Total synthesis as a resource in drug discovery: the first in vivo evaluation of panaxytriol and its derivatives.
[structures: see text] We have conducted key preliminary studies into the in vitro and in vivo cytotoxicity of panaxytriol. Through total synthesis, we prepared and evaluated several synthetic panaxytriol analogues, each of which exhibited enhanced cytotoxicity relative to the natural product. Consequently, we have begun to chart the first in vitro SAR map for the compound, which suggests that the C3 hydroxyl functionality is not critical for biological activity and that, in fact, engagement of the C9-C10 diol as an acetonide actually leads to notably enhanced cytotoxicity. Furthermore, through in vivo investigations, we demonstrated that panaxytriol and panaxytriol acetonide (12) moderately suppress tumor growth with little or no toxicity. Finally, preliminary in vitro evaluation of panaxytriol indicates that it possesses neurotrophic activity.
Yun
Heedong
H
Department of Chemistry, Columbia University, 3000 Broadway, New York, New York, 10027, USA.
Chou
Ting-Chao
TC
Dong
Huajin
H
Tian
Yuan
Y
Li
Yue-ming
YM
Danishefsky
Samuel J
SJ
D000480:Alkynes / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D053281:Enediynes; D005233:Fatty Alcohols / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship
D000480:Alkynes; D000970:Antineoplastic Agents; D053281:Enediynes; D005233:Fatty Alcohols; C057682:panaxytriol