title: High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: structure-activity relationship of daunosamine-modified derivatives of doxorubicin.
abstract: A convenient, high yield conversion of doxorubicin to 3'-deamino-3'-(2''-pyrroline-1''-yl)doxorubicin is described. This daunosamine-modified analog of doxorubicin is 500-1000 times more active in vitro than doxorubicin. The conversion is effected by using a 30-fold excess of 4-iodobutyraldehyde in anhydrous dimethylformamide. The yield is higher than 85%. A homolog of this compound, 3'-deamino-3'-(1'',3''-tetrahydropyridine-1''-yl)doxorubicin, was also synthesized by using 5-iodovaleraldehyde. In this homolog, the daunosamine nitrogen is incorporated into a six- instead of a five-membered ring. This analog was 30-50 times less active than its counterpart with a five-membered ring. A similar structure-activity relationship was found when 3'-deamino-3'-(3''-pyrrolidone-1''-yl)doxorubicin (containing a five-membered ring) and 3'-deamino-3'-(3''-piperidone-1''-yl)doxorubicin (with a six-membered ring) were tested in vitro, the former being 5 times more potent than the latter. To further elucidate structure-activity relationships, 3'-deamino-3'-(pyrrolidine-1''-yl)doxorubicin, 3'-deamino-3'-(isoindoline-2''-yl)doxorubicin, 3'-deamino-3'-(2''-methyl-2''-pyrroline-1''-yl)doxorubicin, and 3'-deamino-3'-(3''-pyrroline-1''-yl)doxorubicin were also synthesized and tested. All the analogs were prepared by using reactive halogen compounds for incorporating the daunosamine nitrogen of doxorubicin into a five- or six-membered ring. These highly active antineoplastic agents can be used for incorporation into targeted cytotoxic analogs of luteinizing hormone-releasing hormone intended for cancer therapy.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70146, USA.
authors.forename: A
authors.initials: A
authors.lastname: Nagy
authors.forename: P
authors.initials: P
authors.lastname: Armatis
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000633:toxicity*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000633:toxicity; D015195:Drug Design; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D011758:Pyrroles / Q000737:chemistry / Q000633:toxicity; D012995:Solubility; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000447:Aldehydes; D000903:Antibiotics, Antineoplastic; D011758:Pyrroles; C098751:AN 204; C098752:4-iodobutyraldehyde; D004317:Doxorubicin