Synthesis, Biological Evaluation and Mechanism Studies of Deoxytylophorinine and Its Derivatives as Potential Anticancer Agents

Abstract

Previous studies indicated that (+)-13a-(S)-Deoxytylophorinine (1) showed profound anti-cancer activities both in vitro and in vivo and could penetrate the blood brain barrier to distribute well in brain tissues. CNS toxicity, one of the main factors to hinder the development of phenanthroindolizidines, was not obviously found in 1. Based on its fascinating activities, thirty-four derivatives were designed, synthesized; their cytotoxic activities in vitro were tested to discover more excellent anticancer agents. Considering the distinctive mechanism of 1 and interesting SAR of deoxytylophorinine and its derivatives, the specific impacts of these compounds on cellular progress as cell signaling transduction pathways and cell cycle were proceeded with seven representative compounds. 1 as well as three most potent compounds, 9, 32, 33, and three less active compounds, 12, 16, 35, were selected to proform this study to have a relatively deep view of cancer cell growth-inhibitory characteristics. It was found that the expressions of phospho-Akt, Akt, phospho-ERK, and ERK in A549 cells were greater down-regulated by the potent compounds than by the less active compounds in the Western blot analysis. To the best of our knowledge, this is the first report describing phenanthroindolizidines alkaloids display influence on the crucial cell signaling proteins, ERK. Moreover, the expressions of cyclin A, cyclin D1 and CDK2 proteins depressed more dramatically when the cells were treated with 1, 9, 32, and 33. Then, these four excellent compounds were subjected to flow cytometric analysis, and an increase in S-phase was observed in A549 cells. Since the molecular level assay results of Western blot for phospho-Akt, Akt, phospho-ERK, ERK, and cyclins were relevant to the potency of compounds in cellular level, we speculated that this series of compounds exhibit anticancer activities through blocking PI3K and MAPK signaling transduction pathways and interfering with the cell cycle progression.

Phytochemical composition and antifeedant activity of five Vincetoxicum taxa against Spodoptera littoralis and Leptinotarsa decemlineata

“…In these phytochemical constituents, phenanthroindolizidine alkaloids are characteristic secondary metabolites of some Asclepiadaceae and Moraceae genera including Cynanchum L., Vincetoxicum, Tylophora R. Br., Pergularia L. and Ficus L. [10,17]. These alkaloids exhibit interesting biological activities such as significant cytotoxic [18] and antitumor activities as well as anti-inflammatory [17], antimicrobial [8], antiviral [19], antiasthmatic [20], insecticidal and insect antifeedant [7,8,21] activities.…”

The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma

“…Compound PF403 is a metabolite of the bioactive natural product 13a-(S)-deoxytylophorinine [101] with strong inhibitory activity against HH pathwayhyperactivated MB cells (IC 50 values of 0.013 nM values assayed by MTT assay in human MB DAOY cells). Mechanistic study revealed that PF403 directly binds SMO in a similar manner as vismodegib thereby inhibiting the receptor activity.…”

Improving the Oral Bioavailability of an Anti-Glioma Prodrug CAT3 Using Novel Solid Lipid Nanoparticles Containing Oleic Acid-CAT3 Conjugates

“…CAT3 ( Figure 1A) is a novel phenanthroindolizidine substance that selectively inhibits the hedgehog signaling pathway, demonstrating a significant inhibitory effect in GBM and TMZ-resistant GBM in orthotopic glioblastoma mice models following oral administration [8][9][10]. Moreover, central nervous system toxicity, one of the main obstacles in the development of phenanthroindolizidines, has not been associated with CAT3 [11]. PF403 ( Figure 1B), reporting an in vitro anti-glioma activity approximately 1000 times higher than CAT3 [8] in human cell lines, is the active metabolite of CAT3 synthesized by esterases in vivo and can penetrate the blood-brain barrier to demonstrate an anti-glioma effect [12][13][14].…”