Controlling the Helical Pitch of Foldamers Through Terminal Functionality: A Solid State Study.

Developing new methods to control the size and shape of the helical structures adopted by foldamers is highly important as the secondary structure displayed by these supramolecular scaffolds often dictates their activity and function. Herein, we report on a systematic study demonstrating that the helical pitch of ortho-azobenzene/2,6-pyridyldicarboamide foldamers can be readily controlled through the nature of the terminal functionality. Remarkably, simply through varying the end group of the foldamer, and without modifying any other structural features of the scaffold, the helical pitch can be over doubled in magnitude (from 3.4 Å to 7.3 Å). Additionally, crystallographic analysis of a library ten foldamers has identified general trends in the influence of a range of terminal functionalities, including carboxylbenzyl (Cbz), diphenylcarbamyl (N(Ph)2), ferrocene (Fc) and tert-butyloxycarbonyl (Boc), in controlling the folding behaviour of these supramolecular scaffolds. These studies could prove useful in the future development of functional foldamers which adopt specific sizes and shapes.

Dual, Photo-Responsive and Redox-Active Supramolecular Foldamers.

We report on dual, light-responsive and redox-active foldamers that demonstrate reversible and robust stimuli-induced behaviour. Herein, UV/Vis, 1H NMR and circular dichroism (CD) spectroscopy and cyclic voltammetry have been used to establish the reversibility and highly robust nature of the light- and redox-driven behaviour of these new foldamers with minimal levels of fatigue observed even upon multiple cyclic treatments with irradiative/non-irradiative and oxidative/reductive conditions. This proof-of-concept work paves the way towards the creation of novel stimuli-responsive foldamers of increasing sophistication capable of demonstrating reversible and robust responses to multiple distinct stimuli.

High-Risk Histopathological Features of Retinoblastoma following Primary Enucleation: A Global Study of 1426 Patients from 5 Continents.

PURPOSE: To evaluate high-risk histopathological features (HRHF) following primary enucleation of eyes with retinoblastoma (RB) and assess the patient outcomes across continents. METHODS: Retrospective study of 1426 primarily enucleated RB eyes from five continents. RESULTS: Of all, 923 (65%) were from Asia (AS), 27 (2%) from Australia (AUS), 120 (8%) from Europe (EUR), 162 (11%) from North America (NA), and 194 (14%) from South America (SA). Based on the continent (AS vs. AUS vs. EUR vs. NA vs. SA), the histopathology features included massive choroidal invasion (31% vs. 7% vs. 13% vs. 19% vs. 27%, p=0.001), post-laminar optic nerve invasion (27% vs. 0% vs. 16% vs. 21% vs. 19%, p=0.0006), scleral infiltration (5% vs. 0% vs. 4% vs. 2% vs. 7%, p=0.13), and microscopic extrascleral infiltration (4% vs. 0% vs. <1% vs. <1% vs. 4%, p=0.68). Adjuvant chemotherapy with/without orbital radiotherapy was given in 761 (53%) patients. Based on Kaplan-Meier estimates in different continents (AS vs. AUS vs. EUR vs. NA vs. SA), the 6-year risk of orbital tumor recurrence was 5% vs. 2% vs. 0% vs. 0% vs. 12% (p<0.001), systemic metastasis was reported in 8% vs. 5% vs. 2% vs. 0% vs. 13% (p=0.001), and death in 10% vs. 3% vs. 2% vs. 0% vs. 11% (p<0.001) patients. CONCLUSION: There is a wide variation in the infiltrative histopathology features of RB across continents, resulting in variable outcomes. SA and AS had a higher risk of orbital tumor recurrence, systemic metastasis, and death compared to AUS, EUR, and NA.

Reversible conformational switching of a photo-responsive ortho-azobenzene/2,6-pyridyldicarboxamide heterofoldamer.

We report on a convenient synthetic route to rapidly access a new photo-responsive ortho-azobenzene/2,6-pyridyldicarboxamide heterofoldamer. The adoption of a stable helical conformation has been established for this scaffold in both the solid state and in solution using single crystal X-ray diffraction and circular dichroism (CD) spectroscopy respectively. Reversible control over the stimuli-driven structural re-ordering of the supramolecular scaffold, from a stable helical conformation under non-irradiative conditions, to a less well-ordered state under irradiative conditions, has been identified. The robust nature of the responsive, conformational, molecular switching behaviour has been determined using UV/Vis, 1H NMR and CD spectroscopy. Minimal loss in the efficiency of the stimuli-driven, structural re-ordering processes of the foldamer scaffold is observed, even upon multiple cyclic treatments with irradiative/non-irradiative conditions.

