期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 23, 期 1, 页码 118-125出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.11.020
关键词
10-Hydroxycamptothecin derivatives; ortho-Quinonemethide intermediate; Antiproliferation; Configuration determination; Nucleophilic addition; Cycloaddition
资金
- Pillar Program for Bio-Pharmaceuticals from Shanghai Committee of Science and Technology [14431900600]
- National High Technology Research and Development Program of China (863 Program) [2013AA092903]
- Science and Technology Planning Project of Zhejiang Province [2012C33091]
- Fudan's undergraduate research opportunities program (Xiyuan Program) [122303]
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 H-1 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. (C) 2014 Elsevier Ltd. All rights reserved.
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