Unique Side Chain Research Articles

Novel Cyanide-Containing Porphyrins: Unleashing In Vitro Photodynamic Therapy Potential

Porphyrins, a class of four-pyrrole nitrogen heterocyclic compounds, have been used in photodynamic cancer therapy. In this study, three distinct pyridine cationic porphyrin photosensitizers were synthesized, each possessing unique side chains containing cyanide groups (H2-P1∼H2-P3). These photosensitizers were prepared using innovative synthetic methods. Subsequently, their theoretical photophysical properties were investigated using density functional theory (DFT). Notably, this research revealed that H2-P2 exhibits the smallest band gap (2.3548 eV) and the lowest energy gap (ΔEST =0.67 eV). Simultaneously, it was confirmed that these three photosensitizers could indeed produce singlet oxygen under illumination using DPBF as a singlet oxygen probe. Additionally, TPP was uesed as a reference to calculate the singlet oxygen yield for all three compounds, with H2-P2 demonstrating the highest yield (ΦΔ = 0.74). The experimental results aligned with the theoretical predictions. The phototoxicity and dark toxicity of the three photosensitizers were further evaluated using the MTT test. Remarkably, H2-P2 exhibited the highest phototoxicity toward HepG2 cancer cells (IC50<9.1 nM), while the lowest dark toxicity toward HUVEC cells (IC50>10 μM). These findings were supported by additional experiments involving cell staining and measurement of reactive oxygen species.

Proscan: a structure-based proline design web server.

The ability to control protein conformations and dynamics through structure-based design has been useful in various scenarios, including engineering of viral antigens for vaccines. One effective design strategy is the substitution of residues to proline amino acids, which due to its unique cyclic side chain can favor and rigidify key backbone conformations. To provide the community with a means to readily identify and explore proline designs for target proteins of interest, we developed the Proscan web server. Proscan provides assessment of backbone angles, energetic and deep learning-based favorability scores, and other parameters for proline substitutions at each position of an input structure, along with interactive visualization of backbone angles and candidate substitution sites on structures. It identifies known favorable proline substitutions for viral antigens, and was benchmarked against datasets of proline substitution stability effects from deep mutational scanning and thermodynamic measurements. This tool can enable researchers to identify and prioritize designs for prospective vaccine antigen targets, or other designs to favor stability of key protein conformations. Proscan is available at: https://proscan.ibbr.umd.edu.

Synthesis and molecular dynamics simulation of biobased “bottle-brush” polyfarnesene via aqueous radical polymerization

The farnesene monomer, obtained through bio-fermentation, offers a unique long side chain structure that serves as an excellent platform for the synthesis of bottle-brush polymers with exceptional thermal properties. Such polymers have immense potential in the production of polyurethane elastomers and adhesives. Molecular dynamics simulations of polyfarnesene were performed using Materials Studio to calculate pivotal mechanical parameters like glass transition temperature (Tg), cohesive energy density (CED), and free volume. The Tg was verified by comparing the results from the simulations with measured values obtained through experimental tests. Additionally, hydroxyl-terminated polyfarnesene was cured with a variety of isocyanate cross-linking agents, using a cross-linking script, to evaluate its mechanical and energetic characteristics. The results from the simulation of trans-1,4-polyfarnesene exhibited a Tg of 202 K, which was in close agreement with the Tg (197 K) obtained from differential scanning calorimetry (DSC) measurements. Moreover, the mechanical properties of hydroxyl-terminated polyfarnesene were significantly enhanced through cross-linking, with the multi-isocyanate (N100) curing system demonstrating the highest efficacy. These findings demonstrate the usefulness of molecular dynamics (MD) simulations in providing a thorough qualitative and quantitative understanding of the intricate connection between the properties and structure of polymers.

