Discovery of Potent and Selective Methylenephosphonic Acid CD73 Inhibitors.

Solid tumors are often associated with high levels of extracellular ATP. Ectonucleotidases catalyze the sequential hydrolysis of ATP to adenosine, which potently suppresses T-cell and NK-cell functions via the adenosine receptors (A2a and A2b). The ectonucleotidase CD73 catalyzes the conversion of AMP to adenosine. Thus, increased CD73 enzymatic activity in the tumor microenvironment is a potential mechanism for tumor immune evasion and has been associated with poor prognosis in the clinic. CD73 inhibition is anticipated to restore immune function by skirting this major mechanism of adenosine generation. We have developed a series of potent and selective methylenephosphonic acid CD73 inhibitors via a structure-based design. Key binding interactions of the known inhibitor adenosine-5'-(α,ß-methylene)diphosphate (AMPCP) with hCD73 provided the foundation for our early designs. The structure-activity relationship study guided by this structure-based design led to the discovery of 4a, which exhibits excellent potency against CD73, exquisite selectivity against related ectonucleotidases, and a favorable pharmacokinetic profile.

Discovery of AB680: A Potent and Selective Inhibitor of CD73.

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 (Ki = 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.

Total Synthesis of Gelsenicine via a Catalyzed Cycloisomerization Strategy.

The first total synthesis of (±)-gelsenicine is reported. The synthetic route is highly efficient (13 steps), featuring (1) a pivotal metal-catalyzed isomerization/rearrangement process that forges the central core of the molecule and (2) two facile C-N bond-forming steps that establish the flanking heterocycles.

C-C Bond Migration in the Cycloisomerization of 1,6-Enynes.

A full account of our investigation of C-C bond migration in the cycloisomerization of oxygen-tethered 1,6-enynes is described. Under Pt(II) and/or Ir(I) catalysis, cyclic and acylic alkyl groups were found to undergo 1,2-shifts into metal carbenoid intermediates. Interestingly, this process does not appear to be driven by the release of ring strain, and thus provides access to large carbocyclic frameworks. The beneficial effect of CO on the Pt(II) and Ir(I) catalytic systems is also evaluated.

C-C bond migration in the cycloisomerization of oxygen-tethered 1,6-enynes.

A C-C bond migration event during the cycloisomerization of 1,6-enynes is described. Two different catalytic systems, iridium- or platinum-based, are able to induce this process. Alkyl migrations of larger rings and acyclic groups indicate that the reaction is not fully driven by the release of ring strain.

Highly enantiospecific platinum-catalyzed cycloisomerizations: synthesis of enantioenriched oxabicycloheptene derivatives.

Enantiospecific cycloisomerizations of 1,6-enynes to form oxabicyclo[4.1.0]heptene derivatives are described. Enantiospecificity is consistently high regardless of alkene or alkyne substitution, providing a general approach to greatly enantioenriched cyclopropanes. Additionally, a model for stereochemical transfer is proposed.