerase IB.

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