Theoretical study of podophyllotoxin and quinolone analogues as antitumor drugs

Abstract

Objective: To study the active sites of podophyllotoxin derivatives. Methods: Some podophyllotoxin derivatives were analyzed by quantum and mechanics method. Results: Some information was given according to the calculation results about HOMO and LUMO electron density. The C-4 position is the position for effective modification. The B ring and E ring are important active centers. Conclusion: The hole of positive charge in B ring easily combines with an acceptor within the molecular. Some quinolones with similar electronic construction to podophyllotoxin may have antitumor activity.Podophyllotoxin is a natural substance with strong antitumor activity m. But due to its toxic side effects, structural modification is essential. It is believed that podophyllotoxin derivatives exert their antitumor activity by forming a stable covalent complex between DNA and Biography: HE Feng (1969-), assistant professor, master of chemistry, Department of Chemistry, Sun Yat-sen University of Medical Sciences, majors in research of anticancer drugs. type II DNA topoisomerase. This leads to inhibition of DNA catenation activity C21.On the basis of our previous studies C3-61, we undertook quantum chemistry calculation and threedimensional quantitative structure-activity analysis for the compounds in literatures Iv-91. Furthermore, we investigated their structural characteristics and structure -activity according to their relationship inhibition of L12~0 leukemia cell lines in vitro. This study would help searching for compounds with more ideal structure and activity.In the process of molecular modeling construction, the trans ring-D juncture is required (Figure 1).Generally, the activities of the drugs are always associated with their HOMO and LUMO orbits. Compared to their ICso (Table 1), compounds whose LUMO components are mainly in the ring-B and HOMO's principal components in the ring-E, have relatively high activity. Therefore, it can be postulated that the parent structure has two functioning regions: one in the ring-E (including the 4'-hydroxyl), the other one in the ring-B.Moreover, the energy of the LUMO and LUMO (+1) is negative, different from that of general compounds which is positive. It becomes clear that the LUMO is responsible for the interaction of the molecular orbit. It suggests that the active compounds' LUMO is quite low. In addition, as the principal components of LUMO are in ring-B, so, it is the ring-B that is responsible for maintaining sufficient activity.Many studies indicated that C-4 position is suitable for modification I1°1. When the C-4 position is substituted by different groups, the density of electronic in ring-B changes. The migration of LUMO from ring-B leads to diminished activity. However, according to the analysis