Plant antitumor agents. 28. Resolution of a key tricyclic synthon, 5'(RS)-1,5-dioxo-5'-ethyl-5'-hydroxy-2'H,5'H,6'H-6'-oxopyrano[3' ,4'- f]delta 6,8-tetrahydro-indolizine: total synthesis and antitumor activity of 20(S)- and 20(R)-camptothecin.
The resolution of the tricyclic ketone (3a + 3b) by the separation of diastereomeric adducts 4a and 4c of the precursor ketal 5 is described. The regenerated enantiomers 3a and 3b of 100% optical purity represent the key intermediates from which 20(R)-camptothecin (1a) and 20(S)-camptothecin (1b), respectively, have been prepared. The 20R analogue 1a was 10-100 times less active than the natural 20(S)-camptothecin (1b) in 9KB and 9PS cytotoxicity assays and almost inactive in in vivo L-1210 leukemia tests as compared to the highly potent and active natural compound 1b.
Wani
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Research Triangle Institute, Research Triangle Park, North Carolina 27709.
Nicholas
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Wall
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D002166:Camptothecin / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
D002166:Camptothecin