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. This result is consistent with the hypothesis that π-π stacking is more important than hydrogen bonding interactions in determining topoisomerase I inhibitor binding in the ternary cleavage complex.

Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: Investigating the hypothesis of shared structure–activity relationships

“…There are several routes known to the aromathecin system, including the condensation of pyrroloquinoline with phthalides,28–29 pyridone benzannulation–Heck coupling,36 and variants of the Friedlander condensation 30,37. Our synthesis of 14-substituted aromathecins proceeds through pyrroloquinolinedione 16 (Scheme 1), first prepared by Shamma and Novak in 1968 38.…”

“…The 12 H -5,11a-diazadibenzo[ b,h ]fluoren-11-one system, called “rosettacin” ( 8 )27 when unsubstituted and “aromathecin” when substituted, was first discovered in the natural product 22-hydroxyacuminatine ( 9 ) 28. This system is an analogue of camptothecin, with the E-ring lactone replaced by a benzene ring.…”

The Hendrickson ‘POP’ reagent and analogues thereof: synthesis, structure, and application in organic synthesis

“…Finally, reduction of the nitrile to the corresponding alcohol to generate 22-hydroxyacuminatine (85) has been previously reported by Cushman (51% yield). 77 Thus, this represents a formal synthesis of 22-hydroxyacuminatine (85) in eight steps and 16% overall yield. Using the same strategy, total synthesis of luotonin A was achieved in five steps and 47% overall yield starting from commercial materials.…”

Synthesis and biological evaluation of 6-fluoro-3-phenyl-7-piperazinyl quinolone derivatives as potential topoisomerase I inhibitors

“…However, the usage of CPT and its analogues was hindered by its rapid inactivation, which was derived from the rapid hydrolysis of the lactone ring under physiological condition [8]. As Top I is proven to be an effective target for cancer treatment, a slice of metabolically stable non-CPT Top I inhibitors with better pharmacokinetic features have been developed [9][10][11][12][13][14], like indolocarbazoles [13] and indenoisoquinolines (Figure 2) [14], some of them are now in clinical assessment [8].…”