TY - JOUR
T1 - High yield conversion of doxorubicin to 2-pyrrolinodoxorubicin, an analog 500-1000 times more potent
T2 - Structure-activity relationship of daunosamine-modified derivatives of doxorubicin
AU - Nagy, Attila
AU - Armatis, Patricia
AU - Schally, Andrew V.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 1996/3/19
Y1 - 1996/3/19
N2 - 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.
AB - 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.
KW - Alkylating agents
KW - Antineoplastic drugs
KW - Cytotoxic agents
KW - Design and synthesis
KW - Steric factors
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U2 - 10.1073/pnas.93.6.2464
DO - 10.1073/pnas.93.6.2464
M3 - Article
C2 - 8637897
AN - SCOPUS:0029965293
VL - 93
SP - 2464
EP - 2469
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 6
ER -