High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent: Structure-activity relationship of daunosamine-modified derivatives of doxorubicin

Attila Nagy, Patricia Armatis, Andrew V. Schally

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

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′-deamino3′-(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.

Original languageEnglish (US)
Pages (from-to)2464-2469
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number6
DOIs
StatePublished - Mar 19 1996
Externally publishedYes

Keywords

  • Alkylating agents
  • Antineoplastic drugs
  • Cytotoxic agents
  • Design and synthesis
  • Steric factors

ASJC Scopus subject areas

  • General
  • Genetics

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