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Discovery of 8,9-seco- ent -Kaurane Diterpenoids as Potential Leads for the Treatment of Triple-Negative Breast Cancer.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2021 Jul 22; Vol. 64 (14), pp. 9926-9942. Date of Electronic Publication: 2021 Jul 08. - Publication Year :
- 2021
-
Abstract
- Triple-negative breast cancer (TNBC) is a lethal malignancy without safe and effective therapeutic drugs. In this study, the anti-TNBC bioassay-guided isolation of the medicinal plant Croton kongensis followed by the structural modification led to the construction of a small ent -kaurane diterpenoid library ( 1 - 25 ). With subsequent biological screening, 20 highly potent compounds (IC <subscript>50</subscript> s < 3 μM) were identified. Among them, 8,9-seco- ent -kaurane 6 displayed comparable activity (IC <subscript>50</subscript> s ∼ 80 nM) to doxorubicin but with better selectivity. The analysis of structure-activity relationships suggested that the cleavage of the C8-C9 bond and the presence of α,β-unsaturated ketone moiety were essential for the activity. The mechanistic study revealed that 6 induced apoptosis, autophagy, and metastasis suppression in TNBC cells via inhibition of Akt. In vivo , 6 significantly suppressed the TNBC tumor growth without causing side effects. All these results suggested that 6 may serve as a promising lead for the development of novel anti-TNBC agents in the future.
- Subjects :
- Animals
Antineoplastic Agents, Phytogenic chemical synthesis
Antineoplastic Agents, Phytogenic chemistry
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Crystallography, X-Ray
Diterpenes, Kaurane chemical synthesis
Diterpenes, Kaurane chemistry
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
Humans
Mammary Neoplasms, Experimental drug therapy
Mammary Neoplasms, Experimental metabolism
Mammary Neoplasms, Experimental pathology
Membrane Potential, Mitochondrial drug effects
Mice
Mice, Inbred NOD
Mice, SCID
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Triple Negative Breast Neoplasms metabolism
Triple Negative Breast Neoplasms pathology
Antineoplastic Agents, Phytogenic pharmacology
Croton chemistry
Diterpenes, Kaurane pharmacology
Drug Discovery
Triple Negative Breast Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 64
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34236840
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.1c00166