The effects of histidine substitution of aromatic residues on the amyloidogenic properties of the fragment 264–277 of nucleophosmin 1

Histidine (His) plays a key role in mediating protein interactions and its unique side chain determines pH responsive self-assembling processes and thus in the formation of nanostructures. In this study, To identify novel self-assembling bioinspired sequences, we analyzed a series of peptide sequences obtained through the point mutation of aromatic residues of 264–277 fragment of nucleophosmin 1 (NPM1) with single and double histidines. Through several orthogonal biophysical techniques and under different pH and ionic strength conditions we evaluated the effects of these substitutions in the amyloidogenic features of derived peptides. The results clearly indicate that both the type of aromatic mutated residue and its position can have different effect on amyloid-like behaviors. They corroborate the crucial role exerted by Tyr271 in the self-assembling process of CTD of NPM1 in AML mutated form and add novel insights in the accurate investigation of how side chain orientations can determine successful design of innovative bioinspired materials.

Recent Advances in Photosynthesis, Plant Hormones and Applications in Plant Growth

Changes in the pigment and protein complexes involved in the light reactions of photosynthesis can be caused by environmental conditions, particularly those related to light quality and intensity during growth. The metabolome analysis of rice and soybean showed that dehydration stress increased the levels of galactinol and raffinose. One key method by which microorganisms control plant development has been proposed to be the generation of auxin or auxin precursors by bacteria associated with roots, or the manipulation of auxin production in plants. The effects of pathogenic and beneficial root-interacting fungi on the hormone content and auxin responsiveness of Arabidopsis, as determined by the auxin-inducible promoter system. Many developmental processes, like stem elongation, germination, vegetative growth, blooming, and reproduction, are regulated by GAs. Analyzing the metabolome of Several distinct defensive mechanisms function in different ways to prevent or lessen harm. Coeluting substances in the sample matrix have an effect on the analyte signals. They can impede or, less frequently, increase the analyte's ionization process, producing stronger or weaker signals, respectively. Furthermore, auxin, a different hormone present in plants, combines with cytokinins to prevent senescence, which, at least in its early stages, serves as a structured metabolic time and a tissue breakdown. Furthermore, synthetic amino acids with unique light-absorbing side chains may be used to add colors to such a new photosystem and rice showed that under circumstances of dehydration stress, levels of galactinol and raffinose were enhanced.

Synthesis of three cisplatin-conjugated asymmetric porphyrin photosensitizers for photodynamic therapy.

Photodynamic therapy provides a promising solution for treating various cancer types. In this study, three distinct asymmetric porphyrin-cisplatin complex photosensitizers (ZnPt-P1, ZnPt-P2, and ZnPt-P3) were synthesized, each having unique side chains. Through a set of experiments involving singlet oxygen detection and density functional theory, ZnPt-P1 was demonstrated to have excellent efficacy, exceeding that of ZnPt-P2 and ZnPt-P3. Notably, ZnPt-1 showed significant phototoxicity while maintaining low dark toxicity when tested on HepG2 cells. Additionally, further examination revealed that ZnPt-P1 had the capability to generate reactive oxygen species within cancer cells when exposed to light irradiation. Taken together, these results highlight the potential of ZnPt-P1 as a photosensitizer for use in photodynamic therapy. This study contributes to enhancing cancer treatment methodologies and provides insights for the future development of innovative drugs for photosensitization.

Impact of a Pharmacist-Conducted Preoperative Beta-Lactam Allergy Assessment on Perioperative Cefazolin Prescribing

