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.
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 (Tripos Associates; Tripos force field), INSIGHT/DISCOVER (Biosym Technologies; CVFF force field), and semiempirical package MOPAC as implemented in SYBYL. The lowest energy conformation generated with the Tripos 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 Tripos 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.
Zhang, YL; Tropsha, A; McPhail, AT; Lee, KH
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