Synthesis and antitumor activity of 9-[(carbamoyloxy)alkyl]anthracyclines: a novel class of anthracycline derivatives.
A number of 4-demethoxyanthracyclines having hydroxylalkyl functions at the 9-position have previously been synthesized and shown to have potent antitumor activity. A series of carbamate derivatives of these (hydroxyalkyl)anthracyclines have now been prepared, many of which possess considerably greater efficacy in an L-1210 leukemia test system than do the parent alcohols or the known anthracyclines daunorubicin (1), doxorubicin (2), and 4-demethoxydaunorubicin (3). Phenylcarbamate 8a was more active than methyl analogue 8b, while the 4'-deoxy and 4'-epi phenylcarbamates 17 and 18 showed particularly high efficacy at optimal dose levels similar to that of doxorubicin. Secondary carbamates were more potent, with the 13R isomer 23 having significantly higher efficacy than 13S analogue 24.
Adams
N
N
Roche Products Limited, Welwyn Garden City, Hertfordshire, England.
Blake
C
C
Broadhurst
M J
MJ
Bushnell
D J
DJ
Hassall
C H
CH
Hartmann
H R
HR
Keech
E
E
Stratton
A R
AR
Thomas
G J
GJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000627:therapeutic use; D002219:Carbamates / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D005260:Female; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000903:Antibiotics, Antineoplastic; D002219:Carbamates