Article
Chemistry, Medicinal
Shengtao Xu, Hong Yao, Yangyi Qiu, Manzhen Zhou, Dahong Li, Liang Wu, Dong-Hua Yang, Zhe-Sheng Chen, Jinyi Xu
Summary: The study identified a novel compound (7f) based on Evodiamine as a topoisomerase I inhibitor, showing potent antitumor activity against triple-negative breast cancer by inducing DNA damage and forming irreversible DNA-protein complexes.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Min Li, Linxu Wang, Yingjie Wei, Wenyan Wang, Zongliang Liu, Aixia Zuo, Wanhui Liu, Jingwei Tian, Hongbo Wang
Summary: In this study, a novel Topo I inhibitor, PCC0208037, was synthesized and demonstrated to have anti-tumor activity by suppressing colorectal cancer cell proliferation and inducing cell cycle arrest. It showed comparable or slightly better anti-tumor activity than the standard treatment CPT-11, with less tissue damage and transient impact on food intake and body weight loss.
Article
Chemistry, Medicinal
Ananda Guha Majumdar, Shikha Shree, Amit Das, Binita K. Kumar, Papiya Dey, Mahesh Subramanian, Birija Sankar Patro
Summary: In this study, a library of candidate dual inhibitors for PARP1 and TOP1 was designed, synthesized and evaluated. DiPT-4 showed promising cytotoxicity against multiple cancers with limited toxicities towards normal cells. Mechanistically, DiPT-4 inhibited the activity of TOP1 and PARP1, inducing DNA double strand breaks, cell cycle arrest and apoptosis in cancer cells. Moreover, DiPT-4 inhibited the PARylation of TOP1cc, leading to long lived TOP1cc with a slower degradation kinetics. These findings suggest that DiPT-4 may serve as a promising dual inhibitor of TOP1 and PARP1 in clinical settings.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Endika Martin-Encinas, Asier Selas, Francisco Palacios, Concepcion Alonso
Summary: This review article provides an overview of the development of selective topoisomerase I inhibitors for cancer therapy, focusing on approved compounds, combination therapies, drawbacks, and future research directions. Studies on improving bioavailability and pharmacokinetics of potent synthetic derivatives are important for addressing the limitations of current clinically approved inhibitors.
EXPERT OPINION ON DRUG DISCOVERY
(2022)
Article
Chemistry, Medicinal
Xiaoling Hu, Junfang Li, Honghua Zhang, Quanwei Yu, Yuying Wang, Xuelin Li, Lin Long, Weifan Jiang, Zhen Wang
Summary: A series of novel tolfenamic acid derivatives were designed and synthesized, among which W10 was identified as a potent dual-target inhibitor with improved solubility and exhibiting promising antitumor effects and pro-apoptosis activity, making it a potential chemotherapeutic candidate for colon cancer treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biology
Masahiro Nishida, Takeshi Terabayashi, Shigeru Matsuoka, Tomoko Okuma, Sawako Adachi, Tadashi Tomo, Masanori Kawano, Kazuhiro Tanaka, Hiroshi Tsumura, Hirofumi Anai, Toshimasa Ishizaki, Yoshihiro Nishida, Katsuhiro Hanada
Summary: This study characterized the effect of a non-camptothecin inhibitor, Genz-644282 (Genz), on TOP1 inhibition. The results showed that Genz exhibited potent activity against camptothecin-resistant cells through double-strand break induced cytotoxicity. The study also revealed the mechanism of action of Genz and the crucial amino acid residues involved in its binding with TOP1.
