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Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) targeting Trop-2 for delivery of SN-38. Sacituzumab govitecan shows anticancer activity[1].

Through the targeting effect of antibodies, Sacituzumab Govitecan delivers SN-38 directly to tumor cells expressing Trop-2. SN-38 is a topoisomerase I inhibitor that can cause DNA double-strand breaks, thereby inhibiting the replication and division of tumor cells.

The lysine derivative 321 was coupled with p-aminobenzyl alcohol, followed by the removal of the carbamate protecting group to afford the α-aminoamide 323. This amine was then coupled with the commercial α,ο-hydrazide 325 to afford the benzyl alcohol 323 in excellent yield. The benzyl alcohol 323 was then reacted with the chloroformate 320 under mild alkaline conditions to afford the carbonate 326. The removal of the silyl ether protecting group under acidic conditions, followed by click cyclization with the alkyne 327 and the removal of the trityl protection in 326, ultimately afforded CL2A-SN-38 (328) in excellent yield. The disulfide bonds of the Trop-2 antibody were first cleaved using tris(2-carboxyethyl)phosphine (TCEP) as a reducing agent. The cleaved disulfide Trop-2 antibody was then reacted with CL2A-SN-38, followed by a clearance reaction using N-ethylmaleimide. This series of reactions resulted in a Michael addition reaction on the reduced antibody, which proceeded at a stoichiometric ratio of approximately 7.6. Through these steps, Sacituzumab Govitecan was finally obtained.

[1] Cardillo TM, et al. Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. Bioconjug Chem. 2015 May 20;26(5):919-31. DOI:10.1021/acs.bioconjchem.5b00223
[2] Goldenberg DM, Cardillo TM, Govindan SV, Rossi EA, Sharkey RM. Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC) [published correction appears in Oncotarget. 2020 Mar 10;11(10):942]. Oncotarget. 2015;6(26):22496-22512. DOI:10.18632/oncotarget.4318
[3] Cardillo TM, et al., Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. Bioconjug Chem. 2015 May 20;26(5):919-31. DOI:10.1021/acs.bioconjchem.5b00223