Synthesis and antitumor activity of quaternary ellipticine glycosides, a series of novel and highly active antitumor agents.
A series of ellipticine glycosides [2-N-glycosyl quaternary pyridinium salts of three ellipticines: ellipticine (1), 9-methoxyellipticine (2), and 9-hydroxyellipticine (4)] were stereoselectively synthesized in good yields by an improved condensation reaction between ellipticines [1, 2, and 9-acetoxyellipticine (3)] and protected (peracylated and perbenzylated) glycosyl halides with cadmium carbonate, followed by deprotection. These glycosides were preliminarily evaluated for their antitumor activity in the L1210 leukemia system. Twenty-six (53%) of the 49 glycosides tested were curative, and five [9-hydroxyellipticine L-arabinopyranoside (41b), D-lyxofuranoside (43a), L-lyxopyranoside (44b), D-xylofuranoside (49a), and L-rhamnopyranoside (56)] were selected for extended evaluation on the basis of their high levels of activity. The structure-activity relationships are discussed. The selected glycosides showed remarkable activity in six different murine tumor systems with excellent therapeutic ratios; their efficacy surpassed that of doxorubicin against three of these systems. On the basis of these results and ease of formulation, the two glycosides 41b (SUN4599) and 49a (SUN5073) were selected for further preclinical evaluation and possible clinical development.
Honda
T
T
Suntory Institute for Biomedical Research, Osaka, Japan.
Kato
M
M
Inoue
M
M
Shimamoto
T
T
Shima
K
K
Nakanishi
T
T
Yoshida
T
T
Noguchi
T
T
D000470:Alkaloids / Q000138:chemical synthesis*; D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D055598:Chemical Phenomena; D002621:Chemistry; D004611:Ellipticines / Q000138:chemical synthesis* / Q000627:therapeutic use; D006027:Glycosides / Q000138:chemical synthesis* / Q000627:therapeutic use; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008813:Mice, Inbred ICR; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D012510:Sarcoma 180 / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000470:Alkaloids; D004611:Ellipticines; D006027:Glycosides