COMMUNICATIONS BIOLOGY
(2022)
Article
Chemistry, Medicinal
Ryad M. Noha, Mohammed K. Abdelhameid, M. Mohsen Ismail, Manal R. Mohammed, Elmeligie Salwa
Summary: A series of benzimidazole derivatives with methoxylated aryl groups were designed and synthesized as potential cytotoxic agents. Some compounds showed strong inhibitory activity on tumor cells in vitro and had effects on key processes such as cell cycle and apoptosis.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Kyung-Hwa Jeon, Seojeong Park, Hae Jin Jang, Soo-Yeon Hwang, Aarajana Shrestha, Eung-Seok Lee, Youngjoo Kwon
Summary: The study revealed that AK-I-190, a novel topoisomerase II inhibitor, exerts potent inhibitory activity by intercalating into DNA without stabilizing the DNA-enzyme cleavage complex, resulting in less DNA toxicity compared to etoposide. AK-I-190 induces G1 arrest and effectively inhibits cell proliferation and colony formation in an androgen receptor-negative CRPC cell line, indicating the potential clinical relevance of topoisomerase II catalytic inhibitors in treating this type of prostate cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Xuemei Deng, Tian Luo, Xi Zhang, Yuehua Li, Liming Xie, Weifan Jiang, Linyi Liu, Zhen Wang
Summary: Through the redesign of 3-aryl isoquinoline alkaloids, we discovered compound 7 with excellent activity and research depth, which exhibits dual inhibitory effects on topoisomerase I and II, and shows potential in inhibiting cell proliferation and inducing apoptosis.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Louise Conilh, Guy Fournet, Eric Fourmaux, Angelique Murcia, Eva-Laure Matera, Benoit Joseph, Charles Dumontet, Warren Viricel
Summary: A novel HER2-targeting antibody-drug conjugate using the topoisomerase I inhibitor exatecan and a polysarcosine drug-linker platform was developed, showing potent anti-tumor activity and potential efficacy against resistant tumors.
Article
Biochemistry & Molecular Biology
Francesco Madeddu, Jessica Di Martino, Michele Pieroni, Davide Del Buono, Paolo Bottoni, Lorenzo Botta, Tiziana Castrignano, Raffaele Saladino
Summary: This study used computational methods to analyze the interaction between two new antitumor drug molecules and hTop1p enzyme. The results showed that these two compounds have a similar inhibitory mechanism to CPT and may have potential antitumor activity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Inken Floerkemeier, Julia S. Hillmann, Joerg P. Weimer, Jonas Hildebrandt, Nina Hedemann, Christoph Rogmans, Astrid Dempfle, Norbert Arnold, Bernd Clement, Dirk O. Bauerschlag
Summary: Although ovarian cancer is rare, it is the fifth leading cause of cancer death among women. This study explores the potential benefits of combining P8-D6, a dual topoisomerase inhibitor, with olaparib, a PARP inhibitor targeting DNA damage repair, in the treatment of ovarian cancer. The combination therapy shows promise in reducing the required dosage while maintaining efficacy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Medicinal
Ruiming Zhang, Yi Luo, Chenghao Du, Ling Wu, Yankang Wang, Yuanduan Chen, Shouqian Li, Xin Jiang, Yongmei Xie
Summary: A novel SN38-glucose conjugate (FSY04) was synthesized to improve the water solubility and bioavailability of SN38. In vitro studies showed that FSY04 had stronger inhibitory effects on colorectal cancer cell lines compared to CPT-11, with lower cytotoxicity against normal cells. FSY04 also showed superior activity in inducing apoptosis, inhibiting migration, and invasion. In vivo experiments demonstrated that FSY04 had better tumor growth inhibition in a xenograft tumor model compared to CPT-11. These findings suggest that FSY04 is a promising agent for CRC therapy.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Yan-Wen Mai, Cheng-Cheng Liang, Jie-Bin Ou, Hua-Ting Xie, Shuo-Bin Chen, Du-Chao Zhou, Pei-Fen Yao, Zhi-Shu Huang, Honggen Wang, Shi-Liang Huang
Summary: The novel compound MSN54 exhibited significant cytotoxicity against various human tumor cell lines in vitro, with particularly strong potency against cells resistant to Topo II poisons. It acts as a specific non-intercalative catalytic inhibitor of Topo II alpha and showed promising antitumor efficacy with low toxicity in animal models, making it a potential candidate for novel antitumor agents.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Mahsa Shahriari, Seyed Mohammad Taghdisi, Khalil Abnous, Mohammad Ramezani, Mona Alibolandi
Summary: The study synthesized an amphiphilic copolymer, self-assembled into polymersomes for targeted co-encapsulation of DOX and CPT, demonstrating sustained release and synergistic cytotoxicity against cancer cells. Aptamer conjugation further enhanced cytotoxicity and tumor-specific accumulation in vivo, suggesting a promising combinatorial delivery platform for non-small cell lung cancer therapy.
JOURNAL OF CONTROLLED RELEASE
(2021)