Synthesis of fluoromethyl-containing analogs of antitumor alkaloid luotonin A

Abstract

A convenient method for the synthesis of hitherto unknown 3 bromomethyl 2 chloro 4 fluoromethylquinolines has been developed. Coupling of 3 bromomethyl 2 chloro 4 trifluo romethylquinoline with 4(3H) quinazolinone with subsequent intramolecular Heck cyclization leads to 7 trifluoromethylluotonin, an analog of the antitumor alkaloid luotonin A. 7 Trifluo romethylluotonin retains the antitumor activity including apoptosis of cultured tumor cells and inhibiting DNA topoisomerase I.

New Approaches to the Synthesis of CF2X-substituted Heterocyclic Antitumor Cytostatic Agents

“…A derivative of 2-trifluoroacetylaniline was used in the synthesis of a CF3-substituted analog of anticancer alkaloid luotonin A [55]. The modification of luotonin A consisted in the introduction of the lipophilic CF3 group at the physiologically important seventh position of a pentacycle.…”

“…For the synthesis of 7-trifluoromethylluotonin 38, we used the strategy of formation of a pentacycle by N-alkylation of 4(3Н)-quinazolinone with 3-bromomethylquinoline 39 followed by the intramolecular Heck cyclization (Scheme 23). 7-Trifluoromethylluotonin 38 was found to retain the anticancer activity, causing death of tumor cells in culture and inhibiting DNA topoisomerase I [55].…”

Recent Advances in the Studies on Luotonins

“…On the other hand, compound 1k with an ethyl group at C14 displayed slightly improved cytotoxicity compared to that of luotonin A [30]. In addition, 14-trifluoromethylluotonin A ( 1m ) caused apoptosis of cultured colon adenocarcinoma and leukemia cells (IC 50 = 17(3) and 21(4) μM, respectively), which also showed inhibitory activity against Topo I at 40 μM/L [59]. These data are summarized in Table 2.…”

A Facile Oxidative Opening of the C-Ring in Luotonin A and Derivatives

“…In search of new anticancer agents, structural modifications of the alkaloid Luotonin A (first isolated in 1997 [ 1 ]) have found considerable interest during the past two decades [ 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Like its more prominent (and more potent) naturally occurring relative, Camptothecin (CPT) [ 13 , 14 , 15 ], Luotonin A can act as a topoisomerase 1 poison by stabilizing the DNA/Topo1 complex [ 2 , 16 ].…”