Antitumor agents. 203. Carbazole alkaloid murrayaquinone A and related synthetic carbazolequinones as cytotoxic agents.
Murrayaquinone A (1) and murrayafoline A (3), isolated from the root bark of Murraya euchrestifolia, were identified as cytotoxic compounds. Murrayaquinone A (1) demonstrated significant cytotoxicity against SK-MEL-5 and Colo-205 cells, with ED(50) values of 2.58 and 3.85 microg/mL, respectively. In contrast, murrayafoline A (3) exhibited marginal or weak cytotoxicity against SK-MEL-5, Colo-205, HCT-8, KB, and A-549 tumor cell lines, with ED(50) values ranging from 5.31 to 7.52 microg/mL. In total, 20 carbazole alkaloids (1-20), isolated previously by Furukawa et al. from various plant sources were also evaluated for their cytotoxic profiles in the NCI's human disease-oriented, 60-cell line, in vitro antitumor screening protocol. Compounds 3 and 15 showed potent cell-line selective cytotoxicity against MOLT-4 cells, with log GI(50) values of -8.60 and -8.49 M, respectively, while 12 demonstrated better selectivity against the colon cancer subpanel. Moreover, synthetic 2-methyl- or 3-methyl-carbazolequinone derivatives with various substituents in the A-ring were evaluated against KB, SK-MEL-5, Colo-205, and HCT-8 tumor cells. 6-Methoxy- (21), 6-methyl- (22), and 6-chloro- (24) 3-methyl-carbazolequinones demonstrated significant cytotoxicity against SK-MEL-5 cells, with ED(50) values of 0.55, 0.66, and 0.83 microg/mL, respectively. Compounds 21 and 22 were also significantly cytotoxic toward KB cells, with ED(50) values of 0.76 and 0.92 microg/mL, respectively, and 21 displayed a similar level of toxicity against Colo-205 cells (ED(50) 0.87 microg/mL).
Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
M
M
Itoigawa
Y
Y
Kashiwada
C
C
Ito
H
H
Furukawa
Y
Y
Tachibana
K F
KF
Bastow
K H
KH
Lee
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D010944:Plants / Q000737:chemistry; D011809:Quinones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D016227:Benzoquinones; D002227:Carbazoles; D011809:Quinones; C062196:murrayaquinone A