2. Academic Validation
  3. Semisynthetic Derivatives of Fradcarbazole A and Their Cytotoxicity against Acute Myeloid Leukemia Cell Lines

Semisynthetic Derivatives of Fradcarbazole A and Their Cytotoxicity against Acute Myeloid Leukemia Cell Lines

  • J Nat Prod. 2019 Aug 23;82(8):2279-2290. doi: 10.1021/acs.jnatprod.9b00468.
Mingpeng Li 1 2 3,  Yanchao Xu 1 2 3,  Mingxing Zuo 1 2 3,  Wen Liu 1 3,  Liping Wang 1 2 3,  Weiming Zhu 1 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Functions and Applications of Medicinal Plants , Guizhou Medical University , Guiyang 550014 , China.
  • 2 School of Pharmaceutical Sciences , Guizhou Medical University , Guiyang 550025 , China.
  • 3 Key Laboratory of Chemistry for Natural Products of Guizhou Province , Chinese Academy of Sciences , Guiyang 550014 , China.
  • 4 Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy , Ocean University of China , Qingdao 266003 , China.
PMID: 31361136 DOI: 10.1021/acs.jnatprod.9b00468
Abstract

Fourteen derivatives of the marine-derived fradcarbazole A were synthesized from staurosporine. Their structures were identified by NMR and high-resolution electrospray ionization mass spectrometry (HRESIMS). The derivatives were screened in vitro for antiproliferative activity against three human leukemic cell lines (MV4-11, HL-60, K562). All of the derivatives displayed cytotoxicity against the human Flt-3 internal tandem duplication (ITD) mutant acute myeloid leukemia (AML) cell line MV4-11 with IC50 values of 0.32-0.96 μM. The mechanism of action studies indicated that the most effective 3-chloro-5‴-fluorofradcarbazole A (6) induced Apoptosis of the MV4-11 cells and arrested the cell cycle at the G0/G1 phase. Furthermore, compound 6 can reduce the expression of Flt-3, CDK2, and c-Kit. The results suggest that 3-chloro-5‴-fluorofradcarbazole A (6) is a potential candidate for developing novel anti-AML agents in the future.

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