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Semi-synthesis, Cytotoxic Evaluation, and Structure-Activity Relationships of Brefeldin A Derivatives with Antileukemia Activity

Cytotoxic Evaluation,Semi-synthesis,Antileukemia Activity

Semi-synthesis, Cytotoxic Evaluation, and Structure-Activity Relationships of Brefeldin A Derivatives with Antileukemia Activity

Yao-Yao Jiang^{1, 2}, Mei-Yan Wei^{1, 2}, Yan-Wei Wu^{1, 2}, Li Xu^{1, 2}, Rui-Qin Zhai^{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.



Chronic myelogenous leukemia (CML) is characterized by the translocation of chromosomes 9 and 22, which generates the BCR-ABL fusion oncogene with constitutively active tyrosine kinase¹. Tyrosine kinase inhibitors (TKIs), such as imatinib mesylate, nilotinib and dasatinib, have been proved to be effective agents in CML treatment. However, the emergence of drug resistance² or the little effect on those patients carrying T315I mutation³ is becoming a problem for their treatment. Therefore, novel agents to improve therapeutic outcomes of CML are urgent needed.

In our previous work, Brefeldin A (BFA) was isolated as the major compound from the marine-derived fungus Penicillium sp. (HS-N-29), which exhibited attractive cytotoxic activity. A series of its ester derivatives were designed and semi-synthesized, and their structures were characterized by spectroscopic methods. Interestingly, most of the monoester derivatives exhibited potent cytotoxic activity to CML cell line K562. Especially, CHNQD-01212 exhibited the strongest inhibitory effect on the proliferation of K562 cells with an IC₅₀ value of 0.84 µM. Further evaluations indicated that CHNQD-01212 induced cell cycle arrest, stimulated cell apoptosis, inhibited phosphorylation of BCR-ABL, and thereby inactivated its downstream AKT signaling pathway. Thus, CHNQD-01212 had the potential to be served as an effective antileukemia agent or lead compound for further exploration.

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. Alfonso Quintas-Cardama, and Jorge Cortes. Molecular Biology of Bcr-Abl–Positive Chronic Myeloid Leukemia, Blood, 2009, 113, 1619–1630.

2. Alfonso Quintas-Cardama, Hagop Kantarjian, and Jorge Cortes. Imatinib and Beyond-Exploring the Full Potential of Targeted Therapy for CML, Nature Reviews Clinical Oncology, 2009, 6, 535–543.

3. Xiaoyan Pan, Liyuan Liang, Ying Sun, Ru Si, Qingqing Zhang, Jin Wang, Jia Fu, Junjie Zhang, and Jie Zhang. Discovery of Novel Bcr-Abl Inhibitors with Flexible Linker. Part 1: Confirmation Optimization of Phenyl-1H-Indazol-3-Amine as Hinge Binding Moiety, European Journal of Medicinal Chemistry, 2019, 178, 232–242.