Synthesis and activity evaluation of the cyclic dipeptides arylidene N-alkoxydiketopiperazines

• Published in: Bioorganic & medicinal chemistry 2016-11, Vol.24 (21), p.5197-5205
• Main Authors: Tian, Xia, Feng, Juan, Fan, Shi-ming, zhen, Xiao-li, Han, Jian-rong, Liu, Shou-xin
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activities; Arylidene N-alkoxydiketopiperazines; Caspase 3 - metabolism; Caspase-3; Cell Line, Tumor; Cell Proliferation - drug effects; Crystallography, X-Ray; Diketopiperazines - chemical synthesis; Diketopiperazines - chemistry; Diketopiperazines - pharmacology; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Inhibitory activity; Models, Molecular; Molecular docking; Molecular Structure; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Structure-Activity Relationship; Synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.08.038

[Display omitted] 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 IC50 values 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.