5 research outputs found
Probing Competitive and Co-operative Hydroxyl and Ammonium Hydrogen-Bonding Directed Epoxidations
The
diastereoselectivities and rates of epoxidation (upon treatment
with Cl<sub>3</sub>CCO<sub>2</sub>H then <i>m</i>-CPBA)
of a range of <i>cis</i>- and <i>trans</i>-4-aminocycloalk-2-en-1-ol
derivatives (containing five-, six-, and seven-membered rings) have
been investigated. In all cases where the two potential directing
groups can promote epoxidation on opposite faces of the ring scaffold,
evidence of competitive epoxidation pathways, promoted by hydrogen-bonding
to either the in situ formed ammonium moiety or the hydroxyl group,
was observed. In contrast to the relative directing group abilities
already established for the six-membered ring system (NHBn â«
OH > NBn<sub>2</sub>), an <i>N</i>,<i>N</i>-dibenzylammonium
moiety appeared more proficient than a hydroxyl group at directing
the stereochemical course of the epoxidation reaction in a five- or
seven-membered system. In the former case, this was rationalized by
the drive to minimize torsional strain in the transition state being
coupled with assistance from hydrogen-bonding to the ammonium moiety.
In the latter case, this was ascribed to the steric bulk of the ammonium
moiety disfavoring conformations in which hydrogen-bonding to the
hydroxyl group results in direction of the epoxidation to the <i>syn</i> face. In cases where the two potential directing groups
can promote epoxidation on the same face of the ring scaffold, an
enhancement of epoxidation diastereoselectivity was not observed,
while introduction of a second, allylic heteroatom to the substrate
results in diminishment of the rate of epoxidation in all cases. Presumably,
reduction of the nucleophilicity of the olefin by the second, inductively
electron-withdrawing heteroatom is the dominant factor, and any assistance
to the epoxidation reaction by the potential to form hydrogen-bonds
to two directing groups rather than one is clearly unable to overwhelm
it
Interfering with HuRâRNA Interaction: Design, Synthesis and Biological Characterization of Tanshinone Mimics as Novel, Effective HuR Inhibitors
The
human antigen R (HuR) is an RNA-binding protein known to modulate
the expression of target mRNA coding for proteins involved in inflammation,
tumorigenesis, and stress responses and is a valuable drug target.
We previously found that dihydrotanshinone-I (DHTS, <b>1</b>) prevents the association of HuR with its RNA substrate, thus imparing
its function. Herein, inspired by DHTS structure, we designed and
synthesized an array of ortho-quinones (tanshinone mimics) using a
function-oriented synthetic approach. Among others, compound <b>6a</b> and <b>6n</b> turned out to be more effective than <b>1</b>, showing a nanomolar <i>K</i><sub>i</sub> and
disrupting HuR binding to RNA in cells. A combined approach of NMR
titration and molecular dynamics (MD) simulations suggests that <b>6a</b> stabilizes HuR in a peculiar closed conformation, which
is incompatible with RNA binding. Alpha screen and RNA-electrophoretic
mobility shift assays (REMSA) data on newly synthesized compounds
allowed, for the first time, the generation of structure activity
relationships (SARs), thus providing a solid background for the generation
of highly effective HuR disruptors
Interfering with HuRâRNA Interaction: Design, Synthesis and Biological Characterization of Tanshinone Mimics as Novel, Effective HuR Inhibitors
The
human antigen R (HuR) is an RNA-binding protein known to modulate
the expression of target mRNA coding for proteins involved in inflammation,
tumorigenesis, and stress responses and is a valuable drug target.
We previously found that dihydrotanshinone-I (DHTS, <b>1</b>) prevents the association of HuR with its RNA substrate, thus imparing
its function. Herein, inspired by DHTS structure, we designed and
synthesized an array of ortho-quinones (tanshinone mimics) using a
function-oriented synthetic approach. Among others, compound <b>6a</b> and <b>6n</b> turned out to be more effective than <b>1</b>, showing a nanomolar <i>K</i><sub>i</sub> and
disrupting HuR binding to RNA in cells. A combined approach of NMR
titration and molecular dynamics (MD) simulations suggests that <b>6a</b> stabilizes HuR in a peculiar closed conformation, which
is incompatible with RNA binding. Alpha screen and RNA-electrophoretic
mobility shift assays (REMSA) data on newly synthesized compounds
allowed, for the first time, the generation of structure activity
relationships (SARs), thus providing a solid background for the generation
of highly effective HuR disruptors
Table_1_Circulating CD81-expressing extracellular vesicles as biomarkers of response for immune-checkpoint inhibitors in advanced NSCLC.docx
PD-L1 in tumor cells is the only used biomarker for anti PD1/PD-L1 immune-checkpoints inhibitors (ICI) in Non Small Cell Lung Cancer (NSCLC) patients. However, this parameter is inaccurate to predict response, especially in patients with low tumor PD-L1. Here, we evaluated circulating EVs as possible biomarkers for ICI in advanced NSCLC patients with low tumoral PD-L1. EVs were isolated from plasma of 64 PD-L1 low, ICI-treated NSCLC patients, classified either as responders (R; complete or partial response by RECIST 1.1) or non-responders (NR). EVs were characterized following MISEV guidelines and by flow cytometry. T cells from healthy donors were triggered in vitro using patientsâ EVs. Unsupervised statistical approach was applied to correlate EVsâ and patientsâ features to clinical response. R-EVs showed higher levels of tetraspanins (CD9, CD81, CD63) than NR-EVs, significantly associated to better overall response rate (ORR). In multivariable analysis CD81-EVs correlated with ORR. Unsupervised analysis revealed a cluster of variables on EVs, including tetraspanins, significantly associated with ORR and improved survival. R-EVs expressed more costimulatory molecules than NR-EVs although both increased T cell proliferation and partially, activation. Tetraspanins levels on EVs could represent promising biomarkers for ICI response in NSCLC.</p
Presentation_1_Circulating CD81-expressing extracellular vesicles as biomarkers of response for immune-checkpoint inhibitors in advanced NSCLC.pptx
PD-L1 in tumor cells is the only used biomarker for anti PD1/PD-L1 immune-checkpoints inhibitors (ICI) in Non Small Cell Lung Cancer (NSCLC) patients. However, this parameter is inaccurate to predict response, especially in patients with low tumor PD-L1. Here, we evaluated circulating EVs as possible biomarkers for ICI in advanced NSCLC patients with low tumoral PD-L1. EVs were isolated from plasma of 64 PD-L1 low, ICI-treated NSCLC patients, classified either as responders (R; complete or partial response by RECIST 1.1) or non-responders (NR). EVs were characterized following MISEV guidelines and by flow cytometry. T cells from healthy donors were triggered in vitro using patientsâ EVs. Unsupervised statistical approach was applied to correlate EVsâ and patientsâ features to clinical response. R-EVs showed higher levels of tetraspanins (CD9, CD81, CD63) than NR-EVs, significantly associated to better overall response rate (ORR). In multivariable analysis CD81-EVs correlated with ORR. Unsupervised analysis revealed a cluster of variables on EVs, including tetraspanins, significantly associated with ORR and improved survival. R-EVs expressed more costimulatory molecules than NR-EVs although both increased T cell proliferation and partially, activation. Tetraspanins levels on EVs could represent promising biomarkers for ICI response in NSCLC.</p