Abstract:Naturally occurring quinones which structurally consist of an anthracene-9,10-dione chromophore are important antitumor agents. The anthracycline antibiotics, in particular, doxorubicin, are major chemothera
peutic agents. The pluramycins and the ene-diynes antibiotics also show pro i mise as antitumor drugs. The synthetic anthracene-9,10-diones such as mitoxantrone are potent antitumor agents. Analogues related to mitoxantrone have been synthesized and biologically evaluated. Aza and diaza bioiso… Show more
“…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…”
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.
“…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…”
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.
“…10,11 The anthracycline antitumor and antibiotic agents doxorubicin and daunorubicin (Figure 1) have been used for the treatment of several types of cancer such as breast and ovarian cancers, acute nonlymphocytic leukemia in adults, and acute lymphocytic leukemia in adults and children. 12 Anthracyclines intercalate between DNA bases, thus blocking DNA synthesis and transcription. They also inhibit the activity of topoisomerase II (Topo II), leading to breaks in genomic DNA.…”
Mono- and bis-N-oxides of a 9-aza-anthrapyrazole derivative having two 2-(dimethylamino)ethyl appendages were prepared by using a mild oxaziridine reagent. Biochemical and cell culture assays indicate that the bis-oxide is an inactive prodrug that readily converts to the active parent molecule under hypoxic conditions that are analogous to those present within certain tumors.
“…Molecular modeling and molecular pharmacology studies of mitoxantrone and several structurally related compounds revealed that the mode of action of this drug is multimodal in nature, though it is considered to be an intercalating agent that exerts its action primarily through binding and interaction with DNA . A great deal of research effort has been directed toward the finding of some new derivatives that might retain the remarkable anticancer activity of this agent, while reducing or eliminating its side effects, mainly cardiotoxicity and the development of resistant tumors (MDR phenotype) . The intensive search for active compounds led to the in corporation of a pyrazole ring fusion at the 1- and 9-positions of the tricyclic skeleton of mitoxantrone.…”
A series of novel pyranoxanthenones, pyranothioxanthenones, and pyranoacridones have been designed and synthesized as analogues of the acridone alkaloid acronycine, and their DNA binding and in vitro cytotoxicities have been investigated. The title compounds were derived by reaction of the corresponding 6-tosylates 5a-e with 2-hydroxyethylhydrazine, followed by conversion of the free hydroxyl of the substituted ethanols 6a-e to the corresponding mesylates, which were then treated with the suitably substituted secondary amines to provide the target derivatives 8-27. An alternative synthetic procedure for the preparation of these types of compounds is also developed, which resulted in an improvement of the overall yield. The new compounds exhibited interesting cytotoxic activity against the murine leukemia L1210 cell line, being more active than the parent compound, and a number of them possessed cytotoxicity against some human solid tumor cell lines. Especially in the case of a colon adenocarcinoma cell line, their IC(50) values were comparable to that of mitoxantrone. The results of this study indicate that the incorporation of an amino-substituted pyrazole ring into the acronycine chromophore, or into its isosteres, results in an improvement of the lead compound's activity, and therefore, it may be of use in the search of new anticancer agents derived from this natural product.
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