Background: Cefazolin is guideline recommended for perioperative prophylaxis in orthopedic surgery. Despite its unique R1 side chain, cefazolin is often avoided in patients with beta-lactam allergy with concern for cross reactivity. Objectives: The primary outcome was the percentage of patients who received cefazolin perioperatively. Secondary outcomes included the percentage of patients with a beta-lactam allergy clarified following the telephone interview and clinical outcomes including acute kidney injury, surgical site infection, Clostridioides difficile infection, and re-admission at 30 and 90 days. Methods: This single-center, quasi-experimental study evaluated a pilot program in which a pharmacist phoned patients > 18 years of age with a scheduled orthopedic surgery and a documented beta-lactam allergy to assess their allergy preoperatively. Recommendations to use cefazolin were based on an algorithm. Patients were divided into pre- and post-intervention cohorts. Results: A total of 832 patients were screened for inclusion with 135 and 66 patients included in the pre- and post-intervention cohorts. No significant difference was identified in the primary outcome. In the post-intervention cohort, 62% had a beta-lactam reaction updated in the electronic medical record. Those with a beta-lactam allergy delabeled or made less severe were numerically more likely to receive cefazolin than those with an unchanged reaction or a reaction made more severe (95.2% vs 68% vs 65%). There were no differences in clinical outcomes between groups. Conclusion: A pharmacist-conducted preoperative beta-lactam allergy interview in adult patients undergoing elective orthopedic surgery improved beta-lactam allergy documentation but, did not result in increased utilization of cefazolin.

High-performance and stable poly(carbazole)-based anion exchange membrane containing rigid-flexible coupled side-chains for fuel cells

A series of novel poly(carbazole)-based copolymers tethered with three different cationic groups at the bottom of rigid-flexible coupled side-chains is prepared via superacid-catalyzed polymerization and developed as anion exchange membrane (AEM) for fuel cells. It aims to improve conductivity by aggregating long alkyl chains with good flexibility to make dense cationic groups form large ion transport channels, and the dimensional stability can be improved by the rigid unit due to its large free volume. Meanwhile, the effects of the three cations on the properties of this series of membrane materials are also further investigated. The results show that these AEMs have an ion exchange capacity (IEC) of 2.03–2.21 mequiv. g−1, exhibiting a high ionic conductivity of 133.7–151.3 mS cm−1, which is attributed to the microphase separation structure constructed by the hydrophilic/hydrophobic difference between this unique side-chain and backbone. These AEMs can remain at least 82% ionic conductivity after immersion in 2 M NaOH solution at 80 °C for 1080 h, indicating excellent alkaline stability. Finally, the AEM and binder prepared in this work are applied to a single cell, displaying a maximum power density of 546 mW cm−2 and an excellent durability, which demonstrates a promising application in fuel cells.

A Quality Improvement Initiative to Optimize Perioperative Clinical Outcomes for Patients Labelled Penicillin Allergic

Patients labelled as penicillin allergic are less likely to receive first line antibiotics in the perioperative setting and are therefore at increased risk for surgical site infections. Cefazolin is the typically preferred perioperative antibiotic with clindamycin often used as an alternative due to allergy concerns. Due to its unique side chain, true cross reactivity between penicillin and cefazolin is exceedingly rare.

PEDIATRIC ANAPHYLAXIS TO PIPERACILLIN-TAZOBACTAM REQUIRES FURTHER ALLERGY TESTING TO OTHER PENICILLINS DUE TO SELECTIVE SENSITIZATION.

<h3>Introduction</h3> Individuals with type-I IgE-mediated reactions to Piperacillin-Tazobactam often avoid other penicillins. Previous studies reveal 70% of those individuals were selectively sensitized to only Piperacillin-Tazobactam and tolerated other penicillins. <h3>Case Description</h3> The patient is a 20-month-old, full term female with a past medical history of maple syrup urine disease s/p liver transplant that presents with anaphylaxis to Piperacillin-Tazobactam. She was treated with Intravenous Piperacillin-Tazobactam and immediately after administration was noted to have vital sign instability and depressed mental status. She was treated with epinephrine, steroids, and supportive care. Her Tryptase level was 49.2. She later followed up in allergy clinic and tolerated an oral amoxicillin challenge. She had negative skin prick testing, but positive intradermal testing to Piperacillin-Tazobactam, confirming her type-1 IgE-mediated reaction. <h3>Discussion</h3> This case demonstrates an additional example of the lack of cross reactivity between Piperacillin and other penicillins. Previous studies have demonstrated that the immune response is directed at the unique side chain of the Piperacillin. Only 33% of individuals were found to have a cross sensitivity to other penicillins after a Type-1 IgE-mediated reaction to Piperacillin-Tazobactam. Individuals with penicillin allergies are often exposed to broad-spectrum antibiotics. This can lead to an increased risk of infection with resistant organisms, further leading to higher death rates and increased hospital costs. After having an allergic reaction to Piperacillin-Tazobactam, it is important that patients are tested for a type-1 IgE-mediated reaction to other penicillins, potentially allowing patients to use other penicillin-class antibiotics.

