Studies on mimicry of naturally occurring annonaceous acetogenins: non-THF analogues leading to remarkable selective cytotoxicity against human tumor cells.
A class of structurally simplified analogues of the naturally occurring annonaceous acetogenins were developed, amongst which some non-THF analogues showed remarkable cytotoxicities against tumor cell lines, as well as good selectivity between human tumor cells and normal cells. The synthetic routes were significantly shortened because of the removal of the chiral centers bearing the THF rings on the natural templates. This simplification also provides access to the parallel synthesis of these mimics by a combinatorial strategy. The remaining stereogenic centers at the positions alpha to the ethereal links were introduced by the Chiron approach from the easily accessible chiral building blocks 6a and/or 6b, made in turn from L-ascorbic acid or D-mannitol, while the one in the butenolide segment was taken from L-lactate. All four diastereomeric non-THF analogues 2a-2d showed remarkable activity against the HCT-8 cell line, and better differentiation was found when testing against the HT-29 cell line. It was also discovered that both the butenolide and ethylene glycol subunits play essential roles in the cytotoxicities against tumor cell lines, while the 10-substituted hydroxy group and the absolute configuration of methyl group at the butenolide moiety are less important for their activity.
Zeng
Bu-Bing
BB
State Key Laboratory of Bio-organic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China.
Wu
Yikang
Y
Jiang
Sheng
S
Yu
Qian
Q
Yao
Zhu-Jun
ZJ
Liu
Zhong-Hai
ZH
Li
Hong-Yan
HY
Li
Yan
Y
Chen
Xiao-Guang
XG
Wu
Yu-Lin
YL
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D029061:Annonaceae / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001671:Biochemistry / Q000379:methods; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D051379:Mice; D018716:Molecular Mimicry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013951:Thymus Hormones / Q000737:chemistry; D018675:Toxicity Tests; D014407:Tumor Cells, Cultured
C471565:2,5-dihydro-3-(13,19-dihydroxy-15,17-dioxaoctacosan-1-yl)-5-methylfuran-2-one; D000970:Antineoplastic Agents; D013951:Thymus Hormones; D015107:4-Butyrolactone