9-Alkyl, morpholinyl anthracyclines in the circumvention of multidrug resistance.
The intramolecular combination of 9-alkyl substitution in the anthracycline A-ring plus incorporation of the amino group of the daunosamine sugar within a morpholinyl ring led to the retention of almost complete activity against P-glycoprotein positive, multidrug resistant variants of a mouse mammary tumour line and a human small cell lung cancer line. Resistance factors were close to unity. These structural elements may prevent efflux by the P-glycoprotein multidrug transporter. The use of 9-alkyl, morpholinyl anthracyclines with resistance circumvention properties may have clinical application.
Coley
H M
HM
Clinical Oncology Unit, Medical Research Council Centre, Cambridge, U.K.
Twentyman
P R
PR
Workman
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015250:Aclarubicin / Q000031:analogs & derivatives / Q000627:therapeutic use; D000276:Adjuvants, Immunologic / Q000627:therapeutic use; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004351:Drug Resistance; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D009363:Neoplasm Proteins / Q000032:analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000276:Adjuvants, Immunologic; D000903:Antibiotics, Antineoplastic; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C011157:aclacinomycins; D015250:Aclarubicin; D004317:Doxorubicin; C048396:NSC 354646; C038555:3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin