Dimeric analogues of non-cationic tricyclic aromatic carboxamides are a new class of cytotoxic agents.
A series of tricyclic aromatic carboxamides, and their corresponding dimeric analogues, were prepared and their growth-inhibitory properties were evaluated in a series of cell lines. The dimeric compounds were prepared by reaction of the appropriate acids with carbonyl-1,1'-diimidazole, isolating the resulting imidazolides, and reacting these with a stoichiometric amount of the diamine. The monomeric carboxamides containing a (CH2)2NMe2 side chain had widely differing inhibitory potencies, with the known nitronaphthalimide (mitonafide) and acridine-4-carboxamide (DACA) being the most potent. The corresponding bis analogues, linked by a (CH2)3NMe(CH2)3 chain, were generally more potent, with the largest increases (dimer/monomer ratio 20- to 30-fold) seen for the nitronaphthalimides and the phenazines. Based on the intrinsic cytotoxicity of the monomers and the highest degree of increase in cytotoxicity on dimerization, the most interesting chromophores appear to be the acridine-4-carboxamide and phenazine-1-carboxamide. Both of these compounds showed significant growth delays (approximately 6 days) in an in vivo colon 38 tumour model in mice.
Spicer
J A
JA
Auckland Cancer Society Research Centre, Faculty of Medicine and Health Science, University of Auckland, New Zealand.
Gamage
S A
SA
Atwell
G J
GJ
Finlay
G J
GJ
Baguley
B C
BC
Denny
W A
WA
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D019281:Dimerization; D004354:Drug Screening Assays, Antitumor; D006131:Growth Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019169:Jurkat Cells / Q000187:drug effects / Q000473:pathology; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D013329:Structure-Activity Relationship
D000577:Amides; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D007364:Intercalating Agents