A series of 5-[(aminoalkyl)amino]-substituted anthra[1,9-cd] pyrazol-6(2H)ones (anthrapyrazoles) were synthesized. These compounds, which differ from the
anthracenediones in that an additional
pyrazole ring has been fused to the
anthracene system in place of one carbonyl group, were evaluated in vivo for their anticancer activity in eight different mouse
tumor systems. Compounds were selected for testing primarily on the basis of their high levels of activity
P388 leukemia and occasionally for structural considerations. Sixty-seven % of the 21 analogues studied were curative in the National Cancer Institute P388 screen. Many of the compounds tested were highly active against each of the
tumors of the National Cancer Institute panel. Thus 82, 73, 45, and 80% of the compounds tested were curative for
L1210 leukemia,
B16 melanoma, M5076
sarcoma, and the MX-1 mammary xenograft, respectively. Several of the compounds studied were curative against every
tumor of the above panel. Because of the high activity of the
anthrapyrazole series as a class in the National Cancer Institute
tumor panel, additional testing was necessary to allow selection of clinical candidates. Twenty-one anthrapyrazoles were tested against mammary
adenocarcinoma 16C,
colon adenocarcinoma 11a, and the Ridgway
osteogenic sarcoma. Four compounds, PD 113,309 (Cl-937), PD 113,785 (Cl-941), PD 111,815 (Cl-942), and PD 115,593, were judged superior to the rest on the basis of the expanded panel testing. The preclinical data to date suggest that these anthrapyrazoles are similar to
doxorubicin in both degree and spectrum of activity. Each of these anthrapyrazoles were significantly more active than were the other synthetic
intercalating agents, the
anthracenediones mitoxantrone and
ametantrone, against the
tumors of the expanded panel. On the basis of their high level of broad spectrum activity in preclinical systems, ease of formulation, possible lack of cross-resistance with
doxorubicin, and potential lack of
cardiotoxicity, Cl-937, Cl-941, and Cl-942 have been selected for further preclinical evaluation and possible clinical development.