Synthesis and activity evaluation of the cyclic dipeptides arylidene N-alkoxydiketopiperazines.
A series of arylidene N-alkoxydiketopiperazines was designed and stereoselectively synthesized via oxime-ether formation and intramolecular acylation. Possible cyclization and acid-catalyzed rearrangement-fragmentation mechanisms were discussed. The crystal structure of the novel diketopiperazine further confirmed the rearrangement mechanism. Most compounds exhibited antitumor activity. Several compounds were more potent against caspase-3. Specifically, compounds 6e, 6g, and 6f inhibited caspase-3 at IC50values lying within the low micromolar range and demonstrated good selectivity. The binding modes of alkoxydiketopiperazines in the active center of caspase-3 were also discussed based on the molecular docking results.
College of Sciences, Hebei University of Science & Technology, Shijiazhuang 050018, People's Republic of China.
Xia
X
Tian
College of Chemical & Pharmaceutical Engineering, Hebei University of Science & Technology, Shijiazhuang 050018, People's Republic of China.
Juan
J
Feng
State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science & Technology, Shijiazhuang 050018, People's Republic of China.
Shi-Ming
SM
Fan
College of Sciences, Hebei University of Science & Technology, Shijiazhuang 050018, People's Republic of China.
Xiao-Li
XL
Zhen
College of Sciences, Hebei University of Science & Technology, Shijiazhuang 050018, People's Republic of China. Electronic address: han_jianrong@126.com.
Jian-Rong
JR
Han
State Key Laboratory Breeding Base-Hebei Province Key Laboratory of Molecular Chemistry for Drug, Hebei University of Science & Technology, Shijiazhuang 050018, People's Republic of China. Electronic address: chlsx@263.net.
Shou-Xin
SX
Liu
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D054659:Diketopiperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D053148:Caspase 3
Antitumor activities; Arylidene N-alkoxydiketopiperazines; Caspase-3; Inhibitory activity; Molecular docking; Synthesis