Synthesis of substituted indeno[1,2-b]quinoline-6-carboxamides, [1]benzothieno[3,2-b]quinoline-4-carboxamides and 10H-quindoline-4-carboxamides: evaluation of structure-activity relationships for cytotoxicity.
New substituted indeno[1,2-b]quinoline-6-carboxamides, [1]benzothieno[3,2-b]quinoline-4-carboxamides and 10H-quindoline-4-carboxamides were prepared from methyl 2-amino-3-formylbenzoate by a new Friedlander synthesis. Evaluation of these carboxamides for cytotoxicity in a panel of cell lines showed that small lipophilic substituents in the non-carboxamide ring, in a pseudo-peri position to the side chain, significantly increased cytotoxic potency while retaining a pattern of cytotoxicity consistent with a non-topo II mode of action. The methyl-substituted indeno[1,2-b]quinoline-6-carboxamide demonstrated substantial effectiveness (20-day growth delays) in a sub-cutaneous colon 38 in vivo tumor model. This is comparable to that reported for the dual topo I/II inhibitor DACA that is in clinical trial.
Chen
J
J
Chemistry Department, La Trobe University, Bundoora, Victoria, Australia.
Deady
L W
LW
Desneves
J
J
Kaye
A J
AJ
Finlay
G J
GJ
Baguley
B C
BC
Denny
W A
WA
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007192:Indenes; D007211:Indoles; D011804:Quinolines; D013876:Thiophenes; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors