Total synthesis and antiproliferative activity screening of (+/-)-aplicyanins A, B and E and related analogues.
The first total synthesis of the indole alkaloids (+/-)-aplicyanins A, B, and E, plus 17 analogues, all in racemic form, is reported. Modifications to the parent compound included changing the number of bromine substituents on the indole, the nature of the substituents on the indole nitrogen (H, Me, or OMe), and/or the oxidation level of the heterocyclic core tetrahydropyrimidine. Each compound was screened against three human tumor cell lines, and 14 of the newly synthesized compounds showed considerable cytotoxicity. The assay results were used to establish structure-activity relationships. These results suggest that the presence of the bromine at position 5 of the indole is critical to activity, as well as the acetyl group on the imine nitrogen does in some compounds.
Sísa
Miroslav
M
Institute for Research in Biomedicine, Barcelona Science Park-University of Barcelona, Baldiri Reixac 10, E-08028 Barcelona, Spain.
Pla
Daniel
D
Altuna
Marta
M
Francesch
Andrés
A
Cuevas
Carmen
C
Albericio
Fernando
F
Alvarez
Mercedes
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D026121:Indole Alkaloids; C544859:aplicyanin A; C544861:aplicyanin B; C544860:aplicyanin E