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  3. F10, a new camptothecin derivative, was identified as a new orally-bioavailable, potent antitumor agent

F10, a new camptothecin derivative, was identified as a new orally-bioavailable, potent antitumor agent

  • Eur J Med Chem. 2020 Sep 15;202:112528. doi: 10.1016/j.ejmech.2020.112528.
Shu Fan 1,  Yong-Xiao Cao 2,  Guang-Yan Li 3,  Hao Lei 1,  Mawusse K I Attiogbe 2,  Jing-Chun Yao 3,  Xue-Yan Yang 1,  Yan-Jie Liu 1,  Yuan-Yuan Hei 1,  Hao Zhang 4,  Lei Cao 5,  Xiao-Yan Zhang 1,  Shuai-Shuai Du 2,  Gui-Min Zhang 3,  San-Qi Zhang 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
  • 2 Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
  • 3 State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co., LTD, Linyi, Shandong, 276000, PR China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China; State Key Laboratory of Generic Manufacture Technology of Chinese Traditional Medicine, Lunan Pharmaceutical Group Co., LTD, Linyi, Shandong, 276000, PR China.
  • 5 Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China. Electronic address: leicao@xjtu.edu.cn.
  • 6 Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China. Electronic address: sqzhang@xjtu.edu.cn.
PMID: 32650182 DOI: 10.1016/j.ejmech.2020.112528
Abstract

Topoisomerases are interesting targets for drug discovery. In the present study, we attached saturated carbon atoms to the 10-position of camptothecin and synthesized 10 new camptothecin derivatives from 10-HCPT or SN-38. The activities of new compounds were evaluated both in vitro and in vivo. The most promising compound F10, 7-ethyl-10-(2-oxo-2-(piperidin-1-yl)ethoxy)camptothecin, inhibited Cancer cells growth with the IC50 of 0.002, 0.003, 0.011 and 0.081 μM on Raji, HCT116, A549 and Lovo cells, respectively. Meanwhile, oral administration of F10 remarkably suppressed the HCT116-xenograft tumor growth in the nude-mice model at the dosage of 0.5, 2.0 and 8.0 mg/kg in vivo. Intraperitoneal administration of F10 can completely inhibit Raji-xenograft tumor growth in established NPG mouse model at 2.0 and 4.0 mg/kg. In addition, the minimum lethal doses of F10 and SN-38 in mice by intravenous administration were 80 and 40 mg/kg (or 0.155, 0.102 mmol/kg), respectively. The solubility of F10 reached 9.86 μg/mL in a buffer solution of pH 4.5. The oral bioavailability of F10 achieved 22.4% in mice. The molecular docking model revealed that F10 can interact with Topoisomerase I-DNA complex. Our findings indicate that F10 is a new orally-oavailable antitumor agent with potent Anticancer effect. Furthermore, attaching a ring hydrophobic moiety to the 10-position of camptothecin provides a favorable approach in the optimization of camptothecin.

Keywords

Acute toxicity; Antitumor agent; Antitumor effect; Camptothecin derivatives; Drug design.

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