Scaffold Hopping Design, Synthesis, Antitumor Activity And Mechanism Of Evodiamine

Evodiamine is the main alkaloid component of the traditional Chinese herbWu-Chu-Yu. In recent years, great progress has been made on the research of evodiamineas an antitumor lead compound. Evodiamine has multi-targeting antitumor effect includingthe induction of apoptosis, inhibition of invasion and metastasis, cell cycle arrest at theG2/M phase and so on. Previously, we performed systemic structural optimization ofevodiamine and identified highly active evodiamine derivatives. Futher mechanism studyrevealed that these evodiamine derivatives acted by dual inhibition of topoisomerase I(Top1) and topoisomerase II (Top2).The present dissertation aims to perform systemic scaffold hopping design ofevodiamine, investigate the effect of scaffold modification on the antitumor activity andfind antitumor lead compounds with new mode of action.1. Scaffold Hopping Design and Antitumor Activity ofEvodiamineOur previous research of evodiamine as an antitumor lead compound was mainlyfocused on design and synthesis of A-ring and E-ring modified evodiamine derivatives,which showed potent in vitro and in vivo antitumor activities. Herein, ten kinds of newevodiamine-like scaffolds (20new compounds) were designed and synthesized bybioisosteric replacement, modifying ring groups, ring extension etc. In vitro antitumoractivity assay showed that the replacement of E-ring phenyl group by a five-memberedheterocyclic ring was helpful to slightly improve the activity. The A-ring hydroxyl groupwas also essential to improve their activity. Compounds D1(C-ring extension derivative)and E1(reverse evodiamine derivative) had novel molecular framework and good in vitroantitumor activity. Interestingly, their structure-activity relationships were different fromevodiamine derivatives. For example, the A-ring methoxy group was important for theantitumor activity instead of the hydroxyl group. Therefore, they could be considered asnew antitumor lead compounds for further structural modification and antitumormechanism study. 2. Design, Synthesis and Antitumor Mechanism of ReverseEvodiamine DerivativesCompound E1was a novel antitumor lead compound derived from scaffold hoppingof evodiamine. It was called “reverse evodiamine” because it had reverse connection typeof B/C rings. Based on the structure of reverse evodiamine, a series of derivatives weredesigned and synthesized. First, various substitutions were introduced on A-and E-ring.Second, substitutions favorable for antitumor activity were combined to afford A,E-ringdi-substituted derivatives; Finally, different substitutions were also introduced on otherpositions of the scaffold. Among the synthesized35new compounds, several derivativesshowed good in vitro antitumor activity. For example, compound E3had broad spectrumantitumor activity, particularly for human colon cancer HCT116cell line (IC50=0.002μM). At the concentration of0.5μM, compound E3could effectively induce the apoptosis.Further biological assays confirmed that compound E3acted by dual inhibition of tubulinand topoisomerase I without inhibitory effect on topoisomerase II. Moreover, compoundE3also showed good in vivo antitumor effect on human colon cancer cell HCT116xenografts in nude mice. At the dose of4mg/kg, the compound reduced31.49%of tumorgrowth. It also exhibited prospects for further optimization because of low toxicity andgood tolerability.In summary, the present research performed systemic scaffold hopping design ofevodiamine on the basis of chemical diversity, drug-likeness and synthetic feasibility. Atotal of55new compounds were designed and synthesized. The novelty of this work lies inthat:(1) Clarify the effect of scaffold modification on the antitumor activity.(2) Two typesof novel antitumor scaffolds were successfully identified from ten evodiamine-basedmolecular frameworks.(3) A highly active reverse evodiamine derivative (E3) showedpotent antitumor activity in vitro and in vivo. Futher mechanism study revealed that itacted by dual inhibition of Top1and tubulin. The results from the present thesis laid thefoundation for the development of new drug candidates with novel antitumor mode ofaction.