title: Synthesis, cytotoxicity and human telomerase inhibition activities of a series of 1,2-heteroannelated anthraquinones and anthra[1,2-d]imidazole-6,11-dione homologues.
abstract: A series of 1,2-heteroannelated anthraquinones and anthra[1,2-d]imidazole-6,11-dione tetracyclic analogues with different side chain were prepared using an various synthetic route via acylation, cyclization, condensation, and intramolecular heterocyclization. Tetracyclic system containing alkyl and aryl, aromatic and heterocyclic, linear and cyclic, polar and apolar, and basic and acids residues were incorporated. They were evaluated for their effects on telomerase activity, hTERT expression, cell proliferations, and in vitro cytotoxicity against NCI's 60 cell line human tumor screen. Compounds 4, 11, 12, 14, 15, 16, 17, 19, 20, 23, 25, and 26 were selected by the NCI for one dose screening program and further studies on 4, 23 and 25 where the curves cross these lines represent the interpolated values to cause 50% growth inhibition (GI(50)), total growth inhibition (TGI) and 50% cell killing (LC(50)), respectively. Further studies did not reveal any compound that showed potent and significant on telomerase inhibitory activity and hTERT repressing ability. Comparative testing of these compounds in the NCI's screen revealed varying levels of potency and differential cytotoxicity, apparently related to the unsaturation levels in and substitution patterns on the core ring system. It appeared that addition of a fourth planar aromatic system to a tricyclic chromophore might enhances potent cytotoxic agents, at a level equivalent to a second side chain in one of the tricyclic series. Although the exact mechanism of how this pharmacophore contributes to its activity is still unclear, however, the group in the extended arm of the tetracyclic system might contribute to proper binding to the residues within the grove of G-quadruplex structure.
authors.affiliation: School of Pharmacy, National Defense Medical Center, Taipei 11490, Taiwan, ROC. huanghs@mail.ndmctsgh.edu.tw
authors.forename: Hsu-Shan
authors.initials: HS
authors.lastname: Huang
authors.forename: Tsung-Chih
authors.initials: TC
authors.lastname: Chen
authors.forename: Ruei-Huei
authors.initials: RH
authors.lastname: Chen
authors.forename: Kuo-Feng
authors.initials: KF
authors.lastname: Huang
authors.forename: Fong-Chun
authors.initials: FC
authors.lastname: Huang
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Jhan
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.forename: Chia-Chung
authors.initials: CC
authors.lastname: Lee
authors.forename: Yang
authors.initials: Y
authors.lastname: Lo
authors.forename: Jing-Jer
authors.initials: JJ
authors.lastname: Lin
mesh_terms: D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; D007093:Imidazoles; D018894:Reverse Transcriptase Inhibitors; D013830:Thiadiazoles; C000604512:anthra(2,1-c)(1,2,5)thiadiazole-6,11-dione; D019098:Telomerase