“…Anthrapyrazoles were initially developed as chromophore-modified anthracene-9,10-diones with the goals of increasing the spectrum of antitumor activity and reducing the cardiotoxic potential exhibited by quinone analogues. − Compounds of this class, such as DuP-941 and DuP-942 (Chart ), were expected to be less prone to undergo bioreduction to anion radicals and thus could inhibit radical-cycling processes which might be responsible for cardiotoxicity. 2 Structures of DuP-941 and DuP-942…”
Section: Introductionmentioning
confidence: 99%
“…It has also been proposed that the reduced peroxidizing activity may be a result of the decreased affinity of these molecules for NADH dehydrogenase responsible for the one-electron transfer to the chromophore . In addition, it has been noted that while molecules such as DuP-941 are quite resistant to metabolic reduction they are susceptible to facile oxidation . However, whereas DuP-941 has demonstrated good clinical efficacy in treatment of breast cancer, cardiac toxicitiy has been observed during clinical trials with both DuP-941 and DuP-942. − …”
Section: Introductionmentioning
confidence: 99%
“…23 In addition, it has been noted that while molecules such as DuP-941 are quite resistant to metabolic reduction they are susceptible to facile oxidation. 32 However, whereas DuP-941 has demonstrated good clinical efficacy in treatment of breast cancer, 36 cardiac toxicitiy has been observed during clinical trials with both DuP-941 and DuP-942. [39][40][41][42][43][44] Of particular interest to us was the preparation of aza analogues related to the anthrapyrazoles (Chart 3).…”
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 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.
“…Anthrapyrazoles were initially developed as chromophore-modified anthracene-9,10-diones with the goals of increasing the spectrum of antitumor activity and reducing the cardiotoxic potential exhibited by quinone analogues. − Compounds of this class, such as DuP-941 and DuP-942 (Chart ), were expected to be less prone to undergo bioreduction to anion radicals and thus could inhibit radical-cycling processes which might be responsible for cardiotoxicity. 2 Structures of DuP-941 and DuP-942…”
Section: Introductionmentioning
confidence: 99%
“…It has also been proposed that the reduced peroxidizing activity may be a result of the decreased affinity of these molecules for NADH dehydrogenase responsible for the one-electron transfer to the chromophore . In addition, it has been noted that while molecules such as DuP-941 are quite resistant to metabolic reduction they are susceptible to facile oxidation . However, whereas DuP-941 has demonstrated good clinical efficacy in treatment of breast cancer, cardiac toxicitiy has been observed during clinical trials with both DuP-941 and DuP-942. − …”
Section: Introductionmentioning
confidence: 99%
“…23 In addition, it has been noted that while molecules such as DuP-941 are quite resistant to metabolic reduction they are susceptible to facile oxidation. 32 However, whereas DuP-941 has demonstrated good clinical efficacy in treatment of breast cancer, 36 cardiac toxicitiy has been observed during clinical trials with both DuP-941 and DuP-942. [39][40][41][42][43][44] Of particular interest to us was the preparation of aza analogues related to the anthrapyrazoles (Chart 3).…”
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 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.
The anticancer activity of 35 2,5-disubstituted 9-Aza-Anthrapyrazoles (9-aza-APs) was analyzed employing the Best Multiple Linear Regression (BMLR) as well as a heuristic method for selection of the best descriptors implemented in the CODESSA software to provide a reliable 2D-QSAR model from a set of nearly 500 descriptors. The Chem-X (version 2000) software was used to develop a corresponding 3D-QSAR model. The steric and electrostatic interactions between a probe atom (H þ ) and a set of aligned molecules were assessed using the comparative molecular field analysis method. The results from 2D-and 3D-QSAR analyses show that the anticancer activity of the studied series of 9-aza-APs is strongly dependent on electrostatic interactions. A binding of these derivatives to DNA has been discussed as a key factor determining the cytotoxic activity against tumor cell. The value of the maximum sum partial negative charge at the nitrogen atoms in 9-aza-APs influences strongly the activity of the compounds. The magnitude of these charges define the hydrogen-bond acceptor properties of the 9-aza-APs. The hydrogenbond donor properties of the NH and OH groups in the studied series of compounds also play a key role in the binding process. The stable ring structure of the 9-aza-APs also appears to be an important factor for the antitumor activity of the compounds.
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