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
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
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DOI：
10.1021/jm00036a011
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发表时间：
1994-05-13
影响因子：
7.3
通讯作者：
LEE, KH
中科院分区：
文献类型：
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作者：
ZHANG, YL;TROPSHA, A;LEE, KH
本文研究了标题化合物NPF对56个人肿瘤细胞株的体外抗肿瘤活性。一般来说，NPF对所有肿瘤细胞系的活性是其母体化合物依托泊苷的约100倍，并且可以被认为是进一步开发抗癌剂的先导结构。为了便于未来的计算机辅助设计的NPF类似物，NPF的特征在于通过X射线晶体学。该晶体结构用作该化合物构象分析的起点，使用几种市售软件包，包括SYBYL（Tripes Associates; Tripes力场）、INSIGHT/DISCOVER（Biosym Technologies; CVFF力场）和半经验软件包MOPAC（如SYBYL中所实施的）。与Tripes力场产生的最低能量构象与X射线结构不一致。另一方面，半经验MOPAC/AM 1计算表明，X-射线结构的能量低于Tripes最低能量构象。随后的NMR研究与X射线结构一致。此外，使用DISCOVER力场对NPF进行构象分析，确定X射线结构为最低能量构象。因此，后者力场是足够的NPF及其类似物的未来分子建模。
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.