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Cytotoxicity, Hemolytic Toxicity, and Mechanism of Action of Pulsatilla Saponin D and Its Synthetic Derivatives.
- Source :
-
Journal of natural products [J Nat Prod] 2018 Mar 23; Vol. 81 (3), pp. 465-474. Date of Electronic Publication: 2017 Nov 13. - Publication Year :
- 2018
-
Abstract
- The strong hemolytic toxicity of pulsatilla saponin D (1, HD <subscript>50</subscript> 6.3 μM) has hampered its clinical development as an injectable anticancer agent. To combat this challenge, 17 new derivatives of 1 with ring C, C-28, or C-3 modifications were synthesized and evaluated for cytotoxicity against several selected human tumor lines, as well as for hemolytic toxicity against rabbit erythrocytes. Structure-activity relationship (SAR) and structure-toxicity relationship (STR) correlations were also elucidated. Compared to the lead compound 1, the hemolytic activity of all 17 derivatives dropped dramatically. Notably, compound 14 exhibited significant cytotoxicity toward A549 human lung cancer cells (IC <subscript>50</subscript> 2.8 μM) in a dose-dependent manner without hemolytic toxicity (HD <subscript>50</subscript> > 500 μM). Molecular studies indicated that 14 induced typical G <subscript>1</subscript> cell cycle arrest and apoptosis in A549 cells, and Western blot assays suggested that both intrinsic and extrinsic apoptosis pathways were activated by 14. Collectively, compound 14 may merit further development as a potential anti-lung cancer agent.
- Subjects :
- A549 Cells
Animals
Apoptosis drug effects
Cell Cycle Checkpoints drug effects
Cell Line, Tumor
Erythrocytes drug effects
G1 Phase drug effects
Humans
KB Cells
MCF-7 Cells
Rabbits
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Cytotoxins pharmacology
Hemolysis drug effects
Lung Neoplasms drug therapy
Saponins pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-6025
- Volume :
- 81
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of natural products
- Publication Type :
- Academic Journal
- Accession number :
- 29131631
- Full Text :
- https://doi.org/10.1021/acs.jnatprod.7b00578