Streptothiazolidine B, a new cytotoxic alkaloid produced by Streptomyces violaceoruber

A new cytotoxic alkaloid, named streptothiazolidine B (1), together with three known compounds (2-4), were isolated from Streptomyces violaceoruber. The structure of the undescribed compound was established using 1D and 2D NMR, and HRESIMS. Streptothiazolidine B was isolated and identified as an amide alkaloid with a unique thiazolidine side chain and its absolute configuration was determined by a combination of NOESY experiment and ECD analysis. Streptothiazolidine B exhibited significant cytotoxic activities against two human tumor cell lines, Li-7 and A2780, with IC50 values of 7.8, and 9.1 μM. Meanwhile, compound 4 showed obvious cytotoxic activities against four human tumor cell lines, THP-1, HT29, Li-7 and A2780, with IC50 values ranging from 3.1 to 10.2 μM.

Crystal structure of the catalytic domain of human RPTPH.

Receptor-type protein tyrosine phosphatases (RPTPs) receive extracellular stimuli and transfer them into cells. They regulate cell growth, differentiation and death via specific signals. They have also been implicated in cancer, diabetes and neurological diseases. RPTPH, a member of the type 3 RPTP (R3-PTP) family, is an important regulator of colorectal cancer and hepatic carcinoma. Despite its importance in drug development, the structure of RPTPH has not yet been resolved. Here, the crystal structure of the catalytic domain of RPTPH was determined at 1.56 Å resolution. Despite similarities to other R3-PTPs in its overall structure, RPTPH exhibited differences in its loop regions and side-chain conformations. Compared with other R3-PTPs, RPTPH has unique side chains near its active site that may confer specificity for inhibitor binding. Therefore, detailed information on the structure of RPTPH provides clues for the development of specific inhibitors.

(Invited) Peering into Electrochemically Active Polymers with Chemically Sensitive Synchrotron X-Rays

The performance of electrochemically active materials, for example, ion-conducting polymer membranes, is defined by their unique molecular architecture and resulting hierarchical morphology across length scales that controls functional properties such as transport. Synchrotron X-ray probes have proven invaluable to reveal details into the chemistry and structure of electrochemical systems. Nevertheless, opportunities remain to uncover new structure-property insights with emerging synchrotron tools. Energy-resolved X-ray absorption spectroscopy coupled with resonant X-ray scattering can elucidate morphology with chemical sensitivity in heterogeneous polymer-based systems. These techniques are amenable to in situ and operando studies. Moreover, they are well-suited to probe thin films, enabling detailed interrogation of relevant interfaces, for example, membrane-electrode interfaces, and how interfacial molecular assembly impacts charge transport and overall electrochemical performance. Herein, we present examples of polymer morphology evolution, including perfluorinated ionomers with unique side chain architectures, leveraging the sensitivity of energy-resolved scattering to reveal detailed aspects of membrane phase separation. These studies highlight opportunities in synchrotron-based resonant scattering coupled with spectroscopy and other techniques to achieve new insights into the bulk and interfacial structure of membranes and other complex electrochemical materials.

Synthesis of Novel Macrocyclic Compounds Derived from Ceftriaxone

Macrocyclization can help improve pharmacological activity, metabolic stability, cell permeability and oral absorption to create better drug candidates. For example, enhancing the oral absorption of the compounds can allow a change in administration route. We tried to improve the oral bioavailability of ceftriaxone, a third-generation cephalosporin having a unique side chain with a 2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl group at the C-3 position of the cephem nucleus. We prepared novel macrocycles of ceftriaxone by valuable synthetic methods and confirmed their oral bioavailabilities.

