Synthesis and anti-metastatic effects of pregn-17(20)-en-3-amine derivatives.
Novel pregn-17(20)-en-3-amine derivatives were synthesized and their anti-metastatic effects were evaluated in human breast cancer cells using chemotaxis assay. Compared with positive control LY294002, a PI3K inhibitor, derivatives 5a, 19a, 20a, 19g, 20f, 5c, 12e and 12f exhibited significant inhibitory effects against cancer cell migration induced by chemokine epidermal growth factor (EGF). Especially, the IC50for compound 20f was as low as 0.03 μM. Preliminary structure-activity relationship studies suggested that most 3β-substituted derivatives were more effective than those 3α-substituted derivatives, provided there was no substituted group at position C-16. Moreover, the α,β-unsaturated fragment in ring D might be critical for their anti-metastatic activities. Further investigations on compound 20f revealed inhibitory effects on cell adhesion, migration and invasion of MDA-MB-231 cells. The mechanisms for the anti-metastatic effect of 20f might be through the inhibition of the phosphorylations of PI3K, Akt, PKCζ, and integrin β1 in a dose-dependent manner. Taken together, the novel steroidal alkaloid derivative 20f could be further explored as an effective anti-metastatic agent for the treatment of human metastatic breast cancer.
Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, People's Republic of China; Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, People's Republic of China. Electronic address: qinnan@tmu.edu.cn.
Nan
N
Qin
Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, People's Republic of China.
Miao
M
Jia
Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, People's Republic of China.
Xiao-Ran
XR
Wu
Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, People's Republic of China.
Xiao-Ai
XA
Shou
Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, People's Republic of China.
Qian
Q
Liu
Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, People's Republic of China.
Chun-Chun
CC
Gan
Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, People's Republic of China.
Mei-Na
MN
Jin
Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, People's Republic of China.
Yang
Y
Yu
Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, People's Republic of China; Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, People's Republic of China. Electronic address: duanhq@tmu.edu.cn.
Hong-Quan
HQ
Duan
D000588:Amines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D019012:Integrin beta1 / Q000378:metabolism; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099221:Protein Kinase C zeta
D000588:Amines; D000970:Antineoplastic Agents; D019012:Integrin beta1; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D051057:Proto-Oncogene Proteins c-akt; D000099221:Protein Kinase C zeta
Akt; Anti-metastatic effect; Breast cancer; Integrin β1; PI3K; PKCζ; Pregn-17(20)-en-3-amine derivatives