TY - JOUR
T1 - The Configuration-Dependent Anti-Leukemic Effect of Manoalide Stereoisomers
T2 - Reignite Research Interest in these Sponge-Derived Sesterterpenoids
AU - Lai, Kuei Hung
AU - Peng, Bo Rong
AU - Hsu, Yu Ming
AU - El-Shazly, Mohamed
AU - Du, Ying Chi
AU - Lu, Mei Chin
AU - Su, Jui Hsin
AU - Liu, Yi Chang
N1 - Funding Information:
This work was supported by the grant from the Ministry of Science and Technology (MOST 107-2320-B259-004-MY3, MOST 108-2320-B-291-001-MY3, MOST 110-2320-B-038-013, and MOST 110-2320-B-038-034), Taiwan; from Ministry of Education (DP2-110-21121-01-N-12-03); and from Taipei Medical University (TMU109-AE1-B15).
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/9
Y1 - 2021/9
N2 - Manoalide was studied as a potential anti-inflammatory agent for the last forty years and more than 200 publications and 180 patents were reported on this compound. However, the configurations at positions 24 and 25 and configuration-dependent bioactivity were not yet studied. In the current report, ten manoalide-like sesterterpenoids were isolated from Luffariella sp. (1–10). These stereoisomers were identified and separated for the first time since 1980 and their configurations at positions 24 and 25 were determined by analyzing their spectroscopic spectra. The configuration-dependent anti-proliferative activity of manoalide derivatives was examined by evaluating their effect on four leukemic cancer cell lines (Molt 4, K562, Sup-T1, and U937). The 24R,25S-isomers exhibited the most potent activity (IC50 0.50–7.67 μM). The anti-proliferative mechanism of action of 24R,25S-manoalide (7) was further studied on Molt 4 cells. Compound 7 exhibited apoptotic activity on Molt 4 cells through the disruption of mitochondrial membrane potential (MMP) and the generation of intracellular reactive oxygen species (ROS). It also inhibited the activity of human topoisomerase I and II. The apoptotic-inducing effect of 7 was further supported by the in vivo experiment by suppressing the volume of xenograft tumor growth (66.11%) compared with the control.
AB - Manoalide was studied as a potential anti-inflammatory agent for the last forty years and more than 200 publications and 180 patents were reported on this compound. However, the configurations at positions 24 and 25 and configuration-dependent bioactivity were not yet studied. In the current report, ten manoalide-like sesterterpenoids were isolated from Luffariella sp. (1–10). These stereoisomers were identified and separated for the first time since 1980 and their configurations at positions 24 and 25 were determined by analyzing their spectroscopic spectra. The configuration-dependent anti-proliferative activity of manoalide derivatives was examined by evaluating their effect on four leukemic cancer cell lines (Molt 4, K562, Sup-T1, and U937). The 24R,25S-isomers exhibited the most potent activity (IC50 0.50–7.67 μM). The anti-proliferative mechanism of action of 24R,25S-manoalide (7) was further studied on Molt 4 cells. Compound 7 exhibited apoptotic activity on Molt 4 cells through the disruption of mitochondrial membrane potential (MMP) and the generation of intracellular reactive oxygen species (ROS). It also inhibited the activity of human topoisomerase I and II. The apoptotic-inducing effect of 7 was further supported by the in vivo experiment by suppressing the volume of xenograft tumor growth (66.11%) compared with the control.
KW - Configuration-dependent anti-proliferative activity
KW - Leukemia, Molt 4 cells
KW - Manoalide stereoisomers
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U2 - 10.1016/j.bioorg.2021.105150
DO - 10.1016/j.bioorg.2021.105150
M3 - Article
AN - SCOPUS:85109615818
SN - 0045-2068
VL - 114
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 105150
ER -