Sequence-Dependent Nanofiber Structures of Phenylalanine and Isoleucine Tripeptides.

The molecular design of short peptides to achieve a tailor-made functional architecture has attracted attention during the past decade but remains challenging as a result of insufficient understanding of the relationship between peptide sequence and assembled supramolecular structures. We report a hybrid-resolution model to computationally explore the sequence–structure relationship of self-assembly for tripeptides containing only phenylalanine and isoleucine. We found that all these tripeptides have a tendency to assemble into nanofibers composed of laterally associated filaments. Molecular arrangements within the assemblies are diverse and vary depending on the sequences. This structural diversity originates from (1) distinct conformations of peptide building blocks that lead to different surface geometries of the filaments and (2) unique sidechain arrangements at the filament interfaces for each sequence. Many conformations are available for tripeptides in solution, but only an extended β-strand and another resembling a right-handed turn are observed in assemblies. It was found that the sequence dependence of these conformations and the packing of resulting filaments are determined by multiple competing noncovalent forces, with hydrophobic interactions involving Phe being particularly important. The sequence pattern for each type of assembly conformation and packing has been identified. These results highlight the importance of the interplay between conformation, molecular packing, and sequences for determining detailed nanostructures of peptides and provide a detailed insight to support a more precise design of peptide-based nanomaterials.

Gas aggregated Ag NPs as a matrix for small molecules: a study on natural amino acids

The use of nanomaterials as a matrix for soft ionization mass spectrometry has been investigated and reported various times. Under certain conditions, measurements of samples containing small molecules enhanced by nanomaterials have better sensitivity compared with other methods. Nanoscaled Ag prepared by various methods was reported as a substrate for surface-assisted LDI MS. Higher desorption and (in some cases) charge transfer through adduct formation with silver ion was reported. But primary ionization mechanism was through attachment of proton or alkali ion. Our approach is to overcoat the sample by Ag nanoparticles (the so-called nanoparticle-assisted LDI MS or nanoPALDI MS). As nanoparticles having adsorption maxima close to the laser wavelength, we expect an improvement in desorption enhancement, release of silver ions and (as a result of latter) increased adduct formation of [analyte+Ag]+ ions. The nanoparticles are produced by gas aggregation under low-pressure, making the process homogeneous over relatively large areas, free from impurities, and absence of capping agent often presented in colloidal nanoparticles. This work reports the detection of natural amino acids with Ag nanoparticles as a matrix. We successfully detected all amino acids (as [analyte+Ag]+ ion), including in the mixtures of few amino acids. Moreover, a formation of other adducts, particularly [analyte+Ag3]+ and [analyte2+Ag]+ is reported. The differences in ion intensity ratios depending on amino acid types are discussed. The obtained results showed that laser ablation is more efficient for amino acids with hydrophobic, unique, and neutral side chains.

First report of bioactive sterols from the muricid gastropod Chicoreus ramosus

Two unusual △5 sterols with unprecedented skeletons were isolated from the organic extract of muricid gastropod Chicoreus ramosus collected off the Gulf of Mannar Coast. This is the first report of isolation of bioactive sterols endowed with anti-inflammatory potentials from this species. The compounds were characterized as (5Z)-24a-homo-cholesta-5,24a1(24a2) dien-3β-ol (1) and 27(25 → 23)-abeo-(5Z)-3β-hydroxy-24-isopropyl cholesteno-26,23-lactone (2) by the interpretation of a series of spectroscopic techniques involving two-dimensional nuclear magnetic resonance and mass spectral data. The compound 1 is unusual in that it has an ethylene attachment stemming from the additional methylene group at the 24a position of the steroid side chain, whereas compound 2 has a unique side chain bearing a γ-valerolactone ring. The △5 sterol bearing ethylene group (1) displayed comparatively better antidiabetic activity as characterized by inhibitory effects towards α-amylase and α-glucosidase enzymes (IC50 1.97 mM and 1.78 mM, respectively), whereas the cholestenolactone analogue (2) manifested higher anti-inflammatory activity (IC50 1.42 mM) as determined by in vitro 5-lipoxygenase inhibitory potential. Structure-activity correlation study showed that the biological activities of the studied sterols were directly related to their electronic properties. The homosterol (1) exhibiting improved antidiabetic properties showed higher lipophilic character coupled with lesser steric restrictions.

