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.
Xiao
Xiangshu
X
Department of Medicinal Chemistry and Molecular Pharmacology and Purdue Cancer Center, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
Antony
Smitha
S
Pommier
Yves
Y
Cushman
Mark
M
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