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.
Sinha
Subhash C
SC
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
Li
Lian-Sheng
LS
Miller
Gregory P
GP
Dutta
Shantanu
S
Rader
Christoph
C
Lerner
Richard A
RA
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