Simultaneous Copy Number Alteration and Single-Nucleotide Variation Analysis in Matched Aqueous Humor and Tumor Samples in Children with Retinoblastoma.

Retinoblastoma (RB) is a childhood cancer that forms in the developing retina of young children; this tumor cannot be biopsied due to the risk of provoking extraocular tumor spread, which dramatically alters the treatment and survival of the patient. Recently, aqueous humor (AH), the clear fluid in the anterior chamber of the eye, has been developed as an organ-specific liquid biopsy for investigation of in vivo tumor-derived information found in the cell-free DNA (cfDNA) of the biofluid. However, identifying somatic genomic alterations, including both somatic copy number alterations (SCNAs) and single nucleotide variations (SNVs) of the RB1 gene, typically requires either: (1) two distinct experimental protocols-low-pass whole genome sequencing for SCNAs and targeted sequencing for SNVs-or (2) expensive deep whole genome or exome sequencing. To save time and cost, we applied a one-step targeted sequencing method to identify both SCNAs and RB1 SNVs in children with RB. High concordance (median = 96.2%) was observed in comparing SCNA calls derived from targeted sequencing to the traditional low-pass whole genome sequencing method. We further applied this method to investigate the degree of concordance of genomic alterations between paired tumor and AH samples from 11 RB eyes. We found 11/11 AH samples (100%) had SCNAs, and 10 of them (90.1%) with recurrent RB-SCNAs, while only nine out of 11 tumor samples (81.8%) had positive RB-SCNA signatures in both low-pass and targeted methods. Eight out of the nine (88.9%) detected SNVs were shared between AH and tumor samples. Ultimately, 11/11 cases have somatic alterations identified, including nine RB1 SNVs and 10 recurrent RB-SCNAs with four focal RB1 deletions and one MYCN gain. The results presented show the feasibility of utilizing one sequencing approach to obtain SCNA and targeted SNV data to capture a broad genomic scope of RB disease, which may ultimately expedite clinical intervention and be less expensive than other methods.

Diagnostic Aqueous Humor Proteome Predicts Metastatic Potential in Uveal Melanoma.

Gene expression profiling (GEP) is clinically validated to stratify the risk of metastasis by assigning uveal melanoma (UM) patients to two highly prognostic molecular classes: class 1 (low metastatic risk) and class 2 (high metastatic risk). However, GEP requires intraocular tumor biopsy, which is limited by small tumor size and tumor heterogeneity; furthermore, there are small risks of retinal hemorrhage, bleeding, or tumor dissemination. Thus, ocular liquid biopsy has emerged as a less-invasive alternative. In this study, we seek to determine the aqueous humor (AH) proteome related to the advanced GEP class 2 using diagnostic AH liquid biopsy specimens. Twenty AH samples were collected from patients with UM, grouped by GEP classes. Protein expression levels of 1472 targets were analyzed, compared between GEP classes, and correlated with clinical features. Significant differentially expressed proteins (DEPs) were subjected to analysis for cellular pathway and upstream regulator identification. The results showed that 45 DEPs detected in the AH could differentiate GEP class 1 and 2 at diagnosis. IL1R and SPRY2 are potential upstream regulators for the 8/45 DEPs that contribute to metastasis-related pathways. AH liquid biopsy offers a new opportunity to determine metastatic potential for patients in the absence of tumor biopsy.

Influence of Ligand and Nuclearity on the Cytotoxicity of Cyclometallated C

A series of cyclometallated mono- and di-nuclear platinum(II) complexes and the parent organic ligand, 2,6-diphenylpyridine 1 (HC^N^CH), have been synthesized and characterized. This library of compounds includes [(C^N^C)PtII (L)] (L=dimethylsulfoxide (DMSO) 2 and triphenylphosphine (PPh3 ) 3) and [((C^N^C)PtII )2 (L')] (where L'=N-heterocycles (pyrazine (pyr) 4, 4,4'-bipyridine (4,4'-bipy) 5 or diphosphine (1,4-bis(diphenylphosphino)butane (dppb) 6). Their cytotoxicity was assessed against four cancerous cell lines and one normal cell line, with results highlighting significantly increased antiproliferative activity for the dinuclear complexes (4-6), when compared to the mononucleated species (2 and 3). Complex 6 is the most promising candidate, displaying very high selectivity towards cancerous cells, with selectivity index (SI) values >29.5 (A2780) and >11.2 (A2780cisR), and outperforming cisplatin by >4-fold and >18-fold, respectively.

