Novel angular benzophenazines: dual topoisomerase I and topoisomerase II inhibitors as potential anticancer agents.
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.
Vicker
Nigel
N
Medicinal Chemistry Department, Xenova Ltd., 957 Buckingham Avenue, Slough, Berkshire, SL1 4NL, UK.
Burgess
Luke
L
Chuckowree
Irina S
IS
Dodd
Rory
R
Folkes
Adrian J
AJ
Hardick
David J
DJ
Hancox
Timothy C
TC
Miller
Warren
W
Milton
John
J
Sohal
Sukhjit
S
Wang
Shouming
S
Wren
Stephen P
SP
Charlton
Peter A
PA
Dangerfield
Wendy
W
Liddle
Chris
C
Mistry
Prakash
P
Stewart
Alistair J
AJ
Denny
William A
WA
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
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