Antoni Riera

Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation

A large proportion of colorectal cancers (CRCs) display mutational inactivation of the TGF-β pathway, yet, paradoxically, they are characterized by elevated TGF-β production. Here, we unveil a prometastatic program induced by TGF-β in the microenvironment that associates with a high risk of CRC relapse upon treatment. The activity of TGF-β on stromal cells increases the efficiency of organ colonization by CRC cells, whereas mice treated with a pharmacological inhibitor of TGFBR1 are resilient to metastasis formation. Secretion of IL11 by TGF-β-stimulated cancer-associated fibroblasts (CAFs) triggers GP130/STAT3 signaling in tumor cells. This crosstalk confers a survival advantage to metastatic cells. The dependency on the TGF-β stromal program for metastasis initiation could be exploited to improve the diagnosis and treatment of CRC.

Stromal gene expression defines poor-prognosis subtypes in colorectal cancer

Recent molecular classifications of colorectal cancer (CRC) based on global gene expression profiles have defined subtypes displaying resistance to therapy and poor prognosis. Upon evaluation of these classification systems, we discovered that their predictive power arises from genes expressed by stromal cells rather than epithelial tumor cells. Bioinformatic and immunohistochemical analyses identify stromal markers that associate robustly with disease relapse across the various classifications. Functional studies indicate that cancer-associated fibroblasts (CAFs) increase the frequency of tumor-initiating cells, an effect that is dramatically enhanced by transforming growth factor (TGF)-β signaling. Likewise, we find that all poor-prognosis CRC subtypes share a gene program induced by TGF-β in tumor stromal cells. Using patient-derived tumor organoids and xenografts, we show that the use of TGF-β signaling inhibitors to block the cross-talk between cancer cells and the microenvironment halts disease progression.

Regioselective ring opening of chiral epoxyalcohols by primary amines

Abstract A reinvestigation of the titanium(IV)-mediated reaction of primary amines with chiral 2,3-epoxyalcohols shows that, contrary to previous reports, this reaction constitutes a general and practical process for the enantioselective synthesis of 3-amino-1,2-diols.

Modular bis(oxazoline) ligands for palladium catalyzed allylic alkylation: Unprecedented conformational behaviour of a bis(oxazoline) palladium η3-1,3-diphenylallyl complex

New families of enantiopure bis(oxazolines) with 4,5-trans (5 a-g) or 4,5-cis (6 c) stereochemistry at the individual rings have been prepared in high yield. Their eta(3)-allyl palladium complexes (8 a-g, 9 c and 10) have been used as catalytic precursors in allylic alkylation reactions with excellent enantioselectivities (up to 96 %) for the trans oxazoline derivatives, while Pd/6 c system was inactive. NMR studies on palladium eta(3)-1,3-diphenylallyl intermediates (11 a, c and e) showed the presence of syn/syn- and syn/anti-allyl isomers in solution; this resembles the first example of eta(3)-eta(1)-eta(3) isomerism in Pd allylic complexes containing bis(oxazolines) derived from malonic acid.

FK-506 synthetic studies. 3. An efficient asymmetric synthesis of the C(24)–C(34) fragment of FK-506, FR-900520, and FR-900523

Abstract An efficient asymmetric synthesis of the C(24)–C(34) fragment of the FK-506 family of immunosuppressants has been achieved.

Primary and Secondary Aminophosphines as Novel P-Stereogenic Building Blocks for Ligand Synthesis†

Chiral phosphine ligands are central to asymmetric metal catalysis. The effect of the majority of these ligands arises from the chirality of their backbones; however, P-stereogenic (P*) ligands have garnered renewed interest. After the decisive work of Knowles and co-workers with PAMP and DIPAMP ligands, several efficient syntheses of all-carbon P* compounds have been reported. In contrast, P* compounds that contain heteroatoms directly linked to the phosphorus center are scarce, and have found little application in catalysis. This class of substances includes secondary phosphine oxides, which exist in equilibrium with their trivalent phosphinite form. P* aminophosphines, which are the corresponding nitrogen analogues, are even more rare, as free primary aminophosphines tend to dimerize with the evolution of ammonia. However, Kolodiazhnyi et al. have reported that borane aminophosphines of type I are stable and that they can be obtained in diastereomerically pure form using 2-phenylethylamine as a chiral amine (Scheme 1). Nonetheless, type I compounds do not have any reported applications in asymmetric catalysis, nor has their hydrogenolysis been described. We envisioned that reductive cleavage of the arylethyl fragment should provide boraneprotected primary aminophosphines of type II, which would be amenable to further transformations and become useful P* building blocks in catalysis. Herein, we report the synthesis of enantiopure P-chiral primary and secondary aminophosphines (II) and diphosphinoamines (III). We began by investigating the hydrogenolysis of the known compound 1a, which contains a tert-butyl(phenyl)phosphinamine moiety (Scheme 2), under various

TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis

Most patients with colorectal cancer die as a result of the disease spreading to other organs. However, no prevalent mutations have been associated with metastatic colorectal cancers. Instead, particular features of the tumour microenvironment, such as lack of T-cell infiltration, low type 1 T-helper cell (TH1) activity and reduced immune cytotoxicity or increased TGFβ levels predict adverse outcomes in patients with colorectal cancer. Here we analyse the interplay between genetic alterations and the tumour microenvironment by crossing mice bearing conditional alleles of four main colorectal cancer mutations in intestinal stem cells. Quadruple-mutant mice developed metastatic intestinal tumours that display key hallmarks of human microsatellite-stable colorectal cancers, including low mutational burden, T-cell exclusion and TGFβ-activated stroma. Inhibition of the PD-1–PD-L1 immune checkpoint provoked a limited response in this model system. By contrast, inhibition of TGFβ unleashed a potent and enduring cytotoxic T-cell response against tumour cells that prevented metastasis. In mice with progressive liver metastatic disease, blockade of TGFβ signalling rendered tumours susceptible to anti-PD-1–PD-L1 therapy. Our data show that increased TGFβ in the tumour microenvironment represents a primary mechanism of immune evasion that promotes T-cell exclusion and blocks acquisition of the TH1-effector phenotype. Immunotherapies directed against TGFβ signalling may therefore have broad applications in treating patients with advanced colorectal cancer.

Stereoselective Synthesis of P-Stereogenic Aminophosphines: Ring Opening of Bulky Oxazaphospholidines

A highly diastereoselective and efficient synthesis of P-stereogenic bulky alkyl and aryl aminophosphines that relies on ring opening of tert-butyl-oxazaphospholidine 2 is described. Ring opening with several organometallic reagents takes place with inversion of configuration at the phosphorus center as it has been demonstrated by X-ray analysis of two ring-opened intermediates. The unprecedented reactivity observed is attributed to the presence of a free NH functionality that facilitates the attack of the organometallic reagent in an S(N)2@P-type process.

Ready access to stereodefined β-hydroxy-γ-amino acids. Enantioselective synthesis of fully protected cyclohexylstatine

Abstract A convenient entry to enantiopure syn or anti β-hydroxy-γ-amino acids is described. The starting compounds for the synthesis, anti 3-amino-1,2-diols, are readily available in high enantiomeric purity through catalytic asymmetric epoxidation of an allylic alcohol and titanium-promoted oxirane opening. After adequate protection of the nitrogen, a stereodivergent sequence leads to both anti and syn N-Boc-aminoalkyl epoxides. Subsequent regioselective ring-opening with cyanide, protection of the resulting secondary alcohol and nitrile to carboxyl conversion afford, in good yields, protected β-hydroxy-γ-amino acids belonging to either the anti (erythro) or syn (threo) series. This methodology has been applied to the enantioselective preparation of cyclohexylstatine, a key component of several aspartyl protease inhibitors, in fully protected form.

Toward the understanding of the mechanism and enantioselectivity of the Pauson-Khand reaction. Theoretical and experimental studies*

Semiempirical and density functional theory (DFT) calculations have been performed on the key steps of the commonly accepted mechanism of the PausonKhand reaction (PKR). In this context, the high reactivity of ynamine complexes in the cycloaddition process has been rationalized on the basis of an anomerically assisted dissociation of CO. Moreover, an explanation has been provided for the correlation between olefin strain and reactivity in the PKR. Inspired by these results, new selective syntheses of cyclopentanones and phenols based on PKR with cyclopropene have been developed. On the other hand, the theoretical analysis of phosphine-substituted dicobalt carbonyl complexes of alkynes has helped in the development of efficient chelating (P,N) and bridging (P,S) ligands for the stereochemical control of the reaction and in the understanding of their action modes.