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2819 4.1. Synthesis of Pyrrolo[2,1-c][1,4]benzodiazepine-5,11-diones (PBD Dilactams) 2820 4.1.1. Cyclization of Methyl and Ethyl N-(2-Nitrobenzoyl)pyrrolidine-2-carboxylates 2820 4.1.2. Cyclization of Methyl N-(2-Azidobenzoyl)pyrrolidine-2-carboxylates 2822 4.1.3. Cyclocondensation of Isatoic Anhydrides with Substituted Prolines 2822 4.1.4. Cyclization of 1-Benzoyl-N-methoxypyrrolidine-2-carboxamides 2825 4.1.5. Cyclization of N-(2-Trifluoromethylsulfonyloxybenzoyl)pyrrolidine-2-carboxylic Esters 2825 4.2. Reduction of PBD Dilactams to PBD N10-C11 Carbinolamines/Imines 2826 5. Cyclization of Substituted N-Benzoylpyrrolidine Precursors 2828 5.1. Reductive Cyclization of N-(2-Nitrobenzoyl)pyrrolidine-2-carboxaldehydes 2828 5.2. Cyclization of N-(2-Aminobenzoyl)pyrrolidine-2-carboxaldehyde Diethyl Thioacetals 2830 5.3. Cyclization of N-(2-Aminobenzoyl)pyrrolidine-2-carboxaldehyde Dimethyl Acetals 2840 5.4. Cyclization of N-(2-Azidobenzoyl)pyrrolidine-2carboxaldehydes 2841 5.5. Oxidative Cyclization of N-(2-(Protected)aminobenzoyl)pyrrolidine-2methanol Precursors 2841 6. Oxidation of Cyclic N10-C11 Secondary Amines 2852 7. Solid-Phase and Parallel Syntheses of Pyrrolo[2,1-c][1,4]benzodiazepines 2853 8. Synthesis of N10-and C11-Substituted Pyrrolo-[2,1-c][1,4]benzodiazepines 2857

Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs.

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