Core-Scaffold-Inspired Asymmetric Synthesis of Polysubstituted Chiral Hexahydropyridazines that Potently Inhibit Breast Cancer Cell Proliferation by Inducing Apoptosis.
The highly enantioselective preparation of pharmacologically interesting hexahydropyridazine derivatives based on a multicomponent cascade reaction is described. This one-pot approach utilizes an organocatalytic Michael reaction followed by intermolecular α-amination and intramolecular hemiaminalization to yield a chiral pyridazine backbone with contiguous stereogenic centers and multiple functional groups in good yield and with high stereoselectivity. Compounds synthesized by this method potently inhibited proliferation of MCF-7 breast cancer cells. Mechanistic studies suggest that compound 5 c exerts these anticancer effects by inducing apoptosis through extracellular signal related kinase (ERK)- and poly(adenosine diphosphate ribose) polymerase (PARP)-regulated pathways, as well as mitochondrial pathways.
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137 (P.R. China).
Hai-Jun
HJ
Leng
School of Chinese Medicine, University of Hong Kong, Hong Kong (P.R. China).
Fu
F
Peng
Department of Chemistry, Armstrong State University, Savannah, GA (USA).
Sarah
S
Zingales
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137 (P.R. China).
Wei
W
Huang
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137 (P.R. China).
Biao
B
Wang
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137 (P.R. China).
Qian
Q
Zhao
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 (P.R. China).
Rui
R
Zhou
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041 (P.R. China). hegu@scu.edu.cn.
Gu
G
He
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137 (P.R. China). pengcheng@cdutcm.edu.cn.
Cheng
C
Peng
State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137 (P.R. China). hanbo@cdutm.edu.cn.
Bo
B
Han
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002384:Catalysis; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D015394:Molecular Structure; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism
D000970:Antineoplastic Agents; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011725:Pyridines
antitumor agents; asymmetric catalysis; heterocycles; medicinal chemistry; organocatalysis