Anthracene-9,10-diones as potential anticancer agents. Synthesis, DNA-binding, and biological studies on a series of 2,6-disubstituted derivatives.
A series of 2,6-bis(omega-aminoalkanamido)anthracene-9,10-diones (9,10-anthraquinones), of general formula Ar(NHCO(CH2)nNR2)2, where Ar = anthracene-9,10-dione and n = 1 or 2, have been synthesized by treatment of the corresponding bis(omega-haloalkanamido) derivatives with appropriate secondary amines. The DNA-binding properties of these compounds were evaluated by thermal denaturation studies, unwinding of closed-circular DNA, determination of association constants in solution, and examined by molecular modeling. A representative compound in the series has been examined by X-ray crystallography. In vitro cytotoxicity data is reported for the compounds and some indications of structure-activity relationships have been discerned. In particular, those compounds with two methylene links (n = 2) in each side chain separating the amide and terminal amine moieties have superior activity and, in general, enhanced DNA binding characteristics. It is postulated that the mode of reversible binding of these compounds to DNA involves the side chains occupying both major and minor grooves and, further, that this may confer cytotoxic properties which are distinct from those of previously reported anthracene-9,10-dione cytotoxins.
Agbandje
M
M
Cancer Research Campaign Biomolecular Structure Unit, Institute of Cancer Research, Sutton, Surrey, U.K.
Jenkins
T C
TC
McKenna
R
R
Reszka
A P
AP
Neidle
S
S
D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002279:Carcinoma 256, Walker / Q000188:drug therapy; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000378:metabolism*; D007939:Leukemia L1210 / Q000188:drug therapy; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004247:DNA