jm9804432_si_001.pdf (807.13 kB)
Synthesis and Antitumor Evaluation of 2,5-Disubstituted- Indazolo[4,3-gh]isoquinolin-6(2H)-ones (9-Aza-anthrapyrazoles)
journal contribution
posted on 1998-12-01, 00:00 authored by A. Paul Krapcho, Ernesto Menta, Ambrogio Oliva, Roberto Di Domenico, Luigi Fiocchi, Martin E. Maresch, Cynthia E. Gallagher, Miles P. Hacker, Gino Beggiolin, Fernando C. Giuliani, Gabriella Pezzoni, Silvano SpinelliThe synthesis and antitumor evaluation of 2,5-disubstituted-indazolo[4,3-gh]isoquinolin-6(2H)-ones (9-aza-APs) are described. The key intermediates in the synthesis are benz[g]isoquinoline-5,10-diones which are substituted at positions 6 and 9 with groups of different nucleofugacity
for SNAr displacements. The initial displacement of fluoride by a substituted hydrazine leads
to the pyrazole analogues. Substitution of the remaining leaving group by an amine or BOC-protected amines leads to the 9-aza-APs 12. These analogues were converted into their maleate
or hydrochloride salts 13. In two cases, namely, 13x and 13z, sidearm buildup was also employed
in the synthetic pathway. In vitro evaluation of 9-aza-APs against the human colon tumor cell
line LoVo uncovered for most of the compounds a cytotoxic potency lower than that of DuP-941 or mitoxantrone and comparable to that of doxorubicin. Only analogues 13c, 13n, and
13ff were as cytotoxic as DuP-941. Interestingly, while DuP-941 was highly cross-resistant in
the LoVo cell line resistant to doxorubicin (LoVo/Dx), the 9-aza-APs carrying a distal lipophilic
tertiary amine moiety in both chains were capable of overcoming the MDR resistance induced
in this cell line. The 9-aza-APs show outstanding in vivo antitumor activity against both
systemic P388 murine leukemia and MX-1 human mammary carcinoma transplanted in nude
mice. At their optimal dosages, congeners 13a−c, 13f, 13n, 13q, 13x, and 13dd were highly
effective against P388 leukemia with T/C% of 200−381, while the T/C% value of DuP-941 was
147. In the MX-1 tumor model, 24 compounds elicited percentages of tumor weight inhibitions
(TWI) ranging from 50% to 99%. Congeners 13d, 13k, 13l, 13x, 13z, and 13ee emerged as the
most effective ones, with TWI% 96, simliar to that of DuP-941 (TWI% = 95). On the basis of
their efficacy profile in additional experimental tumors and lack of cardiotoxicity in preclinical
models, two congeners have surfaced as potential clinical candidates.