Synthesis and antitumor evaluations of symmetrically and unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones and 1,4-bis[(aminoalkyl)amino]-5,8-dihydroxyanthracene-9,10-diones.
The ipso bis displacements of fluoride from 1,4-difluoroanthracene-9,10-dione (3) and 1,4-difluoro-5,8-dihydroxyanthracene-9,10-dione (4) by excess of a diamine (or a monoamine) in pyridine at room temperature lead to the symmetrically substituted 1,4-bis-substituted analogues 5 and 6, respectively. The ipso monodisplacements of fluoride from 3 and 4 can be accomplished by treatment with less than 1 molar equiv of a diamine (or a monoamine) to yield 7 and 8, respectively. Treatment of 7 or 8 with a different diamine leads to the unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones 9 and 10, respectively. Many of the synthetic unsymmetrical analogues have been evaluated for their antitumor activity against L1210 in vitro and in vivo. Cross resistance of analogue 10a with mitoxantrone (2) and doxorubicin was evaluated against MDR lines in vitro against human colon carcinoma LOVO and its subline resistant to DOXO (LOVO/DOXO). Potential mechanisms for the observed cytotoxicity are presented and discussed.
Krapcho
A P
AP
Department of Chemistry, University of Vermont, Burlington 05405.
Getahun
Z
Z
Avery
K L
KL
Vargas
K J
KJ
Hacker
M P
MP
Spinelli
S
S
Pezzoni
G
G
Manzotti
C
C
D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D003110:Colonic Neoplasms / Q000188:drug therapy; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008942:Mitoxantrone / Q000031:analogs & derivatives*; D015394:Molecular Structure; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D000970:Antineoplastic Agents; C081357:BBR 2577; D008942:Mitoxantrone