Synthesis and Cytotoxicity on Human Leukemia Cells of Furonaphthoquinones Isolated from <i>Tabebuia</i> Plants

Abstract

Furonaphthoquinones are promising skeletons for anticancer drug molecules. In particular, methoxylated furonaphthoquinones are characteristic constituents of Tabebuia plants. In this research, we synthesized the furonaphthoquinones by effective one-pot cascade reactions of 3-phenyliodonio-1,2,4-trioxo-1,2,3,4-tetrahydronaphthalenides with 3-butyn-2-ol in the presence of palladium and cuprous catalysts via Sonogashira coupling and intramolecular cyclization. Furthermore, we demonstrated that the synthetic furonaphthoquinones showed moderate cytotoxicity against human leukemia U937 and HL-60 cells. Our work highlights the importance of furonaphthoquinones as antileukemic agents.Key words furonaphthoquinone; Tabebuia plant; Sonogashira coupling; antileukemic activity Tabebuia plants belong to the Bignoniaceae family, which is commonly found in North and South America. The plants have been used for the treatment of cancer as folk medicines, Pau d'Arco, Ipé Roxo, Taheebo, and Lapacho. 1) In 1982, 2-(1-hydroxyethyl) naphtho [2,3-b] furan-4,9-dione FN0-ol and 2-acetylnaphtho[2,3-b] furan-4,9-dione FN0-one were isolated from Tabebuia cassinoides. Both these furonaphthoquinones showed significant activity against human oral epidermoid carcinoma KB cells.2) Subsequently, FN0-one was investigated as an anticancer agent in vitro, and it was found that this quinone shows moderate cytotoxicity against various cancer cell lines, including human oral squamous carcinoma HSC-2, HSC-3, HSC-4, human prostate carcinoma DU-145, human melanoma C8161, human lung adenocarcinoma A549, and human epithelial carcinoma HeLa cells.3-6) Previous phytochemical investigations of Tabebuia plants resulted in the isolation and characterization of a variety of furonaphthoquinones bearing a methoxy group in the benzene ring.7-9) Thus, these methoxylated furonaphthoquinones were confirmed to be characteristic constituents of Tabebuia plants.As described above, furonaphthoquinones are considered interesting natural compounds in biochemical and pharmacological fields. Herein, we report the detailed synthesis of these furonaphthoquinones and their antileukemic activity. Results and DiscussionSome of naturally occurring furonaphthoquinones bear a 1-hydroxyethyl group at the C2-position. Kobayashi et al. reported a synthesis method of furonaphthoquinones based on sequential coupling/ring closure reactions.10) However, the reaction with intact 3-butyn-2-ol was unsuccessful. Thus, we attempted to improve their method, with the aim of making it useful for the synthesis of a wide variety of the compounds having a hydroxy group. 2-(1-Hydroxyethyl)-furonaphthoquinones such as FN0-ol are envisaged to be formed through the in situ generation of iodonaphthoquinones from phenyliodonium ylides in the presence of cuprous oxide (Cu 2 O), followed by Sonogashira coupling with acetylene and subsequent intramolecular cyclization. The phenyliodonium ylide 3-phenyliodonio-1,2,4-trioxo-1,2,3,4-tetrahydronaphthalenide IY0, which would serve as a suitable precursor for the su...

Synthesis, Characterization, and Antileukemic Properties of Naphthoquinone Derivatives of Lawsone

“…[15] Methoxylated furonaphthoquinones were found to possess moderate cytotoxicity.T he aim of this study was to determine the structure-activity relationshipso f naturallyo ccurring naphthoquinones and related analogues in human leukemia cells. [15] Methoxylated furonaphthoquinones were found to possess moderate cytotoxicity.T he aim of this study was to determine the structure-activity relationshipso f naturallyo ccurring naphthoquinones and related analogues in human leukemia cells.…”

Synthetic Studies of Naphtho[2,3-b]furan Moiety Present in Diverse Bioactive Natural Products

“…Reagents and conditions: (i) NBS, CCl 4 , (PhCO) 2 O 2 (cat. ), hν, 75%; (ii) PhSH, NaI, MeOH, reflux, 88%; (iii) NaIO 4 , MeOH/H 2 O, rt, 40 h, 75%; (iv) NaOH, ethanol, 85%; (v) TMSCl, CH 2 Cl 2 , overnight or (vi) Ac 2 O, reflux, 10 h or (vii) (CF 3 CO) 2 O, reflux or PTSA, reflux.…”

“…It also showed an ABq signal at δ 4.44 (2H) corresponding to two α-hydrogen atoms of ethylsulfoxide group. But, all attempts to effect intramolecular Pummerer reaction of 21a with various reagents such as PTSA in C 6 H 6 , Ac 2 O in toluene, (CF 3 CO) 2 Following the above failures, we turned to preparing furan sulfoxide derivative 26 starting from 3-furoic acid and chloromethylsulfanylbenzene (24) and examining its intramolecular cyclisation via Pummerer reaction to obtain 10a. Methylation of thiophenol with sodium hydroxide and dimehylsulfate in acetone under reflux condition gave 23 in 87% yield.…”

“…Particularly, the condensed quinone derivatives of naphtho [2,3-b]furans such as furonaphthoquinones have been proved to possess broad anticancer activities [1]. Recently, M. Koketsu and co-workers reported that the synthetic furonaphthoquinones showed moderate cytotoxicity against human leukemia U937 and HL-60 cells [2]. During the past decades, a wide range of furanoid natural products have been isolated from plant sources.…”

“…The combined organic phases were washed with brine (25 mL), dried (Na2 SO 4 ) and concentrated under reduced pressure. Purification of the crude residue by chromatography on silica gel (1:2 ethyl acetate/petroleum ether, 0.68) gave 17 (360 mg, 85%) as a thick oil.…”