Benchmarking of Halogen Bond Strength in Solution with Nickel Fluorides: Bromine versus Iodine and Perfluoroaryl versus Perfluoroalkyl Donors.

The energetics of halogen bond formation in solution have been investigated for a series of nickel fluoride halogen bond acceptors; trans-[NiF(2-C5 NF4 )(PEt3 )2 ] (A1), trans-[NiF{2-C5 NF3 (4-H)}(PEt3 )2 ] (A2), trans-[NiF{2-C5 NF3 (4-NMe2 )}(PEt3 )2 ] (A3) and trans-[NiF{2-C5 NF2 H(4-CF3 )}(PCy3 )2 ] (A4) with neutral organic halogen bond donors, iodopentafluorobenzene (D1), 1-iodononafluorobutane (D2) and bromopentafluorobenzene (D3), in order to establish the significance of changes from perfluoroaryl to perfluoroalkyl donors and from iodine to bromine donors. 19 F NMR titration experiments have been employed to obtain the association constants, enthalpy, and entropy for the halogen bond formed between these donor-acceptor partners in protiotoluene. For A2-A4, association constants of the halogen bonds formed with iodoperfluoroalkane (D2) are consistently larger than those obtained for analogous complexes with the iodoperfluoroarene (D1). For complexes formed with A2-A4, the strength of the halogen bond is significantly lowered upon modification of the halogen donor atom from I (in D1) to Br (in D3) (for D1: 5≤K285 ≤12 m-1 , for D3: 1.0≤K193 ≤1.6 m-1 ). The presence of the electron donating NMe2 substituent on the pyridyl ring of acceptor A3 led to an increase in -ΔH, and the association constants of the halogen bond complexes formed with D1-D3, compared to those formed by A1, A2 and A4 with the same donors.

Optically Active Vibrational Spectroscopy of α-Aminoisobutyric Acid Foldamers in Organic Solvents and Phospholipid Bilayers.

Helical α-aminoisobutyric acid (Aib) foldamers show great potential as devices for the communication of conformational information across phospholipid bilayers, but determining their conformation in bilayers remains a challenge. In the present study, Raman, Raman optical activity (ROA), infrared (IR) and vibrational circular dichroism (VCD) spectroscopies have been used to analyze the conformational preferences of Aib foldamers in solution and when interacting with bilayers. A 310 -helix marker band at 1665-1668 cm-1 in Raman spectra was used to show that net helical content increased strongly with oligomer length. ROA and VCD spectra of chiral Aib foldamers provided the chiroptical signature for both left- and right-handed 310 -helices in organic solvents, with VCD establishing that foldamer screw-sense was preserved when the foldamers became embedded within bilayers. However, the population distribution between different secondary structures was perturbed by the chiral phospholipid. These studies indicate that ROA and VCD spectroscopies are valuable tools for the study of biomimetic structures, such as artificial signal transduction molecules, in phospholipid bilayers.

H-Bond Acceptor Parameters for Anions.

UV/vis absorption titrations have been used to investigate the formation of H-bonded complexes between anionic H-bond acceptors (HBAs) and neutral H-bond donors (HBDs) in organic solvents. Complexes formed by three different HBDs with 15 different anions were studied in chloroform and in acetonitrile. The data were used to determine self-consistent HBA parameters (ß) for chloride, bromide, iodide, phosphate diester, acetate, benzoate, perrhenate, nitrate, triflimide, perchlorate, hexafluorophosphate, hydrogen sulfate, methyl sulfonate, triflate, and perfluorobutyl sulfonate. The results demonstrate the transferability of H-bond parameters for anions between different solvents and different HBD partners, allowing reliable prediction of anion recognition properties in other scenarios. Carboxylates are the strongest HBAs studied, with ß parameters (≈ 15) that are significantly higher than those of neutral organic HBAs, and the non-coordinating anion hexafluorophosphate is the weakest acceptor, with a ß parameter comparable to that of pyridine. The effects of ion pairing with the counter-cation were found to be negligible, provided small polar cations were avoided in the less polar solvent (chloroform). There is no correlation between the H-bonding properties of the anions and the pKa values of the conjugate acids.

