Two new indolyl diketopiperazines,
gartryprostatins A and B (1 and 2), with
an unusual 2,3-furan-fused pyrano[2,3-g]pyrrolo[1″,2″:4′,5′]pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole nucleus, along with a new naturally occurring compound
(gartryprostatin C, 3) were isolated from the solid culture
of Aspergillus sp. GZWMJZ-258, an endophyte
from Garcinia multiflora (Guttiferae).
The structures of compounds 1–3 were
determined by nuclear magnetic resonance, mass spectrometry, Marfey’s
analysis of amino acids, and chemical calculation. Compounds 1–3 displayed selective inhibition on
human FLT3-ITD mutant AML cell line, MV4-11, with IC50 values
of 7.2, 10.0, and 0.22 μM, respectively.
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 IC 50 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 G 0 /G 1 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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