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Total Synthesis and Biological Evaluation of Aniduquinolone A and Its Analogues

Total Synthesis,Biological Evaluation

Total Synthesis and Biological Evaluation of Aniduquinolone A and Its Analogues

Feng-Wei Guo^{1, 2}, Xiao-Feng Mou^{1, 2}, Yong Qu^{1, 2}，Rui-Qin Zhai^{1, 2}, Jie Hu^{1, 2}, Wei-Feng Xu^{1, 2}, Xue-Mei Hou^{1, 2}, Chang-Yun Wang^{1, 2}, Chang-Lun Shao*<sup>1, 2

1</sup> Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People’s Republic of China.

² Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, People’s Republic of China.

* Email: shaochanglun@163.com.



Historically, natural products (NPs) have held out the best options for finding bioactive scaffolds and serve as an inspiration for the development of new pharmaceuticals; approximately 50% of all small-molecule drugs have an NP derivation or inspiration.¹ The 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one alkaloids constituted a relatively new and steadily growing family of natural products, which were isolated from both terrestrial and marine fungi, of the genera Aspergillus and Penicillium, that has been uncovered piecewise during the last 20 years of research.²

In our previous research work, a series of new natural products were targeted isolation from marine-derived fungi. Especially, aniduquinolone A, a monoterpenoid combined with a 4-phenyl-3,4-dihydroquinolin-2(1H)-one alkaloid, was isolated from the gorgonian coral-derived fungus Scopulariopsis sp. collected in the South China Sea.³ It was discovered to be the most promising non-toxic antilarval settlement candidate. Significantly, it was the strongest antifouling compound in nature until now which showed highly potent activity with picomolar level (EC₅₀ = 17.5 pM) and a very safety and high therapeutic ratio (LC₅₀/EC₅₀ = 1200). Our research interests include the development of new synthetic strategies for bioactive molecules, followed by the structure-activity relationship (SAR) studies in searching for lead structures with therapeutic purpose. And we have accomplished the first scalable total synthesis of (+)-aniduquinolone A in 13 steps (the longest linear sequence) and 3.9% overall yield starting from the commercial available phenol.

This work was supported by the Program of National Natural Science Foundation of China (Nos. U1706210, 41776141, 41906090, 42006092 and 41322037), the Program of Natural Science Foundation of Shandong Province of China (No. ZR2019BD047), the Marine S&T Fund of Shandong Province for Pilot National Laboratory for Marine Science and Technology (Qingdao) (No. 2018SDKJ0403-2), and the Taishan Scholars Program, China (No. tsqn20161010).



References

1. David J. Newman and Gordon M. Cragg. Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019, Journal of Natural Products, 2020, 83, 770−803.

2. Sebastian O. Simonetti, Enrique L. Larghi and Teodoro S. Kaufman. The 3,4-Dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one Alkaloids. Results of 20 Years of Research, Uncovering a New Family of Natural Products, Natural Product Reports, 2016, 33, 1425−1446.

3. Changlun Shao, Rufang Xu, Changyun Wang, Peiyuan Qian, Kailing Wang, Meiyan Wei. Potent Antifouling Marine Dihydroquinolin-2(1H)-one-Containing Alkaloids from the Gorgonian Coral-Derived Fungus Scopulariopsis sp. Marine Biotechnology, 2019, 84, 1228−1237.