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[摘要]：CPT-11 is a clin. used cancer drug, and it is a prodrug of the potent topoisomerase I inhibitor, SN-38 (7-ethyl-10-hydroxycamptothecin, I). To bypass the need for the in vivo conversion of CPT-11 and increase the therapeutic index, bifunctional derivs. of SN-38 were prepd. for use in antibody-based targeted therapy of cancer. The general synthetic scheme incorporated an acetylene-azide click cycloaddn. step in the design, a short polyethylene glycol spacer for aq. soly., and a maleimide group for conjugation. Conjugates of a humanized anti-CEACAM5 monoclonal antibody, hMN-14, prepd. using these SN-38 derivs. 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 derivs. II (R = H, CO2Et; x = 7; A = -Phe-Lys-) were found promising for further development. |
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