Synthesis of NK109, an Anticancer Benzo[c]phenanthridine Alkaloid

Abstract

A total synthesis of NK109 (7-hydroxy-8-methoxy-5-methyl-2,3-methylenedioxybenzo[c]phenanthridinium hydrogensulfate dihydrate), an anticancer benzo[c]phenanthridine alkaloid, is reported. The primary structure of this compound was erroneously communicated in 1973 as fagaridine (from Fagara xanthoxyloides) which is the 8-hydroxy regioisomer. NK109 has not yet been isolated from a natural source and therefore can only be obtained by synthesis. To study a wide variety of analogues, we decided to use a synthetic route via substituted benzylamine 5, which was obtained from the appropriate benzaldehyde and naphthylamine units. The benzo[c]phenanthridine ring was constructed by radical cyclization with tri-n-octyltin hydride and 2,2‘-azobis(2-methylbutyronitrile), followed by oxidative aromatization with MnO2. The resulting benzo[c]phenanthridine 6 was successfully methylated with methyl 2-nitrobenzenesulfonate. After deprotection of the benzyl group and subsequent hydration, NK109 was obtained. All reactions were performed under normal conditions. Purification was achieved only by recrystallization to give an overall yield of 40%.

Identification of benzo[c]phenanthridine metabolites in human hepatocytes by liquid chromatography with electrospray ion-trap and quadrupole time-of-flight mass spectrometry

“…Dihydro derivatives of the alkaloids (DHSG and DHCHE) were prepared to 99% purity from SG and CHE by their reduction with NaBH 4 in methanol [12,13]. The O-demethylated metabolite of DHCHE (Scheme 2) was prepared from alkaloid NK-109 (Scheme 1B, R 1 H, R 2 CH 3 ) [14][15][16] which was reduced in the same way as the dihydro derivatives above [17]. Methanol was Scheme 2.…”

Structural modification of sanguinarine and chelerythrine and their antibacterial activity

“…f. et Thoms., Macleaya and Bocconia species from the Papaveraceae family, and some members of Zanthoxylum (Rutaceae). Although the QBAs are a relatively small class of plant products, they have attracted much attention from researchers because of their bioactivities: anti-inflammatory (Lenfeld et al, 1981), antimicrobial (Mitscher et al, 1978;Navarro, Villarreal, Rojas, & Lozoya, 1996;Odebiyi & Sofowora, 1979), antitumour (Nakanishi, Suzuki, Mashiba, Ishikawa, & Yokotsuka, 1998;Stermitz, Larson, & Kim, 1973;Stermitz et al, 1975;Tin-Wa, Bell, Bevelle, Fong, & Farnsworth, 1974;Zee-Cheng & Cheng, 1975), antiviral (Sethi, 1979), cytotoxic (Cordell & Farnsworth, 1976) and anti-liver mitochondrial monoamine oxidase (Iagodina, Nikol'skaia, & Faddeeva, 2003). With respect to the antimicrobial activities of QBAs, previous research has mainly focused on the total alkaloids containing QBAs from the plant, while only a few studies on 1 and 2 have been reported.…”

Novel N-(3-carboxyl-9-benzyl-β-carboline-1-yl)ethylamino acids: Synthesis, anti-tumor evaluation, intercalating determination, 3D QSAR analysis and docking investigation

“…Some b-carboline alkaloids such as harmine and its derivatives, are highly cytotoxic against human tumor cell lines [14][15][16][17][18][19]. In studies with bcarboline, DNA intercalation and cytotoxicity showed a correlation [20][21][22][23].…”