ABSTRACT
Macrocyclic pyrrolobenzodiazepine dimers were designed and evaluated for use as antibody-drug conjugate payloads. Initial structure-activity exploration established that macrocyclization could increase the potency of PBD dimers compared with non-macrocyclic analogs. Further optimization overcame activity-limiting solubility issues, leading to compounds with highly potent (picomolar) activity against several cancer cell lines. High levels of in vitro potency and specificity were demonstrated with an anti-mesothelin conjugate.
Subject(s)
Antibodies/metabolism , Antineoplastic Agents/pharmacology , Benzodiazepines/pharmacology , Macrocyclic Compounds/pharmacology , Pyrroles/pharmacology , Antibodies/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzodiazepines/chemical synthesis , Benzodiazepines/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dimerization , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/chemistry , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Solubility , Structure-Activity RelationshipABSTRACT
Traditionally, C-H oxidation reactions install oxidized functionality onto a preformed molecular skeleton, resulting in a local molecular change. The use of C-H activation chemistry to construct complex molecular scaffolds is a new area with tremendous potential in synthesis. We report a Pd(II)/bis-sulfoxide-catalyzed dehydrogenative Diels-Alder reaction that converts simple terminal olefins into complex cycloadducts in a single operation.
Subject(s)
Alkenes/chemistry , Cycloparaffins/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Catalysis , Cyclization , Cycloparaffins/chemistry , Heterocyclic Compounds/chemistry , Models, Molecular , Molecular Structure , Oxidation-Reduction , Palladium/chemistry , Safrole/analogs & derivatives , Safrole/chemistry , StereoisomerismABSTRACT
Among the frontier challenges in chemistry in the twenty-first century are the interconnected goals of increasing synthetic efficiency and diversity in the construction of complex molecules. Oxidation reactions of C-H bonds, particularly when applied at late stages of complex molecule syntheses, hold special promise for achieving both these goals. Here we report a late-stage C-H oxidation strategy in the total synthesis of 6-deoxyerythronolide B (6-dEB), the aglycone precursor to the erythromycin antibiotics. An advanced intermediate is cyclized to give the 14-membered macrocyclic core of 6-dEB using a late-stage (step 19 of 22) C-H oxidative macrolactonization reaction that proceeds with high regio-, chemo- and diastereoselectivity (>40:1). A chelate-controlled model for macrolactonization predicted the stereochemical outcome of C-O bond formation and guided the discovery of conditions for synthesizing the first diastereomeric 13-epi-6-dEB precursor. Overall, this C-H oxidation strategy affords a highly efficient and stereochemically versatile synthesis of the erythromycin core.
