Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic acids.
Analogues of 9-oxo-9H-xanthene-4-acetic acid (XAA) bearing small, lipophilic 5-substituents are among the most dose-potent compounds yet reported with the capability of causing hemorrhagic necrosis of implanted colon 38 tumors in mice. To further extend structure-activity relationships among this class of compound, a series of XAA derivatives bearing two small lipophilic groups at various positions have been prepared and evaluated. The 5,6-disubstituted compounds in particular show consistently high levels of both dose potency and activity, suggesting this is the optimal configuration among substituted 9-oxo-9H-xanthene-4-acetic acids. The 5,6- dimethyl and 5-methyl-6-methoxy are the most effective analogues, showing in vivo colon 38 activity comparable to that of FAA at 10-15-fold lower doses and superior activity to FAA at the respective optimal doses, and the former has been selected for detailed evaluation.
Rewcastle
G W
GW
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Atwell
G J
GJ
Li
Z A
ZA
Baguley
B C
BC
Denny
W A
WA
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D007202:Indicators and Reagents; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014966:Xanthenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D044004:Xanthones
D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan