title: Novel angular benzophenazines: dual topoisomerase I and topoisomerase II inhibitors as potential anticancer agents.
abstract: A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23 parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576 ((R)-4j' '). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.
authors.affiliation: Medicinal Chemistry Department, Xenova Ltd., 957 Buckingham Avenue, Slough, Berkshire, SL1 4NL, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Vicker
authors.forename: Luke
authors.initials: L
authors.lastname: Burgess
authors.forename: Irina S
authors.initials: IS
authors.lastname: Chuckowree
authors.forename: Rory
authors.initials: R
authors.lastname: Dodd
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Folkes
authors.forename: David J
authors.initials: DJ
authors.lastname: Hardick
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Hancox
authors.forename: Warren
authors.initials: W
authors.lastname: Miller
authors.forename: John
authors.initials: J
authors.lastname: Milton
authors.forename: Sukhjit
authors.initials: S
authors.lastname: Sohal
authors.forename: Shouming
authors.initials: S
authors.lastname: Wang
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Wren
authors.forename: Peter A
authors.initials: PA
authors.lastname: Charlton
authors.forename: Wendy
authors.initials: W
authors.lastname: Dangerfield
authors.forename: Chris
authors.initials: C
authors.lastname: Liddle
authors.forename: Prakash
authors.initials: P
authors.lastname: Mistry
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Stewart
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010619:Phenazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C446952:4-methoxybenzo(a)phenazine-11-carboxylic acid (2-(dimethylamino)-1-methylethyl)amide; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010619:Phenazines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors