Tuning the acyclic ether moiety of anticancer agent AA005 with conformationally constrained fragments.
A new series of anticancer annonaceous acetogenin mimetics were designed, synthesized, and evaluated based on our previously developed compound AA005, in which a variety of conformationally constrained fragments were introduced. Parallel syntheses of all new compounds were accomplished by replacement of the acyclic bis-ether functionality of AA005 with certain conformationally constrained fragments. Slight effects to the anticancer activity were exerted by altering stereochemistries in the middle modification region. Similar to AA005, most newly synthesized mimetics were found to exhibit potent activities against breast cancer cells, and showed satisfactory selectivities between cancerous and non-cancerous cells. An N,N'-dimethyl bis-amide compound 67 exhibits 30 times more potency against MDA-MB-468 cells than its parent molecule AA005. This study indicates that the introduction of appropriate conformational constraints is a useful optimizing tool for this class of anticancer agents. Successes in the bis-amide analogues of AA005 make this unique class of anticancer agents much simpler and more flexible for future further developments.
Liu
Hai-Xia
HX
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai, China.
Shao
Fei
F
Li
Gang-Qin
GQ
Xun
Guo-Liang
GL
Yao
Zhu-Jun
ZJ
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005233:Fatty Alcohols / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D021241:Spectrometry, Mass, Electrospray Ionization
C483824:AA005; D000970:Antineoplastic Agents; D005233:Fatty Alcohols; D007783:Lactones