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Published on: June 7, 2019
Total Synthesis of Antiausterity Agent Callistrilone O Reveals Promising Antitumor Activity in a Melanoma Homograft
Kensuke Okuda1, Akira Takagi1, Ryohei Shimizu2,3
1Laboratory of Bioorganic & Natural Products Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe, Hyogo, 658-8558, Japan.
Abstract:
The antiausterity strategy in anticancer drug discovery has attracted much attention as a way to exterminate cancer cells under nutrient deprived conditions which are commonly found in solid tumors. These tumors under low nutrient stress are known to be malignant and often resist conventional drug therapy. As a potential drug candidate, we focused on the meroterpenoid natural product callistrilone O which has demonstrated extremely potent antiausterity properties toward PANC-1 pancreatic carcinoma in vitro. Here, we report for the first time the total synthesis of callistrilone O in seven steps from phloroglucinol. A Friedel-Crafts-type Michael addition and an oxidative [3+2] cycloaddition with Fetizon's reagent were used to construct the molecular skeleton. The preferential cytotoxicity of callistrilone O was also evaluated with multiple starvation-resistant cancer cell lines under low nutrient conditions. Furthermore, callistrilone O was found to strongly suppress B16 melanoma tumor growth without critical toxicity in vivo. Overall, this study presents a novel anticancer agent candidate from natural products with a concise synthetic route which can be readily applied to the synthesis of derivatives.
Insights
This study details the first total synthesis of callistrilone O, a potent antiausterity compound effective against pancreatic cancer cells. It also shows promising in vivo efficacy against melanoma, highlighting its potential as a novel anticancer drug candidate.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Cancer Biology
Background:
- Solid tumors often exhibit nutrient deprivation, leading to malignant phenotypes and resistance to conventional therapies.
- Antiausterity strategies offer a promising approach to target cancer cells under these stressful conditions.
- Meroterpenoid natural products are being explored for their therapeutic potential in oncology.
Purpose of the Study:
- To achieve the first total synthesis of the natural product callistrilone O.
- To evaluate the anticancer properties of callistrilone O against various cancer cell lines under nutrient-deprived conditions.
- To assess the in vivo efficacy and toxicity of callistrilone O in a preclinical cancer model.
Main Methods:
- Total synthesis of callistrilone O in seven steps from phloroglucinol.
- Utilized Friedel-Crafts-type Michael addition and oxidative [3+2] cycloaddition for skeleton construction.
- In vitro cytotoxicity assays on starvation-resistant cancer cell lines and in vivo studies using B16 melanoma models.
Main Results:
- Successfully synthesized callistrilone O via a concise seven-step route.
- Demonstrated potent antiausterity activity of callistrilone O against PANC-1 pancreatic cancer cells in vitro.
- Showed significant suppression of B16 melanoma tumor growth in vivo with minimal toxicity.
Conclusions:
- Callistrilone O is a promising natural product-derived anticancer agent with potent antiausterity properties.
- The developed synthetic route is efficient and amenable to the generation of callistrilone O derivatives.
- Callistrilone O warrants further investigation as a potential therapeutic for nutrient-deprived solid tumors.
