Anthracycline antitumor agent

R) -( + )-2-Acetyl-5,8-dimethoxy-l,2,3,4-tetrahydro-2-naphthol (173) is a key intermediate in the asymmetric synthesis of anthracycline antitumor agents demethoxyadriamycin (174 X = Y = OH) and 4-demethoxydaunomycin (174 X = Y = H) <94JOCli84>. The crucial step in a highly efficient asymmetric synthesis of (173) involves the enantioselective hydroxylation (>95% ee) of the potassium enolate of (171) with (—)-[(8,8-dimethoxycamphoryl)sulfonyl]-oxaziridine (158) to afford (172). Conversion to (173) was accomplished in three steps in 50% overall yield from (171) without racemization (Scheme 32). 

L-Daunosamine (166) (R=H), (3-amino-2,3,6-trideoxy-L-/yxo-hexose), is an essential component of both natural and unnatural anthracycline antitumor agents. The 1,3-addition of ketene silyl acetal 164 to the chiral nitrone (Z)-[(4i )- ra 5-2,2,5-trimethyl-l,3-dioxolan-4-yl]methylene[(l S)-l-phenylethyl] amine 7V-oxide (163), prepared by the conversion of 141 to 103 [62] and then reaction of 103 with the hydroxylamine 162, provides the 0-silylated addition product 165 in quantitative yield with an anti relative stereochemistry at C-3 and C-4 (anti syn =>100 1). Efficient transformation of 165 to 166 (R=COPh) is achieved in three steps [63] (Scheme 39). 

Daunorubicin -anthracycline antitumor antibiotic DNA intercalating agent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -vesicant if extravasated —cardiotoxicity (550 mg/M2) -Liposomal daunorubicin there is significantly less bone marrow suppression, nausea and vomiting, stomatitis, and cardiotoxicity... 

Daunomycin and its analog adriamycin are in clinical use as potent antitumor agents in combination chemotherapy against acute lymphocytic leukemia. It has been suggested that the antitumor properties are associated with intercalation of the anthracycline ring of the antibiotic into the DNA of rapidly proliferating neoplastic cells and subsequent blocking of RNA synthesis (72-75). [5]... 

Daunorubicin, doxorubicin, epirubicin, idarubicin, and mitoxantrone are among the most important antitumor agents. They are derived from the fungus S. peucetius var. caesius. Idarubicin and epirubicin are analogs of the naturally produced anthracyclines, differing only slightly in chemical structure, but having somewhat distinct patterns of clinical activity. Daunorubicin and idarubicin have been used primarily in acute leukemias, whereas doxorubicin... 

There are now more than forty drugs approved for the treatment of human cancer in the United States. Considering the thousands of compounds that have been tested as candidate antitumor agents, this is a highly select group. Among them are two drugs that require a metal ion as part of their structures. One is the simple metal complex cis-diamminedichloroplatinum(ii). The other, bleomycin, is a natural product that must form an iron complex to display cytotoxicity. In addition, two anthracycline natural products, doxorubicin or adriamycin, and daunomycin, may also function as iron complexes or utilize cellular iron in an indirect way in their mechanisms of action. 

Johdo O, Nishimura M, Tone H, Okamoto R (1993) Preparation of anthracycline compounds as antitumor agents. Jpn Kokai Tokkyo Koho JP Patent 05039242 (Chem Abstr 119 93691)... 

The hydroxyl group in C-9 is very important for the antitumor activity of anthracyclines, and many derivatives have been synthesized confirming this. The only compound with an interesting activity was amrubicin (SM-5887), a 9-aminoanthracychne that in clinical trials showed almost the same antitumor activity and less cystic irritability as compared to DOXO and EPI [31,32]. When this hydroxyl group was substituted with a fluorine atom, the correspondent derivative showed lower activity as an antitumor agent than the reference compoimds (personal impubhshed data). Therefore, only chemical references are present in the literature on these derivatives. 

The anthracycline quinine antibiotics daunonibicin (DNR) and doxorubicin (DOX) (Figure 5) are potent antitumor agents against a variety of human solid... 

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