Synthesis of a C2-aryl-pyrrolo[2, 1-c][1, 4]benzodiazepine monomer enabling the convergent construction of symmetrical and non-symmetrical dimeric analogs. Issue 30 (22nd July 2015)

• Record Type: Journal Article
• Authors: Kolakowski, Robert V.; Young, Thomas D.; Howard, Philip W.; Jeffrey, Scott C.; Senter, Peter D.
• Is Part Of: Tetrahedron letters. Volume 56:Issue 30(2015)
• Page Start: 4512
• Page End: 4515
• Publication Date: 2015-07-22
• Subjects: Pyrrolobenzodiazepines -- Antibody–drug conjugates -- Payloads -- Drug-linker -- Anti-cancer; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2015.05.116
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Abstract: We disclose the synthesis of a versatile C2-aryl-pyrrolo[2, 1- c ][1, 4]benzodiazepine (PBD) monomer that enables the late-stage diversification and synthesis of PBD dimers. The monomer unit was elaborated and dimerized utilizing different tethers to yield symmetric and non-symmetrical C2-aryl-PBD dimers. The dimers were tested for cytotoxic activity on a number of cancer cell lines and showed potent cytotoxicity in the nanomolar to picomolar range. The synthesis of PBD monomers enables the modular construction of PBD free drugs and drug-linkers that may have application for the development of antibody–drug conjugations.