ANTITUMOR AGENTS .152. IN-VITRO INHIBITORY ACTIVITY OF ETOPOSIDE DERIVATIVE NPF AGAINST HUMAN TUMOR-CELL LINES AND A STUDY OF ITS CONFORMATION BY X-RAY CRYSTALLOGRAPHY, MOLECULAR MODELING, AND NMR-SPECTROSCOPY

被引:36
作者
ZHANG, YL
TROPSHA, A
MCPHAIL, AT
LEE, KH
机构
[1] UNIV N CAROLINA,SCH PHARM,DIV MED CHEM & NAT PROD,MOLEC MODELING LAB,CHAPEL HILL,NC 27599
[2] UNIV N CAROLINA,SCH PHARM,NAT PROD LAB,CHAPEL HILL,NC 27599
[3] DUKE UNIV,DEPT CHEM,CTR X RAY STRUCT,DURHAM,NC 27706
关键词
D O I
10.1021/jm00036a011
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
NPF, the title compound, was studied for its in vitro antitumor activity against 56 human tumor cell lines derived from seven cancer types. In general, NPF is about 100 times more active as compared to its parent compound, etoposide, toward all the tumor cell lines and can be considered as a lead structure for further development of anticancer agents. In order to facilitate future computer-assisted design of NPF analogs, NPF was characterized by X-ray crystallography. This crystal structure was used as the starting point for conformational analysis of this compound using several commercially available software packages, including SYBYL (Tripes Associates; Tripes force field), INSIGHT/DISCOVER (Biosym Technologies; CVFF force field), and semiempirical package MOPAC as implemented in SYBYL. The lowest energy conformation generated with the Tripes force field disagreed with the X-ray structure. On the other hand, semiempirical MOPAC/AM1 calculations showed that the X-ray structure had a lower energy than the Tripes lowest energy conformation. Subsequent NMR studies agreed well with the X-ray structure. Furthermore, conformational analysis of NPF using the DISCOVER force field identified the X-ray structure as the lowest energy conformation. Thus, the latter force field is adequate for future molecular modeling of NPF and its analogs.
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页码:1460 / 1464
页数:5
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