Synthesis of a novel tetrahydroisoquinolino[2,1-c][1,4]benzodiazepine ring system with DNA recognition potential

Design, Synthesis, and Structure–Activity Relationships of Novel Tetrahydroisoquinolino Benzodiazepine Dimer Antitumor Agents and Their Application in Antibody–Drug Conjugates

“…The resulting suspension was stirred at room temperature for 1 day and then filtered, washing with 10% MeOH/chloroform. The filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound 18 as a white solid (11 (S)-10-Hydroxy-2-methoxy-3-((5-(((S)-2-methoxy-6,14dioxo-5-((2-(trimethylsilyl)ethoxy) methyl)-5,6,6a,7,12,14hexahydrobenzo [5,6] (19). To a solution of 4b (135 mg, 0.208 mmol) and 8f (110 mg, 0.198 mmol) in DMSO (3 mL) was added potassium carbonate (82 mg, 0.595 mmol).…”

“…Based on molecular modeling studies, we envisioned that replacement of the pyrrolidine ring in PBD, DC - 81 , with tetrahydroisoquinoline (THIQ) would result in compound 3 with additional DNA binding to provide improved activity (Figure ). − We report here our structure–activity relationship (SAR) findings for various THIQ-based dimers with different spacer lengths and functional groups. Finally, compound 17 was conjugated to anti-mesothelin and anti-FucGM1 antibodies using a lysosome-cleavable valine–citrulline dipeptide linker, and the ADCs were evaluated for antitumor activity in mouse xenograft models.…”