ABSTRACT
Herein, a series of 11- or 12-substituted benzophenanthridinone derivatives was designed and synthesized for the discovery of dual topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors. Enzyme-based assays indicated that two compounds 12 and 38 showed high TOP1 inhibitory potency (+++), and four compounds 35, 37, 39 and 43 showed good TDP1 inhibition with IC50 values ranging from 10 to 18â µM. 38 could induce cellular TOP1cc formation, resulting in the highest cytotoxicity against HCT-116â cells (0.25â µM). The most potent TDP1 inhibitor 43 (10â µM) could induce cellular TDP1cc formation and enhance topotecan-induced DNA damage and showed strong synergistic cytotoxicity with topotecan in both MCF-7 and MCF-7/TDP1â cells.
Subject(s)
DNA Topoisomerases, Type I , Phosphodiesterase Inhibitors , Humans , Phosphodiesterase Inhibitors/pharmacology , DNA Topoisomerases, Type I/metabolism , Topotecan , Phosphoric Diester Hydrolases/metabolism , Topoisomerase I Inhibitors/pharmacologyABSTRACT
A series of new thiazole-based stilbene analogs were designed, synthesized and evaluated for DNA topoisomerase IB (Top1) inhibitory activity. Top1-mediated relaxation assays showed that the synthesized compounds possessed variable Top1 inhibitory activity. Among them, (E)-2-(3-methylstyryl)-4-(4-fluorophenyl)thiazole (8) acted as a potent Top1 inhibitor with high Top1 inhibition of ++++ which is comparable to that of CPT. A possible binding mode of compound 8 with Top1-DNA complex was further provided by molecular docking. An MTT assay against human breast cancer (MCF-7) and human colon cancer (HCT116) cell lines revealed that the majority of these compounds showed high cytotoxicity, with IC50 values at micromolar concentrations. Compounds 8 and (E)-2-(4-tert-butylstyryl)-4-(4-fluorophenyl)thiazole (11) exhibited the most potent cytotoxicity with IC50 values of 0.78 and 0.62 µM against MCF-7 and HCT116, respectively. Moreover, the preliminary structure-activity relationships of thiazole-based stilbene analogs was also discussed.
Subject(s)
Antineoplastic Agents/chemistry , Stilbenes/chemistry , Thiazoles/chemistry , Topoisomerase Inhibitors/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Design , HCT116 Cells , Humans , MCF-7 Cells , Molecular Docking Simulation , Neoplasms/drug therapy , Stilbenes/chemical synthesis , Stilbenes/pharmacology , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Topoisomerase Inhibitors/chemical synthesis , Topoisomerase Inhibitors/pharmacologyABSTRACT
As a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1) removes topoisomerase IB (TOP1)-mediated DNA protein cross-links. Inhibiting TDP1 can potentiate the cytotoxicity of TOP1 inhibitors and overcome cancer cell resistance to TOP1 inhibitors. On the basis of our previous study, herein we report the synthesis of benzophenanthridinone derivatives as TOP1 and TDP1 inhibitors. Seven compounds (C2, C4, C5, C7, C8, C12, and C14) showed a robust TOP1 inhibitory activity (+++ or ++++), and four compounds (A13, C12, C13, and C26) showed a TDP1 inhibition (half-maximal inhibitory concentration values of 15 or 19 µM). We also show that the dual TOP1 and TDP1 inhibitor C12 induces both cellular TOP1cc, TDP1cc formation and DNA damage, resulting in cancer cell apoptosis at a sub-micromolar concentration. In addition, C12 showed an enhanced activity in drug-resistant MCF-7/TDP1 cancer cells and was synergistic with topotecan in both MCF-7 and MCF-7/TDP1 cells.
Subject(s)
Benzophenanthridines/chemistry , DNA Topoisomerases, Type I/metabolism , Phosphodiesterase Inhibitors/chemical synthesis , Phosphoric Diester Hydrolases/metabolism , Topoisomerase I Inhibitors/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Benzophenanthridines/metabolism , Benzophenanthridines/pharmacology , Benzophenanthridines/therapeutic use , Binding Sites , Cell Line, Tumor , Cell Survival/drug effects , DNA Damage/drug effects , DNA Topoisomerases, Type I/chemistry , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Humans , Molecular Dynamics Simulation , Neoplasms/drug therapy , Phosphodiesterase Inhibitors/metabolism , Phosphodiesterase Inhibitors/pharmacology , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/chemistry , Structure-Activity Relationship , Topoisomerase I Inhibitors/metabolism , Topoisomerase I Inhibitors/pharmacology , Topoisomerase I Inhibitors/therapeutic useABSTRACT
Based on our previous study on the development of the furoquinolinedione and isoxazoloquinolinedione TDP2 inhibitors, the further structure-activity relationship (SAR) was studied in this work. A series of furoquinolinedione and isoxazoloquinolinedione derivatives were synthesized and tested for enzyme inhibitions. Enzyme-based assays indicated that isoxazoloquinolinedione derivatives selectively showed high TDP2 inhibitory activity at sub-micromolar range, as well as furoquinolinedione derivatives at low micromolar range. The most potent 3-(3,4-dimethoxyphenyl)isoxazolo[4,5-g]quinoline-4,9-dione (70) showed TDP2 inhibitory activity with IC50 of 0.46 ± 0.15 µM. This work will facilitate future efforts for the discovery of isoxazoloquinolinedione TDP2 selective inhibitors.
