Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20S)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives
| Autor: | Ruijuan Yin, Xiaomin Zhang, Guanzhao Wu, Qi Xin, Tao Jiang, Jing Li, Yixuan Zhang, Xiufen Dai |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male FL118 Transcription Genetic Apoptosis Camptothecin Analogue lcsh:Chemistry Mice 0302 clinical medicine Neoplasms Cytotoxic T cell lcsh:QH301-705.5 Spectroscopy Mice Inbred BALB C Chemistry Indolizines General Medicine Hep G2 Cells Computer Science Applications XIAP 030220 oncology & carcinogenesis medicine.drug molecular design Mice Nude Antineoplastic Agents HL-60 Cells Irinotecan Catalysis Article Inorganic Chemistry 03 medical and health sciences In vivo Cell Line Tumor Survivin medicine Animals Humans Benzodioxoles Physical and Theoretical Chemistry Molecular Biology 12e Cell Proliferation A549 cell Cell growth Organic Chemistry Cell Cycle Checkpoints Camptothecin derivatives anticancer agent 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 A549 Cells Cancer research K562 Cells Camptothecin |
| Zdroj: | International Journal of Molecular Sciences Volume 21 Issue 22 International Journal of Molecular Sciences, Vol 21, Iss 8495, p 8495 (2020) |
| ISSN: | 1422-0067 |
| Popis: | A novel camptothecin analogue, (20S)-10,11-methylenedioxy-camptothecin (FL118), has been proven to show significant antitumor efficacy for a wide variety of solid tumors. However, the further development of FL118 is severely hindered due to its extremely poor water solubility and adverse side effects. Here, two series of novel 20-substituted (20S)-10,11-methylenedioxy-camptothecin coupled with 5-substituted uracils and other heterocyclic rings through glycine were synthesized. All the derivatives showed superior cytotoxic activities in vitro with IC50 values in the nanomolar range. Among them, 12e displayed higher cytotoxic activities in several cancer cell lines with better water solubility than FL118. Our results further showed that, like FL118, 12e inhibited cell proliferation resulting from cell cycle arrest and apoptosis by blocking the anti-apoptotic gene transcription of survivin, Mcl-1, Bcl-2, and XIAP in both A549 cells and NCI-H446 cells. Furthermore, 12e did not show any inhibitory activity on Topo I, which is involved in hematopoietic toxicity. In vivo, 12e showed similar antitumor efficacy to FL118 but lower toxicity. Our findings indicate that 12e is a promising therapeutic agent for cancer treatment, and the core structure of FL118 represents a promising platform to generate novel FL118-based antitumor drugs. |
| Databáze: | OpenAIRE |
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