Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 51, Issue 21, Pages 6916-6926Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm800719t
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Funding
- National Cancer Institute of the NIH [CA 114802-01A1]
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CPT-11 is a clinically used cancer drug, and it is a prodrug of the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin). To bypass the need for the in vivo conversion of CPT-11 and increase the therapeutic index, bifunctional derivatives of SN-38 were prepared for use in anti body-based targeted therapy of cancer. The general synthetic scheme incorporated an acetylene-azide click cycloaddition step in the design, a short polyethylene glycol spacer for aqueous solubility, and a maleimide group conjugation. Conjugates of a humanized anti-CEACAM5 monoclonal antibody, hMN-14, prepared using, these SN-38 derivatives were evaluated in vitro for stability in buffer and human serum and for antigen-binding and cytotoxicity in a human colon adenocarcinoma cell line. Conjugates of hMN-14 and SN-38 derivatives 16 and 17 were found promising for further development.
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