New cycloartane saponin and monoterpenoid glucoindole alkaloids from Mussaenda luteola

A new cycloartane-type saponin with unusual hydroxylation at C-17 and a unique side chain, 9 (R), 19, 22 (S), 24 (R) bicyclolanost-3β, 12α, 16β, 17α tetrol-25-one 3-O-β-d-glucopyranosyl-(1→2)-β-d-glucopyranoside (1) and two new monoterpenoid glucoindole alkaloids, 10-methoxy pumiloside (2) and the previously chemically synthesized, 10-methoxy strictosidine (3) along with other five known compounds, 7α-morroniside (4), 7-epi-loganin (5), (7β)-7-O-methylmorroniside (6), 5(S)-5-carboxystrictisidine (7) and apigenin-7-O-neohesperidoside (8) were isolated from the aerial parts of Mussaenda luteola (Rubiaceae). The structural elucidation of the isolates was accomplished by extensive (1D and 2D NMR) spectroscopic data analysis and HR-ESI-MS. Compounds 4–8 were reported for the first time from the genus Mussaenda. Interestingly, this is the first report for the occurrence of the monoterpenoid glucoindole-type alkaloids in the genus which might be useful for the chemotaxonomic evaluation of the genus Mussaenda. All isolates were evaluated for their antiprotozoal activities. Compound 7 showed good antitrypanosomal activity with IC50 and IC90 values of 13.7 and 16.6μM compared to IC50 and IC90 values of 13.06 and 28.99μM for the positive control DFMO, difluoromethylornithine.

D-Alanylation in the Assembly of Ansatrienin Side Chain Is Catalyzed by a Modular NRPS.

Ansatrienins are a group of ansamycins with an N-cyclohexanoyl d-alanyl side chain. Though ansatrienins have been identified for decades, the mechanism for the addition of this unique side chain was not established. Here, we report the biochemical characterization of a tridomain nonribosomal peptide synthetase (NRPS), AstC, and an N-acyltransferase, AstF1, encoded in the biosynthetic pathway of ansatrienins. We demonstrate that AstC can efficiently catalyze the transfer of d-alanine to the C-11 hydroxyl group of ansatrienins, and AstF1 is able to attach the cyclohexanoyl group to the amino group of d-alanine. Remarkably, AstC presents the first example that a modular NRPS can catalyze intermolecular d-alanylation of the hydroxyl group to form an ester bond, though alanyl natural products have been known for decades. In addition, both AstC and AstF1 have broad substrate specificity toward acyl donors, which can be utilized to create novel ansatrienins.

The Pleiotropic Effect of Glycodelin‐A in Early Pregnancy

Successful pregnancy depends largely on adequate placentation and maternal tolerance of the fetus. Glycodelin-A is a glycoprotein abundant in the decidua during early pregnancy. It plays an important role in placental development and fetomaternal defense. Glycodelin-A interacts by its unique carbohydrate side chains with the cell surface of various cell types in the human fetomaternal interface, particularly the trophoblasts and the immune cells, and modulates their functions and differentiation to permit successful pregnancy. Abnormal levels of glycodelin-A in the endometrium, uterine flushings, and/or maternal serum correlate with unexplained infertility, early pregnancy loss, and recurrent miscarriage. This review integrates recent studies on the role of glycodelin-A in placental development and fetomaternal tolerance in early pregnancy.