Design and synthesis of ellipticinium salts and 1,2-dihydroellipticines with high selectivities against human CNS cancers in vitro.
9-Methoxy-2-methylellipticinium acetate (6), along with the 9-methyl and 9-chloro derivatives (7, and 8, respectively) have shown remarkable selectivities in vitro against the NCI human CNS cancer subpanel. In order to target these types of compounds to the CNS in vivo, a series of 1,2-dihydroellipticines was synthesized. 9-Methoxy-2-methyl-1,2-dihydroellipticine (9) retained the potency and selectivity of the parent compound 6 but was unstable toward oxidation to 6. In order to improve the stability of 9, it was converted to the vinylogous amide 33 by introduction of a formyl group in the 4-position. Compound 33 proved to be much more stable than 9, but it was also less potent than 9 by about 1 order of magnitude, and it was less selective for the CNS subpanel than 9. To overcome the limited water solubilities of the ellipticines and dihydroellipticines, several ellipticine analogues incorporating polar groups on the N-2 nitrogen were prepared. The 2-(methoxymethyl)ellipticinium salts 24 and 25, as well as the (methylthio)methyl congener 26, were relatively potent anticancer agents which displayed cytotoxicity selectivity profiles similar to compound 6. The cytotoxic dihydroellipticines 9 and 10 exhibited potencies approaching that of ellipticine itself in facilitating the formation of a "cleavable complex", while the least cytotoxic ellipticine derivatives exhibited no cleavage above background.
Department of Medicinal Chemistry and Pharmacognosy, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907.
J
J
Jurayj
R D
RD
Haugwitz
R K
RK
Varma
K D
KD
Paull
J F
JF
Barrett
M
M
Cushman
D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004611:Ellipticines / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004611:Ellipticines; D059005:Topoisomerase II Inhibitors