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

Abstract

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.

9-[(Furan-2-ylmethyl)amino]-5-(3,4,5-trimethoxyphenyl)-5,5a,8a,9-tetrahydrofuro[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6(8H)-one

“…In title compound, bond lengths and angles are normal and in good agreement with those reported previously for related compounds (Feng et al, 2008;Zhang, et al, 1994;Zuo, et al, 2009). The tetrahydrofuran ring (C15-C18/O4) and the six-membered ring (C6-C7/C13-C15/C18) fused to it both display envelope conformations.…”

“…The furan ring is disordered over two sets of sites with occupancies of 0.722 (7) and 0.278 (7) Related literature For podophyllotoxin derivatives synthesized by our group, see: Lu et al (2010); Yu et al (2008); Zhao et al (2009). For bond-length and angle data of related structures, see: Feng et al (2008); Zhang et al (1994); Zuo et al (2009 Table 1 Hydrogen-bond geometry (Å , ). Symmetry codes: (i) Àx þ 2; y þ 1 2 ; Àz þ 1; (ii) Àx þ 1; y þ 1 2 ; Àz þ 1; (iii) x À 1; y; z; (iv) Àx þ 1; y À 1 2 ; Àz þ 2.…”

A one-pot, efficient and facile synthesis of 4β-arylaminopodophyllotoxins: synthesis of NPF and GL-331 as DNA topoisomerase II inhibitors

“…A large number of 4b-amino substituted congeners have been prepared and some of these derivatives (e.g. NPF and GL-331) 5,6 have displayed a better pharmacological profile than those of etoposide. One of them, 4%-O-demethyl-4b-(4%%-nitroanilino)-4-desoxypodophyllotoxin (GL-331) is currently in phase-II of the clinical trials against gastric carcinoma, colon cancer, non-small cell carcinoma and etoposide resistant malignancies.…”

Synthesis of Novel 4β-(1, 2, 3-Triazol-1-yl) Podophyllotoxins as Potential Antitumor Drugs

“…The considerable simplification in the sugar structure of 2 led to two highly active 4~-arylaminopodophyllotoxins, 3 and 4, which exhibited superior parmacological properties to 2 and have been brought into clinical evaluation3*. In previous studies7'13, we also found that a number of 4p-aminO-or amido-podophyllotoxins were as active or more active than 2.…”