Extracellular adenosine (ADO), present in high concentrations in the tumor microenvironment (TME), suppresses immune function via inhibition of T cell and NK cell activation. Intratumoral generation of ADO depends on the sequential catabolism of ATP by two ecto-nucleotidases, CD39 (ATP → AMP) and CD73 (AMP → ADO). Inhibition of CD73 eliminates a major pathway of ADO production in the TME and can reverse ADO-mediated immune suppression. Extensive interrogation of structure−activity relationships (SARs), structure-based drug design, and optimization of pharmacokinetic properties culminated in the discovery of AB680, a highly potent (K i = 5 pM), reversible, and selective inhibitor of CD73. AB680 is further characterized by very low clearance and long half-lives across preclinical species, resulting in a PK profile suitable for long-acting parenteral administration. AB680 is currently being evaluated in phase 1 clinical trials. Initial data show AB680 is well tolerated and exhibits a pharmacokinetic profile suitable for biweekly (Q2W) iv-administration in human.
The first syntheses of Jadomycin A and the carbosugar analogue of Jadomycin B have been achieved in 6 and 20 longest linear steps respectively. The key ring system of the aglycone was prepared by a 6π-electron electrocyclic ring closure and subsequent hemi-aminal ring closure. Acid sensitivity of the glycosidic bond in Jadomycin B precluded its synthesis but led to the synthesis of the carbasugar analogue.
The first synthesis of any and all members of the mezzettiaside family of natural products has been achieved. The reported synthesis features the iterative use of the Taylor catalyst in a dual nucleophilic boron/electrophilic palladium catalyzed regioselective glycosylation. In addition, the de novo approach utilizes atomless protecting groups and the minimal use of protecting groups (2 chloroacetates for the synthesis of 10 natural products). These divergent syntheses occurred in a range of 13 to 22 longest linear steps and required only 41 total steps to prepare the entire family of mezzettiasides.
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