期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 22, 期 3, 页码 1049-1062出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.12.042
关键词
Chiral derivatives of xanthones; Enantiomerically pure; TBTU; Antitumor; Enantioselectivity
资金
- FCT - Fundacao para a Ciencia e a Tecnologia [CEQUIMED-PEst-OE/SAU/UI4040/2011, CESPU 10-GCQF-CICS-09, FCT-GRICES/CAPES 00770 29/05/08]
- University of Porto/Santander Totta (Investigacao Cientifica na Pre-Graduacao)
- FEDER funds through the COMPETE program [FCOMP-01-0124-FEDER-011057]
- Faculty of Science
- Department of Zoology
- Kasetsart University
A highly efficient and practical methodology for synthesis of new chiral derivatives of xanthones (CDXs) in enantiomerically pure form has been developed. According to this approach, thirty CDXs (3-32) were synthesized by coupling a carboxyxanthone (1) and a carboxymethoxyxanthone (2) with both enantiomers of commercially available chiral building blocks, namely six amino alcohols, one amine and one amino ester. The activation of the carboxylic acid group of the xanthonic scaffold was carried out with the coupling reagent O-(benzotriazol-1-yl)-N-N-N'-N'-tetramethyluronium tetrafluoroborate (TBTU), in the presence of a catalytic amount of TEA in anhydrous THF. The coupling reactions with the chiral blocks were performed at room temperature with short reactions times, excellent yields (ranging from 94% to 99%), and very high enantiomeric excess. The synthesized CDXs were evaluated for their effect on the in vitro growth of three human tumor cell lines, namely A375-C5 (melanoma), MCF-7 (breast adenocarcinoma), and NCI-H460 (non-small cell lung cancer). The most active compound was CDX 15 being active in all human tumor cell lines with values of GI(50) of 32.15 +/- 2.03 mu M for A375-C5, 22.55 +/- 1.99 mu M for MCF-7, and 14.05 +/- 1.82 mu M for NCI-H460. Nevertheless, some CDXs showed cell-type selectivity. Furthermore, the growth inhibitory effects, in some cases, demonstrated to be depending on the stereochemistry of the CDXs. An interesting example was observed with the enantiomers 3 and 4, which demonstrated high enantioselectivity for MCF-7 and NCI-H460 cell lines. It can be inferred that the effects on the growth of the human tumor cell lines can be ascribed not only to the nature and positions of substituents on the xanthonic scaffold but also to the stereochemistry of the CDXs. Some considerations regarding structure-activity relationship within this class of compounds will be highlighted. (C) 2013 Elsevier Ltd. All rights reserved.
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