Total synthesis and biological evaluation of 22-hydroxyacuminatine.
A total synthesis of 22-hydroxyacuminatine, a cytotoxic alkaloid isolated from Camptotheca acuminata, is reported. The key step in the synthesis involves the reaction of 2,3-dihydro-1H-pyrrolo[3,4-b]quinoline with a brominated phthalide to generate a substituted pentacyclic 12H-5,11a-diazadibenzo[b,h]fluoren-11-one intermediate. Despite its structural resemblance to camptothecin and luotonin A, a biological evaluation of 22-hydroxyacuminatine in a topoisomerase I-deficient cell line P388/CPT45 has confirmed that the observed cytotoxicity is not due to topoisomerase I inhibition, even though 22-hydroxyacuminatine has a hydroxyl group that can theoretically hydrogen bond to Asp533. This result is consistent with the hypothesis that pi-pi stacking is more important than hydrogen-bonding interactions in determining topoisomerase I inhibitor binding in the ternary cleavage complex.
Department of Medicinal Chemistry and Molecular Pharmacology and Purdue Cancer Center, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Xiangshu
X
Xiao
Smitha
S
Antony
Yves
Y
Pommier
Mark
M
Cushman
D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D029769:Camptotheca / Q000737:chemistry*; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000235:genetics; D006860:Hydrogen Bonding; D007212:Indolizines / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors
C508964:22-hydroxyacuminatine; D000470:Alkaloids; D000970:Antineoplastic Agents; D007212:Indolizines; D011804:Quinolines; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I