Krapcho, A. Paul; Menta, Ernesto; Oliva, Ambrogio; Di Domenico, Roberto; Fiocchi, Luigi; Maresch, Martin E.; Gallagher, Cynthia E.; Hacker, Miles P.; Beggiolin, Gino; Giuliani, Fernando C.; Pezzoni, Gabriella; Spinelli, Silvano published the artcile< Synthesis and Antitumor Evaluation of 2,5-Disubstituted-Indazolo[4,3-gh]isoquinolin-6(2H)-ones (9-Aza-anthrapyrazoles)>, Recommanded Product: 6,9-Difluorobenzo[g]isoquinoline-5,10-dione, the main research area is indazoloisoquinolinone antitumor preparation; azaanthrapyrazole antitumor preparation; anthrapyrazole aza antitumor preparation.
The 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 analogs. Substitution of the remaining leaving group by an amine or BOC-protected amines leads to the 9-aza-APs. These analogs were converted into their maleate or hydrochloride salts. In 2 cases, 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 3 analogs 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 have 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, these 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%. Some of theses compounds emerged as the most effective ones, with TWI% 96, similar to that of DuP-941 (TWI% = 95). On the basis of their efficacy profile in addnl. exptl. tumors and lack of cardiotoxicity in preclin. models, 2 congeners have surfaced as potential clin. candidates.
Journal of Medicinal Chemistry published new progress about Antitumor agents. 144511-13-7 belongs to class isoquinoline, and the molecular formula is C13H5F2NO2, Recommanded Product: 6,9-Difluorobenzo[g]isoquinoline-5,10-dione.
Referemce:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem