Systematic Chemical Modification Research Articles

Dissecting the Conformational Stability of a Glycan Hairpin.

Systematic structural studies of model oligopeptides revealed important aspects of protein folding and offered design principles to access non-natural materials. In the same way, the rules that regulate glycan folding could be established by studying synthetic oligosaccharide models. However, their analysis is often limited due to the synthetic and analytical complexity. By utilizing a glycan capable of spontaneously folding into a hairpin conformation as a model system, we investigated the factors that contribute to its conformational stability in aqueous solution. The modular design of the hairpin model featured a trisaccharide turn unit and two β-1,4-oligoglucoside stacking strands that allowed for systematic chemical modifications of the glycan sequence, including the introduction of NMR labels and staples. Nuclear magnetic resonance assisted by molecular dynamics simulations revealed that stereoelectronic effects and multiple glycan-glycan interactions are the major determinants of folding stabilization. Chemical modifications in the glycan primary sequence (e.g., strand elongation) can be employed to fine-tune the rigidity of structural motifs distant from the modification sites. These results could inspire the design of other glycan architectures, with implications in glycobiology and material sciences.

Antibiotic Charge Profile Determines the Extent of L3 Dynamics in OmpF: An Expedited Passage for Molecules with a Positive Charge.

Efficient permeation into Gram-negative bacterial cells is a much-desired property in the design of antibacterial agents. The goal is to arrive at one or more chemical modifications of molecules that improve their uptake into the cell while maintaining a good binding affinity to the intracellular target. Previously, we proposed a mechanistic rationale for the fast permeation of bulky antibiotics that involves induced conformational dynamics in the constriction loop L3 of the OmpF channel. This flexibility is caused by the perturbation of a hydrogen bond network stabilizing the L3 loop due to the strong interactions of the positively charged moiety on the antibiotic with the residues of the L3 loop. In the present work, we examine how differences in the charge profile of antibiotic molecules can affect the permeation process, in particular, the L3 dynamics. To this end, we have performed all-atom molecular dynamics simulations to study the permeation process of molecules with differences in the net charge through the Escherichia coli OmpF channel. The results from these simulations suggest that a positively charged moiety on the antibiotic is responsible for strong interactions with the negatively charged residues of the L3 loop, promoting conformational dynamics in the L3 loop. In contrast, antibiotics without a positively charged moiety are unable to initiate such a dynamic response in the L3 loop. This distinct behavior of the L3 loop in the presence of molecules with different charge characteristics provides a plausible mechanism whereby large molecules with an appropriate charge distribution can leverage an L3 dynamic-dependent pathway to permeate efficiently. The results are relevant to the structure-based design of molecules with improved uptake properties achieved through systematic chemical modifications that effectively engage the L3 loop.

PSMA-Targeting Imaging and Theranostic Agents-Current Status and Future Perspective.

In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL by the United States Food and Drug Administration (US-FDA) for positron emission tomography (PET) imaging to identify suspected metastases or recurrence in patients with prostate cancer, PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors have advanced to clinical practice and trials of prostate cancer. The focus of current development of new PSMA-targeting agents has thus shifted to the improvement of in vivo pharmacokinetics and higher specific binding affinity with the aims to further increase the detection sensitivity and specificity and minimize the toxicity to non-target tissues, particularly the kidneys. The main strategies involve systematic chemical modifications of the linkage between the targeting moiety and imaging/therapy payloads. In addition to a summary of the development history of PSMA-targeting agents, this review provides an overview of current advances and future promise of PSMA-targeted imaging and theranostics with focuses on the structural determinants of the chemical modification towards the next generation of PSMA-targeting agents.

Targeted Chemical Modifications Identify Key Features of Carbohydrate Assemblies and Generate Tailored Carbohydrate Materials.

The molecular level description of carbohydrate assemblies is hampered by their structural complexity and the lack of suitable analytical methods. Here, we employed systematic chemical modifications to identify key non‐covalent interactions that triggered the supramolecular assembly of a disaccharide model. While some modifications disrupted the supramolecular organization, others were tolerated, delivering important information on the aggregation process. The screening identified new geometries, including nanotubes, and twisted ribbons that were characterized with electron tomography and electron diffraction (ED) methods. This work demonstrates that the combination of synthetic chemistry and ED methods is a powerful tool to draw correlations between the molecular structure and the nanoscale architecture of carbohydrate assemblies.

Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors

The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss of TRPML1 is associated with neurodegeneration and lysosomal storage disease, while temporary inhibition of this ion channel has been proposed to be beneficial in cancer therapy. Currently available TRPML1 channel inhibitors are not TRPML isoform selective and block at least two of the three human isoforms. We have now identified the first highly potent and isoform-selective TRPML1 antagonist, the steroid 17β-estradiol methyl ether (EDME). Two analogs of EDME, PRU-10 and PRU-12, characterized by their reduced activity at the estrogen receptor, have been identified through systematic chemical modification of the lead structure. EDME and its analogs, besides being promising new small molecule tool compounds for the investigation of TRPML1, selectively affect key features of TRPML1 function: autophagy induction and transcription factor EB (TFEB) translocation. In addition, they act as inhibitors of triple-negative breast cancer cell migration and invasion.

Tailoring Ultrafast Singlet Fission by the Chemical Modification of Phenazinothiadiazoles.

Quantum chemistry and time-resolved spectroscopy are applied to rationalize how singlet fission (SF) is affected by systematic chemical modifications introduced into phenazinothiadiazoles (PTD). Substitution of the terminal aromatic ring of TIPS-tetracene by a thiadiazole group leads to a considerable change in the relative energies of its S1 and T1 states. Thus, in contrast to TIPS-tetracene, SF becomes exothermic for various PTD derivatives, which show S1-2T1 energy differences as high as 0.15 eV. This enables SF in PTD as corroborated by femtosecond transient absorption spectroscopy and TD-DFT calculations. The latter report T-T spectra consistent with thin film UV-vis femtosecond transient absorption of PTDs at long delays. TD-DFT calculations also show that the S1-T1 energy gap can be rationally tuned by introducing N atoms into the aromatic scaffold and by the halogenation of one side ring of the PTD. In addition, the specific S1-to-1(T1T1) electronic coupling depends on the crystal morphology and the electronic properties simultaneously. Thus, both of them govern the strength and the interplay between direct and superexchange couplings, which in the most favorable cases accelerate SF to rate constants beyond (100 fs)-1. Remarkably, direct coupling was found to contribute considerably to the total effective coupling and even to dominate it for some PTDs investigated here. A quantum yield of 200% is obtained on the early picosecond time scale for all compounds studied here, which is reduced to 100% due to triplet-triplet annihilation after a few nanoseconds.

Semisynthetic Quercetin Derivatives with Potent Antitumor Activity in Colon Carcinoma

Quercetin has been found to possess diverse pharmacological properties including in different types of cancers. The application of quercetin in the pharmaceutical field is limited due to its poor bioavailability resulting from poor water solubility and poor permeability. We report a systematic chemical modification of quercetin toward the development of semisynthetic derivatives through a selective synthetic methodology, which enables the installation of different substitutions at C-3′ and C-5 positions of quercetin. The hypothesis of the present manuscript was to modulate the log D value and aqueous solubility of quercetin through the attachment of some facilitator moieties. The semisynthetic derivatives with an ideal log D value and improved aqueous solubility will possess a better cell-penetrating ability compared to quercetin. Representative compound 17 shows 96-fold increase in the cytotoxic activity in HCT-116 colon cancer cells as compared to quercetin. The in vivo treatment of 17 in CT-26 tumor-be...

Understanding organic matter heterogeneity and maturation rate by Raman spectroscopy

Solid organic matter (OM) in sedimentary rocks produces petroleum and solid bitumen when it undergoes thermal maturation. The solid OM is a ‘geomacromolecule’, usually representing a mixture of various organisms with distinct biogenic origins, and can have high heterogeneity in composition. Programmed pyrolysis is a common method to reveal bulk geochemical characteristics of the dominant OM, while detailed organic petrography is required to reveal information about the biogenic origin of contributing macerals. Despite the advantages of programmed pyrolysis, it cannot provide information about the heterogeneity of chemical compositions present in the individual OM types. Therefore, other analytical techniques such as Raman spectroscopy are necessary.In this study, we compared geochemical characteristics and Raman spectra of two sets of naturally and artificially matured Bakken source rock samples. A continuous Raman spectral map on solid bitumen particles was created from the artificially matured hydrous pyrolysis residues, in particular, to show the systematic chemical modifications in microscale. Spectroscopic data was plotted for both sets against thermal maturity to compare maturation rate/path for these two separate groups. The outcome showed that artificial maturation through hydrous pyrolysis does not follow the same trend as naturally-matured samples although having similar solid bitumen reflectance values (%SBRo).Furthermore, Raman spectroscopy of solid bitumen from artificially matured samples indicated the heterogeneity of OM decreases as maturity increases. This may represent an alteration in chemical structure towards more uniform compounds at higher maturity. This study may emphasize the necessity of using analytical methods such as Raman spectroscopy along with conventional geochemical methods to better reveal the underlying chemical structure of OM. Finally, observation by Raman spectroscopy of chemical alteration of OM during artificial maturation may assist in the proposal of improved pyrolysis protocols to better resemble natural geologic processes.

Entropy/Enthalpy Compensation in Anion Binding: Biotin[6]uril and Biotin-l-sulfoxide[6]uril Reveal Strong Solvent Dependency

Binding of anions using macrocyclic structures with a nonpolar interior using the CH···anion interaction as the recognition motif has gained popularity in the past few years, and such receptors often rely on a subtle interplay between enthalpic and entropic factors. For these types of receptors solvation of both the anion and the binding pocket of the macrocyclic host play important roles in the overall energetic picture of the binding event. Systematic chemical modifications of synthetic receptors that are able to bind anions in a variety of solvents is an important tool to gain understanding of the factors that determine the supramolecular chemistry of anions. Here we present the chiral macrocyclic structure biotin-l-sulfoxide[6]uril as a host molecule that binds anions in both water and in organic solvents. Biotin-l-sulfoxide[6]uril is prepared in a highly diastereoselective one-pot synthesis from the macrocycle biotin[6]uril. We compare the binding properties with that of biotin[6]uril, also studied in acetonitrile and in aqueous buffer at neutral pH. The biotin-l-sulfoxide[6]uril generally exhibits stronger recognition of anions in acetonitrile, but weaker binding in water as compared to the biotin[6]uril macrocycle. We have studied the binding events using a combination of NMR spectroscopy, isothermal titration calorimetry (ITC), and computational methods.

Systematic chemical modifications of single stranded siRNAs significantly improved CTNNB1 mRNA silencing

Single-stranded silencing RNAs (ss siRNA), while not as potent as duplex RNAs, have the potential to become a novel platform technology in RNA interference based gene silencing by virtue of their simplicity and plausibly favorable characteristics in pharmacokinetics and biodistribution. Like other therapeutic pharmaceutical agents, ss siRNA can be optimized to achieve higher potency through a structure–activity based approach. Systematic chemical modification at each position of a 21-mer oligonucleotide identified 2′,5′-linked 3′-deoxythymidine (3dT) at position 1 and locked nucleic acids (LNAs) at the seed region as key components to afford significant enhancement in knockdown activity both in vitro and in vivo. Further optimization by additional chemical modifications should enable ss siRNA as an alternative gene silencing modality.

Linker Modification Strategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors.

Since prostate-specific membrane antigen (PSMA) is up-regulated in nearly all stages of prostate cancer (PCa), PSMA can be considered as a viable diagnostic biomarker and treatment target in PCa. This project is focused on the development and evaluation of a series of compounds directed against PSMA. The modifications to the linker are designed to improve the binding potential and pharmacokinetics for theranostic application. In addition, the results help to further elucidate the structure-activity relationships (SAR) of the resulting PSMA inhibitors. Both in vitro and in vivo experiments of 18 synthesized PSMA inhibitor variants showed that systematic chemical modification of the linker has a significant impact on the tumor-targeting and pharmacokinetic properties. This approach can lead to an improved management of patients suffering from recurrent prostate cancer by the use of one radiolabeling precursor, which can be radiolabeled either with (68)Ga for diagnosis or with (177)Lu or (225)Ac for therapy.

Preclinical Evaluation of a Tailor-Made DOTA-Conjugated PSMA Inhibitor with Optimized Linker Moiety for Imaging and Endoradiotherapy of Prostate Cancer.

Despite many advances in the past years, the treatment of metastatic prostate cancer still remains challenging. In recent years, prostate-specific membrane antigen (PSMA) inhibitors were intensively studied to develop low-molecular-weight ligands for imaging prostate cancer lesions by PET or SPECT. However, the endoradiotherapeutic use of these compounds requires optimization with regard to the radionuclide-chelating agent and the linker moiety between chelator and pharmacophore, which influence the overall pharmacokinetic properties of the resulting radioligand. In an effort to realize both detection and optimal treatment of prostate cancer, a tailor-made novel naphthyl-containing DOTA-conjugated PSMA inhibitor has been developed. The peptidomimetic structure was synthesized by solid-phase peptide chemistry and characterized using reversed-phase high-performance liquid chromatography and matrix-assisted laser desorption/ionization mass spectrometry. Subsequent (67/68)Ga and (177)Lu labeling resulted in radiochemical yields of greater than 97% or greater than 99%, respectively. Competitive binding and internalization experiments were performed using the PSMA-positive LNCaP cell line. The in vivo biodistribution and dynamic small-animal PET imaging studies were investigated in BALB/c nu/nu mice bearing LNCaP xenografts. The chemically modified PSMA inhibitor PSMA-617 demonstrated high radiolytic stability for at least 72 h. A high inhibition potency (equilibrium dissociation constant [K(i)] = 2.34 ± 2.94 nM on LNCaP; K(i) = 0.37 ± 0.21 nM enzymatically determined) and highly efficient internalization into LNCaP cells were demonstrated. The small-animal PET measurements showed high tumor-to-background contrasts as early as 1 h after injection. Organ distribution revealed specific uptake in LNCaP tumors and in the kidneys 1 h after injection. With regard to therapeutic use, the compound exhibited a rapid clearance from the kidneys from 113.3 ± 24.4 at 1 h to 2.13 ± 1.36 percentage injected dose per gram at 24 h. The favorable pharmacokinetics of the molecule led to tumor-to-background ratios of 1,058 (tumor to blood) and 529 (tumor to muscle), respectively, 24 h after injection. The tailor-made DOTA-conjugated PSMA inhibitor PSMA-617 presented here is sustainably refined and advanced with respect to its tumor-targeting and pharmacokinetic properties by systematic chemical modification of the linker region. Therefore, this radiotracer is suitable for a first-in-human theranostic application and may help to improve the clinical management of prostate cancer in the future.

Tetrahydrohyperforin: a neuroprotective modified natural compound against Alzheimer's disease.

According to the World Health Organization (WHO), a total of 35.6 million cases of dementia were estimated in 2010, with close to 7.7 million new cases each year. In 2008, WHO declared dementia a priority condition. 90% of all dementia cases are considered to be Alzheimer's disease (AD). Therefore, great effort was made to understand the etiology of the disease and stop or slow down AD progression.

Effect of structural variation on photovoltaic characteristics of phenyl substituted diketopyrrolopyrroles

A comprehensive study has been performed on a series of solution processable phenyl substituted diketopyrrolopyrroles blended with [6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) in order to investigate how systematic chemical modifications such as solubilizing groups and conjugation length impact solar cell performance. We find that replacement of linear alkyl chains with bulky ethyl-hexyl groups or the removal of linear alkyl chains on the terminal thiophene units leads to micron scale phase segregation at high donor:acceptor blend ratios. It is found that the conjugation length can be used to simultaneously tune energy levels, solubility, and molecular ordering. We show that over-extending the conjugation length can reduce solubility making film fabrication difficult while decreasing the conjugation length past a critical limit can significantly enhance molecular ordering thereby inducing micron scale phase segregation in blend films. This work shows that a material's potential device performance can be limited by slight chemical modifications which prevent device optimization at high donor:acceptor blend ratios and elevated annealing temperatures where charge mobility is balanced and charge collection is enhanced in the donor and acceptor phase.

Systematic study of exciton diffusion length in organic semiconductors by six experimental methods

Six techniques are used to measure the exciton diffusion length as a function of systematic chemical modifications.

4‐Aminoquinoline‐Triazine‐Based Hybrids with Improved In Vitro Antimalarial Activity Against CQ‐Sensitive and CQ‐Resistant Strains of Plasmodium falciparum

A systematic chemical modification in the triazine moiety covalently attached via suitable linkers to 4-amino-7-chloroquinolines yielded a series of new 7-chloro-4-aminoquinoline-triazine hybrids exhibiting high in vitro activity against W2 (chloroquine-resistant) and D6 (chloroquine-sensitive) strains of Plasmodium falciparum without any toxicity against mammalian cell lines (Vero, LLC-PK11, HepG2). Many of the compounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) showed excellent potency against chloroquine sensitive and resistant strains. In particular, compounds 6, 8, 14, 16 and 29 were found to be significantly more active than chloroquine against the chloroquine-resistant strains (W2 clone) of P.falciparum.

Cyclodextrin functionalization: Simple routes to tailored solubilities and nanoscopic polymer networks

AbstractThe systematic chemical modification of cyclodextrins (CDs) provides an opportunity to create new substances with novel phase transfer, guest–host, solubility, and network properties. Such materials have several potential applications in polymer science, including free‐volume modifiers, stabilizers or compatibilizers, and scaffolds or templates for synthesizing new materials. In this study, we describe simple, inexpensive, and easy purification one‐pot methods to selectively functionalize CD rings with short‐ and long‐chain alkyl derivatives of varying polarity. Using bifunctional reagents in the same reaction scheme yields CD‐based polymer networks. Particular attention is devoted to solution and solid‐state NMR experiments that reveal the type and extent of functionalization, which may be used to control solubility and swelling. Alkyl chain functionalization may be expressed as the average number of CH2 units attached per CD ring, the magnitude of which can reach at least 16 and the product still be water soluble, but products become insoluble in water at a value of 32. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012

Synthetic and spectroscopic studies of some new 2‐[1‐aryl‐4{4‐methoxyphenyl}‐6‐thioxo‐1,6‐dihydro‐1,3,5‐triazinyl]amino/hydrazonothiazolidin‐4‐ones

Abstractmagnified imageA series of 4‐thiazolidinones having triazinethione moieties have been synthesized by the systematic chemical modification of S‐benzylmercapto‐1‐aryl‐4‐(4‐methoxyphenyl)‐1,6‐dihydro‐1,3,5‐triazine‐6‐thione.

Synthesis and structure–activity relationships of N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide derivatives as novel CCR3 antagonists

A novel class of potent CCR3 receptor antagonists were designed and synthesized starting from N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide ( 1),which was found by subjecting our chemical library to high throughput screening (HTS). The CCR3 inhibitory activity of the synthesized compounds against eotaxin-induced Ca 2+ influx was evaluated using CCR3-expressing preB cells. Systematic chemical modifications of 1 revealed that the 6-fluoro-2-naphthylmethyl moiety was essential for CCR3 inhibitory activity in this new series of CCR3 antagonists. Further structural modifications of the benzamide and piperidine moieties of 1 led to the identification of N-{8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3- yl}biphenyl-2-carboxamide ( 31) as a potent CCR3 antagonist with an IC 50 value of 0.020 μM.

Endomorphin-1 analogs with enhanced metabolic stability and systemic analgesic activity: Design, synthesis, and pharmacological characterization

We synthesized four new analogs of endomorphin-1 by systematic chemical modifications. To identify the best possible drug candidates for clinical pain management and to investigate the potential contribution of these alterations to the biological activity, their pharmacological properties were determined. All of the analogs showed significantly enhanced metabolic stability. The fact that centrally mediated analgesia following peripheral administration was observed with one of the analogs suggested the approach design undertaken here had validity in the development of endomorphin-1 as a successful opioid drug for the clinic.