Total synthesis and biological evaluation of 22-hydroxyacuminatine

Abstract

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.

Figure 1

AM1 Optimized structure of 11.

Figure 2

Hypothetical model of the binding of 22-hydroxyacuminatine (2b) in the Top1-DNA-inhibitor ternary complex. The cleaved DNA strand is on the left, while the uncleaved strand is on the right. The DNA minor groove side is facing forward, while the major groove is on the back. The model is programmed for walleyed (relaxed) viewing.

Figure 3

Electrostatic potential surfaces of 22-hydroxyacuminatine (top) and camptothecin (bottom) mapped on their total electron densities calculated at the HF/6–31G** level of theory. Both electrostatic potential surface maps are scaled to a range of −38 to +38 kcal/mol.

Scheme 1

Retrosynthetic Analysis of Aromathecin 2c

Scheme 1

Retrosynthetic Analysis of Aromathecin 2c

Scheme 2

Synthesis of Bromide 4

Scheme 3

Synthesis of 2c and Its Reaction with n-BuLi

Scheme 4

Synthesis of 22-Hydroxyacuminatine (2b)

Scheme 4

Synthesis of 22-Hydroxyacuminatine (2b)