title: Antitumor Activity of a 5-Hydroxy-1H-Pyrrol-2-(5H)-One-Based Synthetic Small Molecule In Vitro and In Vivo.
abstract: Alternative chemo-reagents are in great demand because chemotherapy resistance is one of the major challenges in current cancer treatment. 5-hydoxy-1H-pyrrol-2-(5H)-one is an important N-heterocyclic scaffold that is present in natural products and medicinal chemistry. However, its antitumor activity has not been systematically explored. In this study, we screened a panel of 5-hydoxy-1H-pyrrol-2-(5H)-one derivatives and identified compound 1d as possessing strong anti-proliferative activity in multiple cancer cell lines. Cell cycle analysis revealed that 1d can induce S-phase cell cycle arrest and that HCT116 was sensitive to 1d-induced apoptosis. Further analysis indicated that 1d preferentially induced DNA damage and p53 activation in HCT116 cells and that 1d-induced apoptosis is partly dependent on p53. Furthermore, we showed that 1d significantly suppressed tumor growth in xenograft tumor models in vivo. Taken together, our results suggest that 5-hydoxy-1H-pyrrol-2-(5H)-one derivatives bear potential antitumor activity and that 1d is an effective agent for cancer treatment.
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
authors.forename: Xiaojian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
authors.forename: Luo
authors.initials: L
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
authors.forename: Haili
authors.initials: H
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
authors.forename: Ruiping
authors.initials: R
authors.lastname: She
authors.affiliation: The Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, 100084, China.
authors.forename: Mei-Xiang
authors.initials: MX
authors.lastname: Wang
authors.affiliation: Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China.
authors.forename: De-Xian
authors.initials: DX
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Agrobiotechnology and College of Veterinary Medicine, China Agricultural University, Beijing, 100193, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011758:Pyrroles / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011758:Pyrroles; D011760:Pyrrolidinones; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53