Fluorescent and colorimetric molecular recognition probe for hydrogen bond acceptors.

The association constants for formation of 1 : 1 complexes between a H-bond donor, 1-naphthol, and a diverse range of charged and neutral H-bond acceptors have been measured using UV/vis absorption and fluorescence emission titrations. The performance of 1-naphthol as a dual colorimetric and fluorescent molecular recognition probe for determining the H-bond acceptor (HBA) parameters of charged and neutral solutes has been investigated in three solvents. The data were employed to establish self-consistent H-bond acceptor parameters (ß) for benzoate, azide, chloride, thiocyanate anions, a series of phosphine oxides, phosphate ester, sulfoxide and a tertiary amide. The results demonstrate both the transferability of H-bond parameters between different solvents and the utility of the naphthol-based dual molecular recognition probe to exploit orthogonal spectroscopic techniques to determine the HBA properties of neutral and charged solutes. The benzoate anion is the strongest HBA studied with a ß parameter of 15.4, and the neutral tertiary amide is the weakest H-bond acceptor investigated with a ß parameter of 8.5. The H-bond acceptor strength of the azide anion is higher than that of chloride (12.8 and 12.2 respectively), and the thiocyanate anion has a ß value of 10.8 and thus is a significantly weaker H-bond acceptor than both the azide and chloride anions.

Conformational Switching of a Foldamer in a Multicomponent System by pH-Filtered Selection between Competing Noncovalent Interactions.

Biomolecular systems are able to respond to their chemical environment through reversible, selective, noncovalent intermolecular interactions. Typically, these interactions induce conformational changes that initiate a signaling cascade, allowing the regulation of biochemical pathways. In this work, we describe an artificial molecular system that mimics this ability to translate selective noncovalent interactions into reversible conformational changes. An achiral but helical foldamer carrying a basic binding site interacts selectively with the most acidic member of a suite of chiral ligands. As a consequence of this noncovalent interaction, a global absolute screw sense preference, detectable by (13)C NMR, is induced in the foldamer. Addition of base, or acid, to the mixture of ligands competitively modulates their interaction with the binding site, and reversibly switches the foldamer chain between its left and right-handed conformations. As a result, the foldamer-ligand mixture behaves as a biomimetic chemical system with emergent properties, functioning as a "proton-counting" molecular device capable of providing a tunable, pH-dependent conformational response to its environment.

Helical peptaibol mimics are better ionophores when racemic than when enantiopure.

Helical peptide foldamers rich in α-aminoisobutyric acid (Aib) act as peptaibol-mimicking ionophores in the phospholipid bilayers of artificial vesicles. Racemic samples of these foldamers are more active than their enantiopure counterparts, which was attributed to differing propensities to form aggregates with crystal-like features in the bilayer.

Designing foldamer-foldamer interactions in solution: the roles of helix length and terminus functionality in promoting the self-association of aminoisobutyric acid oligomers.

The biological activity of antibiotic peptaibols has been linked to their ability to aggregate, but the structure-activity relationship for aggregation is not well understood. Herein, we report a systematic study of a class of synthetic helical oligomer (foldamer) composed of aminoisobutyric acid (Aib) residues, which mimic the folding behavior of peptaibols. NMR spectroscopic analysis was used to quantify the dimerization constants in solution, which showed hydrogen-bond donors at the N terminus promoted aggregation more effectively than similar modifications at the C terminus. Elongation of the peptide chain also favored aggregation. The geometry of aggregation in solution was investigated by means of titrations with [D6]DMSO and 2D NOE NMR spectroscopy, which allowed the NH protons most involved in intermolecular hydrogen bonds in solution to be identified. X-ray crystallography studies of two oligomers allowed a comparison of the inter- and intramolecular hydrogen-bonding interactions in the solid state and in solution and gave further insight into the geometry of foldamer-foldamer interactions. These solution-based and solid-state studies indicated that the preferred geometry for aggregation is through head-to-tail interactions between the N and C termini of adjacent Aib oligomers.

Conformational analysis of helical aminoisobutyric acid (Aib) oligomers bearing C-terminal ester Schellman motifs.

