“…Silica gel chromatography (eluant ethyl acetate/methanol/acetic acid from 96:4:0 to 90: 10:1) led to 9 (0.80 g): mp > 220 °C; R f 0.5 (silica gel, ethyl acetate/methanol/acetic acid, 85:15:1); 1 H NMR (DMSO-d6) δ 8.97 (s, 1H), 8.61 (d, 1H), 7.21 (d, 1H), 7.12-6.91 (m, 3H), 4.33 (s, 2H), 3.70 (s, 3H). 9-Fluoro-10-hydroxy-6-methoxybenz[g]isoquinoline (10). A mixture of 9 (0.63 g, 2.41 mmol) and polyphosphoric acid (15 g) was heated at 110-120 °C for 2 h with stirring.…”
“…Many useful therapeutic drugs have their discoveries rooted in serendipity. In particular, one might note the development of the important anticancer drugs doxorubicin and mitoxantrone (Chart ). − Mitoxantrone, an anthracene-9,10-dione, has gained an important position in the clinical management of leukemia and lymphomas as well as in combination therapy of advanced breast and ovarian cancers. − Although mitoxantrone is endowed with an improved tolerance profile when compared with doxorubicin and other anthracyclines, it is not devoid of significant toxic side effects, especially those associated with myelosuppression and cardiotoxicity. , Mitoxantrone also shows a cross-resistance to cell histotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein P. − The cell-killing effects elicited by mitoxantrone are probably multimodal in nature . Several studies suggest that intercalation into DNA is a major cellular event and this intercalative interaction may serve as an anchor for the drug at specific base pair sites, , which is then followed by the critical cell-killing events. − 1 Structures of Mitoxantrone and BBR 2778…”
Section: Introductionmentioning
confidence: 99%
“…[5][6][7] Although mitoxantrone is endowed with an improved tolerance profile when compared with doxorubicin and other anthracyclines, 8 it is not devoid of significant toxic side effects, especially those associated with myelosuppression and cardiotoxicity. 9,10 Mitoxantrone also shows a cross-resistance to cell histotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein P. [11][12] The cell-killing effects elicited by mitoxantrone are probably multimodal in nature. 13 Several studies suggest that intercalation into DNA is a major cellular event and this intercalative interaction may serve as an anchor for the drug at specific base pair sites, 14,15 which is then followed by the critical cell-killing events.…”
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.
“…Silica gel chromatography (eluant ethyl acetate/methanol/acetic acid from 96:4:0 to 90: 10:1) led to 9 (0.80 g): mp > 220 °C; R f 0.5 (silica gel, ethyl acetate/methanol/acetic acid, 85:15:1); 1 H NMR (DMSO-d6) δ 8.97 (s, 1H), 8.61 (d, 1H), 7.21 (d, 1H), 7.12-6.91 (m, 3H), 4.33 (s, 2H), 3.70 (s, 3H). 9-Fluoro-10-hydroxy-6-methoxybenz[g]isoquinoline (10). A mixture of 9 (0.63 g, 2.41 mmol) and polyphosphoric acid (15 g) was heated at 110-120 °C for 2 h with stirring.…”
“…Many useful therapeutic drugs have their discoveries rooted in serendipity. In particular, one might note the development of the important anticancer drugs doxorubicin and mitoxantrone (Chart ). − Mitoxantrone, an anthracene-9,10-dione, has gained an important position in the clinical management of leukemia and lymphomas as well as in combination therapy of advanced breast and ovarian cancers. − Although mitoxantrone is endowed with an improved tolerance profile when compared with doxorubicin and other anthracyclines, it is not devoid of significant toxic side effects, especially those associated with myelosuppression and cardiotoxicity. , Mitoxantrone also shows a cross-resistance to cell histotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein P. − The cell-killing effects elicited by mitoxantrone are probably multimodal in nature . Several studies suggest that intercalation into DNA is a major cellular event and this intercalative interaction may serve as an anchor for the drug at specific base pair sites, , which is then followed by the critical cell-killing events. − 1 Structures of Mitoxantrone and BBR 2778…”
Section: Introductionmentioning
confidence: 99%
“…[5][6][7] Although mitoxantrone is endowed with an improved tolerance profile when compared with doxorubicin and other anthracyclines, 8 it is not devoid of significant toxic side effects, especially those associated with myelosuppression and cardiotoxicity. 9,10 Mitoxantrone also shows a cross-resistance to cell histotypes developing resistance against doxorubicin mediated by overexpression of glycoprotein P. [11][12] The cell-killing effects elicited by mitoxantrone are probably multimodal in nature. 13 Several studies suggest that intercalation into DNA is a major cellular event and this intercalative interaction may serve as an anchor for the drug at specific base pair sites, 14,15 which is then followed by the critical cell-killing events.…”
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.
“…Three cases of mitoxantrone-induced bradycardia have been previously reported. 10,14,18 These authors did not report bradycardia with PVCs. The precise mechanism of mitoxantrone-induced cardiotoxicity is u nknown.…”
Section: Discussionmentioning
confidence: 92%
“…14 The pathogenesis of anthracyclin einduced cardiotoxicity is thought to be multifactorial and may include a disturbance in myocardial adrenergic function, or the release of vasoactive amines and inflammatory cytokines. 1,14 Prior to her therapy with mitoxantrone, this patient received an anthracycline as part of her induction therapy for acute myelogenous leukemia. It is probable that her previous anthracycline therapy contributed to the cardiotoxic reaction seen with mitoxantrone.…”
Anthracycline-induced cardiotoxicity has been well documented in the literature. Doxorubicin has been most commonly implicated; however, electrocardiogram changes have also been reported with the use of mitoxantrone. We report a case of a 55-year-old female with recurrent acute myelogenous leukemia who underwent reinduction therapy with mitoxantrone and etoposide daily for five doses. Nearing completion of her fifth mitoxantrone dose, she complained of chest tightness and developed bradycardia. Her symptoms resolved with discontinuation of the agent; however, upon rechallenge, she again developed sinus bradycardia with premature ventricular contractions and a corrected QT interval of 0.499 seconds. Clinicians should be aware of the risk factors for mitoxantrone-induced cardiotoxicity and monitor their patients appropriately while on therapy.
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