Synthesis and antiproliferative evaluation of certain indolo[3,2-c]quinoline derivatives.
The present report describes the synthesis and antiproliferative evaluation of certain indolo[3,2-c]quinoline derivatives. For the C(6) anilino-substituted derivatives, (11H-indolo[3,2-c]quinolin-6-yl)phenylamine (6a) was inactive. Structural optimization of 6a by the introduction of a hydroxyl group at the anilino-moiety resulted in the enhancement of antiproliferative activity in which the activity decreased in an order of para-OH, 7a>meta-OH, 8a>ortho-OH, 9a. For the C(6) alkylamino-substituted derivatives, 11a, 12a, 13a, 14a, and 15a exhibited comparable antiproliferative activities against all cancer cells tested and the skin Detroit 551 normal fibroblast cells. Three cancer cells, HeLa, A549, and SKHep, are very susceptible with IC(50) of less than 2.17 microM while PC-3 is relatively resistant to this group of indolo[3,2-c]quinolines. For the 2-phenylethylamino derivatives, compound 20a is active against the growth of HeLa with an IC(50) of 0.52 microM, but is less effective against the growth of Detroit 551 with an IC(50) of 19.32 microM. For the bis-indolo[3,2-c]quinolines, N,N-bis-[3-(11H-indolo[3,2-c]quinolin-6-yl)aminopropyl]amine hydrochloride (25) is more active than its N-methyl derivative 26 and the positive Doxorubicin. Mechanism studies indicated 25 can induce caspase-3 activation, gamma-H2AX phosphorylation, cleavage of poly(ADP-ribose)polymerase and DNA fragmentation. These results provide evidence that DNA, topo I, and topo II are the primary targets of indolo[3,2-c]quinoline derivatives and that consequently inhibits proliferation and causes apoptosis in cancer cells.
Lu
Chih-Ming
CM
Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
Chen
Yeh-Long
YL
Chen
Hui-Ling
HL
Chen
Chyi-An
CA
Lu
Pei-Jung
PJ
Yang
Chia-Ning
CN
Tzeng
Cherng-Chyi
CC
D000218:Adamantane / Q000031:analogs & derivatives; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D000644:Quaternary Ammonium Compounds; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000972:Antineoplastic Agents, Phytogenic; D002243:Carbolines; C549979:N,N-bis-(3-(11H-indolo(3,2-c)quinolin-6-yl)aminopropyl)amine; D000644:Quaternary Ammonium Compounds; D011804:Quinolines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; C013473:diadonium; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D000218:Adamantane