Prodrugs of dynemicin analogs for selective chemotherapy mediated by an aldolase catalytic Ab.
Prodrugs of dynemicin analogs were synthesized, and their activation by aldolase antibody (Ab) 38C2 was evaluated by DNA-cleaving activity, as well as tumor cell growth inhibition. Further, we provide evidence that the activated enediynes underwent covalent crosscoupling with the aldolase Ab, which appears to be a limiting factor of their tumor cell growth-inhibiting activity and should be of general interest in the field of enediyne chemotherapy. These findings might open new avenues for defined conjugations of small molecule drugs to mAbs in general and aldolase Abs in particular.
The Skaggs Institute for Chemical Biology and Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. subhash@scripps.edu
Subhash C
SC
Sinha
Lian-Sheng
LS
Li
Gregory P
GP
Miller
Shantanu
S
Dutta
Christoph
C
Rader
Richard A
RA
Lerner
D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017151:Antibodies, Catalytic / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms; D015195:Drug Design; D005634:Fructose-Bisphosphate Aldolase / Q000276:immunology*; D006801:Humans; D007202:Indicators and Reagents; D013058:Mass Spectrometry; D011355:Prodrugs / Q000737:chemistry / Q000633:toxicity
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D017151:Antibodies, Catalytic; D007202:Indicators and Reagents; D011355:Prodrugs; D005634:Fructose-Bisphosphate Aldolase