The effect of Schellman motifs on the adoption of stable 310 helical conformations in a series of aminoisobutyric (Aib) oligomers has been studied in the solid state and solution. The destabilising effect of the Schellman motif (a local inversion of helical screw-sense due to a C-terminal ester residue) was quantified in the solid state using X-ray crystallography through analysis of the torsion angles and their deviation from those observed in an ideal 310 helix. Investigation of the intramolecular hydrogen-bonding interactions in the solid state led to the identification of a fully extended C5 conformation in one oligomer, which is a novel folding motif for Aib oligomers. The effect of ester groups with differing steric demands on intermolecular hydrogen-bonding contacts in the solid state was also ascertained. In solution, the adoption of a 310 conformation in Aib oligomers appeared to be more finely tuned, depending on a number of factors, including chain length and the steric demands of the C-terminal destabilising Schellman motif.

Retinoblastoma Outcomes in the Americas: A Prospective Analysis of 491 Children With Retinoblastoma From 23 American Countries.

PURPOSE: Globally, disparities exist in retinoblastoma treatment outcomes between high- and low-income countries, but independent analysis of American countries is lacking. We report outcomes of American retinoblastoma patients and explore factors associated with survival and globe salvage. DESIGN: Subanalysis of prospective cohort study data. METHODS: Multicenter analysis at 57 American treatment centers in 23 countries of varying economic levels (low income [LIC], lower-middle income [LMIC], upper-middle income [UMIC], and high income [HIC]) of 491 treatment-naïve retinoblastoma patients diagnosed in 2017 and followed through 2020. Survival and globe salvage rates analyzed with Kaplan-Meier analysis and Cox proportional hazard models. RESULTS: Of patients, 8 (1.6%), 58 (11.8%), 235 (47.9%), and 190 (38.7%) were from LIC, LMIC, UMIC, and HIC groups, respectively. Three-year survival rates in LICs were 60.0% (95% confidence interval [CI] 12.6-88.2) compared with 99.2% (95% CI 94.6%-99.9%) in HICs. Death was less likely in patients >4 years of age (vs ≤4 years, HR = 0.45 [95% CI 0.27-0.78], P = .048). Patients with more advanced tumors (eg, cT3 vs cT1, HR = 4.65 × 109 [95% CI 1.25 × 109-1.72 × 1010], P < .001) and females (vs males, HR = 1.98 [95% CI 1.27-3.10], P = .04) were more likely to die. Three-year globe salvage rates were 13.3% (95% CI 5.1%-25.6%) in LMICs and 46.2% (95% CI 38.8%-53.3%) in HICs. At 3 years, 70.1% of cT1 eyes (95% CI 54.5%-81.2%) vs 8.9% of cT3 eyes (95% CI 5.5%-13.3%) were salvaged. Advanced tumor stage was associated with higher enucleation risk (eg, cT3 vs cT1, subhazard ratio = 4.98 [95% CI 2.36-10.5], P < .001). CONCLUSIONS: Disparities exist in survival and globe salvage in American countries based on economic level and tumor stage demonstrating a need for childhood cancer programs.

Anterior plaque brachytherapy placement for treatment of iris and iridociliary melanomas - Surgical procedure and institutional experience.

Surgical placement of eye plaque brachytherapy (EPB) is the standard of care for the treatment of uveal melanomas, including iris/iridociliary melanomas. However, unique challenges exist in anterior EPB placement. Here, we describe a surgical technique for anterior EPB placement when placement requires plaque positioning onto the cornea. Blunt conjunctival peritomy exposes the sclera overlying the tumor. A "dummy" plaque is placed, with positioning confirmed by direct visualization. The amniotic membrane is draped across the cornea and anchored with the eyelet sutures, the plaque is placed overlying the membrane, the conjunctiva is closed over the plaque, and a temporary tarsorrhaphy is performed. One week later, the conjunctival incision is reopened for plaque/amniotic membrane removal. This technique was employed in the treatment of 12 iris/iridociliary melanomas at our institution, with no instances of corneal damage. In placing an anterior plaque, employing this technique allows appropriate cancer treatment while optimizing patient comfort and corneal integrity.

Retinoblastoma with MYCN Amplification Diagnosed from Cell-Free DNA in the Aqueous Humor.

