Synthesis of Enantioenriched Tetra-ortho-3,3′-substituted Biaryls by Small-Molecule-Catalyzed Noncanonical Polyketide Cyclizations

The arene-forming aldol condensation is a fundamental reaction in the biosynthesis of aromatic polyketides. Precisely controlled by the polyketide synthases, the highly reactive poly-β-carbonyl substrates are diverged into numerous aromatic natural products by selective cyclization reactions; a fascinating biosynthetic strategy that sparked our interest to investigate atroposelective aldol condensations. In this Account, we contextualize and highlight the ability of small-molecule catalysts to selectively convert noncanonical hexacarbonyl substrates in a double arene-forming aldol condensation resulting in the atroposelective synthesis of tetra-ortho-3,3′-substituted biaryls. The hexacarbonyl substrates were obtained by a fourfold ozonolysis enabling a late-stage introduction of all carbonyl functions in one step. Secondary amine catalysts capable of forming an extended hydrogen-bonding network triggered the noncanonical polyketide cyclization in order to form valuable biaryls in high yields and with stereocontrol of up to 98:2 er

Atroposelective synthesis of tetra-ortho-substituted biaryls by catalyst-controlled non-canonical polyketide cyclizations

The cyclization of poly-β-carbonyl-substrates controlled by polyketide synthases intricately governs the biosynthesis of a wide range of aromatic polyketides. Analogous small-molecule-catalysed processes would conceivably induce selective cyclizations of non-canonical polycarbonyl substrates to provide products distinct from natural polyketides. Here, we report a secondary amine-catalysed twofold cyclization of non-canonical hexacarbonyl substrates, furnishing enantioenriched tetra-ortho-substituted binaphthalenes. The substrates were prepared by a fourfold ozonolysis of dicinnamyl biindenes and converted under catalyst control with high atroposelectivity. Privileged catalysts, helicenes and ligands are readily accessible from the binaphthalene products stemming from the non-canonical polyketide cyclizations

Integrating precision medicine through evaluation of cell of origin in treatment planning for diffuse large B-cell lymphoma

Precision medicine is modernizing strategies for clinical study design to help improve diagnoses guiding individualized treatment based on genetic or phenotypic characteristics that discriminate between patients with similar clinical presentations. Methodology to personalize treatment choices is being increasingly employed in clinical trials, yielding favorable correlations with improved response rates and survival. In patients with diffuse large B-cell lymphoma (DLBCL), disease characteristics and outcomes may vary widely, underscoring the importance of patient classification through identification of sensitive prognostic features. The discovery of distinct DLBCL molecular subtypes based on cell of origin (COO) is redefining the prognosis and treatment of this heterogeneous cancer. Owing to significant molecular and clinical differences between activated B-cell-like (ABC)- and germinal center B-cell-like (GCB)-DLBCL subtypes, COO identification offers opportunities to optimize treatment selection. Widespread adoption of COO classification would greatly improve treatment and prognosis; however, limitations in interlaboratory concordance between immunohistochemistry techniques, cost, and availability of gene expression profiling tools undermine universal integration in the clinical setting. With advanced methodology to determine COO in a real-world clinical setting, therapies targeted to specific subtypes are under development. The focus here is to review applications of precision medicine exemplified by COO determination in DLBCL patients

Species D Adenoviruses as Oncolytics against B-cell Cancers

Purpose: Oncolytic viruses are self-amplifying anticancer agents that make use of the natural ability of viruses to kill cells. Adenovirus serotype 5 (Ad5) has been extensively tested against solid cancers, but less so against B-cell cancers because these cells do not generally express the coxsackie and adenoviral receptor (CAR). To determine whether other adenoviruses might have better potency, we mined the adenovirus virome of 55 serotypes for viruses that could kill B-cell cancers. Experimental Design: Fifteen adenoviruses selected to represent Ad species B, C, D, E, and F were tested in vitro against cell lines and primary patient B-cell cancers for their ability to infect, replicate in, and kill these cells. Select viruses were also tested against B-cell cancer xenografts in immunodeficient mice. Results: Species D adenoviruses mediated most robust killing against a range of B-cell cancer cell lines, against primary patient marginal zone lymphoma cells, and against primary patient CD138þ myeloma cells in vitro. When injected into xenografts in vivo, single treatment with select species D viruses Ad26 and Ad45 delayed lymphoma growth. Conclusions: Relatively unstudied species Dadenoviruses have a unique ability to infect and replicate in B-cell cancers as compared with other adenovirus species. These data suggest these viruses have unique biology in B cells and support translation of novel species D adenoviruses as oncolytics against B-cell cancers

Catalytic Arene-forming Aldol Condensation: Stereoselective Synthesis of Rotationally Restricted Aromatic Compounds

By taking inspiration from the fascinating biosynthetic machinery that creates aromatic polyketides, our group investigates analogous reactions catalyzed by small molecules. We are particularly captivated by the prospects of intramolecular aldol condensation reactions to generate different rotationally restricted aromatic compounds. In a first project of our independent research group, a highly stereoselective amine catalyzed synthesis of axially chiral biaryls, tertiary aromatic amides and oligo-1,2-naphthylenes has been developed. In this article, we outline the twists and turns for our escape from the aromatic flatland to structurally intriguing chiral arene scaffolds relevant for various fields of application

A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma

The phosphatidylinositol 3-kinase signal transduction pathway members are often activated in tumor samples from patients with non-Hodgkin's lymphoma (NHL). Everolimus is an oral agent that targets the raptor mammalian target of rapamycin (mTORC1). The goal of this trial was to learn the antitumor activity and toxicity of single-agent everolimus in patients with relapsed/refractory aggressive NHL. Patients received everolimus 10 mg PO daily. Response was assessed after two and six cycles, and then every three cycles until progression. A total of 77 patients with a median age of 70 years were enrolled. Patients had received a median of three previous therapies and 32% had undergone previous transplant. The overall response rate (ORR) was 30% (95% confidence interval: 20–41%), with 20 patients achieving a partial remission and 3 a complete remission unconfirmed. The ORR in diffuse large B cell was 30% (14/47), 32% (6/19) in mantle cell and 38% (3/8) in follicular grade 3. The median duration of response was 5.7 months. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 14, 18 and 38% of patients, respectively. Everolimus has single-agent activity in relapsed/refractory aggressive NHL and provides proof-of-concept that targeting the mTOR pathway is clinically relevant