2. Academic Validation
  3. Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan hydrochloride as ortho-quinonemethide precursor

Synthesis of novel 10-hydroxycamptothecin derivatives utilizing topotecan hydrochloride as ortho-quinonemethide precursor

  • Bioorg Med Chem. 2015 Jan 1;23(1):118-25. doi: 10.1016/j.bmc.2014.11.020.
Hanyi Tan 1,  Guolin Wang 2,  Jiajun Li 1,  Guangrong Meng 1,  Zhenfeng Liu 2,  Mengjie Dong 2,  Yubin Li 3,  Dianwen Ju 4,  Qian Zhang 5
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 2 PET Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China.
  • 3 Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 4 Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: dianwenju@gmail.com.
  • 5 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: zhangqian511@shmu.edu.cn.
PMID: 25481395 DOI: 10.1016/j.bmc.2014.11.020
Abstract

A series of 9-(alkylthiomethyl)-10-hydroxycamptothecins and pyrano-fused camptothecin derivatives were synthesized via the reaction of topotecan hydrochloride with various thiols and alkyl vinyl ethers respectively. In the reactions, topotecan hydrochloride was utilized as ortho-quinonemethide (o-QM) precursor. The configuration of 19 was determined by (1)H NMR and NOESY spectra as syn-isomers, suggesting that the cycloaddition of topotecan with alkyl vinyl ethers could undergo a hetero Diels-Alder reaction. All the synthesized compounds were screened on Cancer cell lines HepG2, KB, HCT-8 and SGC7901. Some compounds were selected to assess their inhibitory activity against Topo I via Topo I mediated DNA cleavage assays. The results showed that among those tested 9-(alkylthiomethyl)-10-hydroxycamptothecins, the compounds with bulkier hydrophobic side chains at 9-position have better bioactivities. As well as all pyrano-fused Camptothecins possess antiproliferative activity against the tested Cancer cell lines. Docking studies suggested that there are more interactions between the novel analogues and the binding site of Topo I.

Keywords

10-Hydroxycamptothecin derivatives; Antiproliferation; Configuration determination; Cycloaddition; Nucleophilic addition; ortho-Quinonemethide intermediate.

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