Total synthesis of the cyclodepsipeptide apratoxin A and its analogues and assessment of their biological activities.
A novel total synthesis of apratoxin A is described, with key steps including the assembly of its ketide segment through a D-proline-catalyzed direct aldol reaction and Oppolzer's anti aldol reaction and the preparation of its thiazoline unit in a biomimetic synthesis. An oxazoline analogue of apratoxin A has also been elaborated by a similar approach. This compound has a potency against HeLa cell proliferation only slightly lower than that of apratoxin A, whilst a C(40)-demethylated oxazoline analogue of apratoxin A displays a much lower cytotoxicity and the C(37)-epimer and C(37) demethylation product of this new analogue are inactive. These results suggest that the two methyl groups at C(37) and C(40) and the stereochemistry at C(37) are essential for the potent cellular activity of the oxazoline analogue of apratoxin A. Further biological analysis revealed that both synthetic apratoxin A and its oxazoline analogue inhibited cell proliferation by causing cell cycle arrest in the G1 phase.
Ma
Dawei
D
State Key Laboratory of Bioorganic and Natural Products Chemistry Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences 354 Fenglin Lu, Shanghai 200032, China. madw@mail.sioc.ac.cn
Zou
Bin
B
Cai
Guorong
G
Hu
Xiaoyi
X
Liu
Jun O
JO
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001427:Bacterial Toxins / Q000138:chemical synthesis; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008745:Methylation; D010080:Oxazoles; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D047630:Depsipeptides; D010080:Oxazoles; D010456:Peptides, Cyclic; C442201:apratoxin A