Introduction: The objective of this study was to report the clinicopathologic features of three cases of MYCN-amplified retinoblastoma identified genetically by aqueous humor sampling. Methods: Whole-genome sequencing was performed using isolated cell-free DNA (cfDNA) from aqueous humor of 3 retinoblastoma patients. We analyzed genomic copy number and mutational alterations, histologic and pathologic features, and clinical data. Results: The most common genetic alteration identified in these three retinoblastoma cases was a focal MYCN amplification on 2p. All tumors showed an early age of diagnosis with a median of 9 months. The tumor histopathologic features included neovascularization and subretinal seeding in case 1, diffuse nature with choroidal and prelaminar optic nerve invasion in case 2, and complete vitreous seeding in case 3. Case 1 expressed RB protein and had no RB1 mutation, case 2 did not express RB protein and had an RB1 mutation, and case 3 did not express RB protein and likely had an epigenetic effect on RB expression. Conclusions: Our report shows 3 cases of unilateral retinoblastomas diagnosed in patients ranging from 4 months to 18 months old. Genomic analysis from AH cfDNA revealed MYCN amplification with intact RB protein staining in case 1 and lack of RB staining in cases 2 and 3. RB1 mutational analysis in the AH confirmed a pathogenic variant in case 2. Clinical pathology showed features requiring aggressive treatment, specifically enucleation. Importance: MYCN-amplified retinoblastomas demonstrate unique pathogenesis and aggressive behavior, regardless if MYCN is a primary or secondary driver of disease. Genomic analysis from aqueous humor may be useful when deciding to enucleate as opposed to treating conservatively. Focal MYCN amplification on 2p might be relevant for tumor growth in this subset of the retinoblastoma population in terms of targeted therapeutics.

Treatment Outcomes and Definition Inconsistencies in High-Risk Unilateral Retinoblastoma: Outcomes and Definition Variances in High-Risk Rb.

PURPOSE: To compare the clinical outcomes of children with unilateral retinoblastoma (Rb) and high-risk histopathology features (HRHF) following upfront enucleation with/without adjuvant chemotherapy, and investigate cases locally considered non-HRHF but converted to a standardized HRHF definition. DESIGN: Retrospective multinational clinical cohort study. METHODS: Children with Rb who presented to 21 centers from 12 countries between 2011-2020, and underwent primary enucleation were recruited. Centers retrieved clinical data and were asked to report detailed histopathology findings, as well as indicate cases defined locally as high-risk. For analysis, only unilateral cases with standardized HRHF, defined as retrolaminar optic nerve invasion, massive choroidal invasion, scleral invasion, anterior-segment involvement, and/or combined non-massive choroidal and prelaminar/laminar optic nerve invasion, were included. Main Outcome Measures included orbital tumor recurrence, systemic metastasis, survival and number and outcome of cases converted to standardized HRHF. RESULTS: A total of 600 children presenting to 14 centers in 9 countries were included. Of these, 505 (84.2%) were considered locally as HRHF and received adjuvant chemotherapy. After a median follow-up period of 39.2±1.6 months (range: 0.8-60.0 months), 36 (6.0%) had orbital tumor recurrence, 49 (8.2%) metastasis, and 72 (12.0%) children died. Children not receiving adjuvant chemotherapy were at significantly increased risk of orbital tumor recurrence, metastasis, and death (p ≤0.002). Of the study children, 63/600 (10.5%) were considered locally non-HRHF, but converted to standardized HRHF and included in the analysis. Of these, 6/63 (9.5%) had orbital tumor recurrence, 5/63 (7.9%) metastasis, and 6/63 (9.5%) children died. Isolated minor choroidal invasion with prelaminar/laminar optic nerve invasion was reported in 114 (19.0%) children, but considered locally as HRHF only in 68/114 (59.6%). Of these, 6/114 (5.3%) children developed metastasis and subsequently died, yielding a number needed to treat of 15. CONCLUSION: Based on this multinational cohort of children with Rb, we recommend the use of adjuvant chemotherapy following upfront enucleation and diagnosis of HRHF. Variation exists worldwide among centers when defining HRHF, resulting in adverse patient outcomes, warranting standardization.

Diastereotopic fluorine substituents as 19F NMR probes of screw-sense preference in helical foldamers.

Ligating simple amino alcohol or amino ester monomers containing enantiotopic fluorine substituents to the C-terminus of a helical peptide places the fluorine atoms in diastereotopic environments, and gives two distinct and easily identifiable signals in the (19)F NMR spectrum. In the case of a dynamically inverting helix built from achiral monomers, the chemical shift separation between the (19)F signals provides a simple means of analysing the ratio of screw-sense conformers in the oligomer, in cases where an asymmetric bias leads to a screw-sense preference.