Subject(s)
DNA-Binding Proteins/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacology , Quinolones/pharmacology , Animals , DNA-Binding Proteins/metabolism , Dose-Response Relationship, Drug , Humans , Mice , Models, Molecular , Molecular Structure , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , Phosphoric Diester Hydrolases/metabolism , Quinolones/chemical synthesis , Quinolones/chemistry , Structure-Activity RelationshipABSTRACT
Based on DNA topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibition of the ethanol extract of the roots of Isodon ternifolius (D. Don) Kudo (Labiatae), its secondary metabolites has been studied. Two new compounds, an ent-abietane diterpenoid isodopene A (1) and a 2,3-seco-triterpene isodopene B (13), along with 25 known compounds were isolated. Their structures were elucidated by spectroscopic analysis and theoretical calculations. The enzyme-based assays indicated that 1 and 13 showed strong (+++) and moderate (++) TOP1 inhibition, respectively. Two chalcone derivatives 11 and 12 were firstly found as dual TDP1 and TOP1 natural inhibitors, and showed synergistic effect with the clinical TOP1 inhibitors topotecan in MCF-7 cells. Compounds 8, 16, and 22 acted as TOP1 catalytic inhibitors with equipotent TOP1 inhibition to camptothecin (++++). Compounds 7 and 8 exhibited significant cytotoxicity against MCF-7, A549, and HCT116 cells with GI50 values in the range of 2.2-4.8 µM. This work would provide valuable information that secondary metabolites from I. ternifolius could be developed as anticancer agents.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , DNA Topoisomerases, Type I/metabolism , Isodon/chemistry , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Topoisomerase I Inhibitors/pharmacology , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Cattle , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Isodon/metabolism , Molecular Structure , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/isolation & purification , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/isolation & purification , Tumor Cells, CulturedABSTRACT
A series of novel indole-pyrazoline hybrid derivatives were designed, synthesized, and evaluated for topoisomerase 1 (Top1) inhibitory activity. Top1-mediated relaxation assays showed that our synthesized compounds had variable Top1 inhibitory activity. Among these compounds, 3-(5-(naphthalen-1-yl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)-1-(phenylsulfonyl)-1H-indole (6n) was found to be a strong Top1 inhibitor with better inhibitory activity than CPT and hit compounds. Our further experiments rationalized the mode of action for this new type of inhibitors, which showed no significant binding to supercoiled DNA.
Subject(s)
DNA Topoisomerases, Type I/chemistry , Indoles/chemistry , Pyrazoles/chemistry , Topoisomerase I Inhibitors/chemical synthesis , Binding Sites , DNA Topoisomerases, Type I/metabolism , DNA, Superhelical/chemistry , DNA, Superhelical/metabolism , Drug Design , Humans , Molecular Dynamics Simulation , Structure-Activity Relationship , Topoisomerase I Inhibitors/metabolismABSTRACT
DNA topoisomerase IB (TOP1) regulates DNA topological structure in many cellular metabolic processes and is a validated target for development of antitumor agents. Our previous study revealed that the benzophenanthridone scaffold is a novel chemotype for the discovery of TOP1 inhibitors. In this work, a series of novel 5-aminoethyl substituted benzophenanthridone derivatives have been synthesized and evaluated for TOP1 inhibition and cytotoxicity. Compound 12 exhibits the most potent TOP1 inhibition (+++) and cytotoxicity in human cancer cell lines with GI50 values at nanomolar concentration range. 12 induces the cellular TOP1cc formation and DNA damage, resulting in HCT116â¯cell apoptosis. The pharmacokinetics, acute toxicity and antitumor efficiency in vivo of 12 were also studied.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Benzophenanthridines/pharmacokinetics , Topoisomerase I Inhibitors/pharmacokinetics , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Benzophenanthridines/chemical synthesis , Benzophenanthridines/metabolism , Benzophenanthridines/therapeutic use , Breast Neoplasms/drug therapy , Cell Line, Tumor , DNA Damage/drug effects , DNA Topoisomerases, Type I/chemistry , DNA Topoisomerases, Type I/metabolism , Drug Screening Assays, Antitumor , Humans , Mice, Nude , Molecular Docking Simulation , Molecular Structure , Protein Binding , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/metabolism , Topoisomerase I Inhibitors/therapeutic use , Xenograft Model Antitumor AssaysABSTRACT
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a recently discovered enzyme repairing DNA lesions resulting from stalled topoisomerase IB (TOP1)-DNA covalent complex. Inhibiting TDP1 in conjunction with TOP1 inhibitors can boost the action of the latter. Herein, we report the discovery of the natural product oxynitidine scaffold as a novel chemotype for the development of TOP1 and TDP1 inhibitors. Three kinds of analogues, benzophenanthridinone, dihydrobenzophenanthridine, and benzophenanthridine derivatives, were synthesized and evaluated for both TOP1 and TDP1 inhibition and cytotoxicity. Analogue 19a showed high TOP1 inhibition (+++) and induced the formation of cellular TOP1cc and DNA damage, resulting in cancer cells apoptosis at nanomolar concentration range. In vivo studies indicated that 19a exhibits antitumor efficiency in HCT116 xenograft model. 41a exhibited additional TDP1 inhibition with IC50 value of 7 µM and synergistic effect with camptothecin in MCF-7 cells. This work will facilitate future efforts for the discovery of natural product-based TOP1 and TDP1 inhibitors.