Cis Counterparts Research Articles

Protocol of a drug-drug interaction study between bictegravir/emtricitabine/tenofovir alafenamide and feminizing hormones in trans women living with HIV.

Trans/transfeminine women are disproportionally affected by HIV. Concerns regarding negative drug-drug interactions (DDIs) between ART drugs and gender-affirming hormone therapy (GAHT), specifically feminizing hormone therapy (FHT), may contribute to the lower ART uptake by trans women with HIV compared with their cis counterparts. The aim of this study is to investigate the bidirectional pharmacokinetic effects of components of FHT regimens (oral oestradiol and androgen-suppressing medications) with the ART regimen (bictegravir/emtricitabine/tenofovir alafenamide [B/F/TAF)]. We present a protocol for a three-armed, parallel-group, longitudinal (6-month), DDI study. Group 1 includes 15 3trans women with HIV taking FHT and ART; group 2 includes 15 premenopausal cis women with HIV taking ART; group 3 includes 15 trans women without HIV taking FHT. Women with HIV must be on or switch to B/F/TAF at baseline and be virally suppressed for ≥3months. Trans women must be taking a stable regimen of ≥2mg daily oral oestradiol and an anti-androgen (pharmaceutical, and/or surgical, and/or medical) for ≥3months. Plasma ART drug concentrations will be sampled at Month 2 and compared between groups 1 and 2. Serum oestradiol concentrations will be sampled at baseline and Month 2 visits and compared between groups 1 and 3. The primary outcomes are B/F/TAF pharmacokinetic parameters (Cmin, Cmax and AUC) and oestradiol concentrations (Cmin, C4h, Cmax and AUC) at month 2. This study is of global importance as it provides critical information regarding safe coadministration of B/F/TAF and FHT, both of which are life-saving therapies for trans women with HIV.

Synthesis of 4'-Thionucleoside Analogues Bearing a C2' Stereogenic All-Carbon Quaternary Center.

The design of novel 4'-thionucleoside analogues bearing a C2' stereogenic all-carbon quaternary center is described. The synthesis involves a highly diastereoselective Mukaiyama aldol reaction, and a diastereoselective radical-based vinyl group transfer to generate the all-carbon stereogenic C2' center, along with different approaches to control the selectivity of the N-glycosidic bond. Intramolecular SN2-like cyclization of a mixture of acyclic thioaminals provided analogues with a pyrimidine nucleobase. A kinetic bias favoring cyclization of the 1',2'-anti thioaminal furnished the desired β-D-4'-thionucleoside analogue in a 7:1 ratio. DFT calculations suggest that this kinetic resolution originates from additional steric clash in the SN2-like transition state for 1',4'-trans isomers, causing a significant decrease in their reaction rate relative to 1',4'-cis counterparts. N-glycosylation of cyclic glycosyl donors with a purine nucleobase enabled the formation of novel 2-chloroadenine 4'-thionucleoside analogues. These proprietary molecules and other derivatives are currently being evaluated both in vitro and in vivo to establish their biological profiles.

Toward a Trans* Masculine Genealogy in South America

Toward a Trans* Masculine Genealogy in South America

Quality of Life in Chilean Transgender Children and Adolescents

Introduction: Transgender (TG) children and adolescents experience problems in school as well as with family and social relationships that can adversely affect their physical and psychosocial health and impair their quality of life (QoL). This study aimed to assess health-related quality of life (HRQoL) in TG children. Methods: We performed a cross-sectional study comparing HRQoL in gender non-conforming (Trans) and gender-conforming (CIS) children and adolescents using the Spanish version of KIDSCREEN-52 in 120 Chilean Trans and CIS children (aged 8–18 years) and their parents. All scores were standardized according to the KIDSCREEN manual. Results: Among the 100 questionnaires answered, 38 corresponded to children and adolescents aged 8.4–18 years. Twenty-one of them were TG (71% trans males) and 17 were CIS (76% females). Sixty-two parents answered the questionnaires: 33 from families of TG children (PTrans) and 29 from families of CIS children (PCis). Trans children had lower HRQoL scores in all domains than CIS children. The lowest-scoring domains for TG children were “Moods and Emotions,” “Psychological Well-Being” and “Social Acceptance,” and the highest-scoring domain was “School Environment.” The PTrans group had significantly higher scores than the Trans group for 3 of the 10 domains: “Psychological Well-Being,” “Moods and Emotions,” and “Parent Relations and Home Life.” Conclusion: Our results revealed that TG children and adolescents have lower QoL than their CIS counterparts, especially regarding items related to mental health. Furthermore, their parents may underestimate their well-being, confirming the vulnerability of the TG population. This finding underlies the need to perform early assessments of QoL for early detection and intervention in aspects that could deteriorate their quality of life.

Light-Gated Nano-Porous Capsules from Stereoisomer-Directed Self-Assemblies.

Structuring pores into stable membrane and controlling their opening is extremely useful for applications that require nanopores as channels for material exchange and transportation. In this work, nanoporous vesicles with aggregation-induced emission (AIE) properties were developed from the amphiphilic polymer PEG550-TPE-Chol, in which the hydrophobic part is composed of a tetraphenylethene (TPE) group and a cholesterol moiety and the hydrophilic block is a poly(ethylene glycol) (PEG, Mn = 550 Da). Two stereoisomers, trans-PEG550-TPE-Chol and cis-PEG550-TPE-Chol, were successfully synthesized. These thermally stable stereoisomers showed distinct self-assembly behavior in water: trans-PEG550-TPE-Chol formed classical vesicles, while cis-PEG550-TPE-Chol self-assembled into cylindrical micelles. Interestingly, trans/cis mixtures of PEG550-TPE-Chol (trans/cis = 60/40), either naturally synthesized without isomers' separation during the synthesis or intentionally mixed using trans- and cis-isomers, constructed perforated vesicles with nanopores. Moreover, under the illumination of high intensity UV light (365 nm, 15 mW/cm2), the classical vesicles of trans-PEG550-TPE-Chol were perforated by its cis counterparts generated from the trans-cis photoisomerization, while the cylindrical micelles of cis-PEG550-TPE-Chol interweaved to form meshes and nanoporous membranes due to the trans-isomers produced by cis-trans photoisomerization. All of these assemblies in water emitted bright cyan fluorescence under UV light, while their constituent molecules were not fluorescent when solubilized in organic solvent. The AIE fluorescent normal vesicles and nanoporous vesicles may find potential applications in biotechnology as light-gated delivery vehicles and capsules with nanochannels for material exchange.

Exploring ground and low-lying excited states for diquat, paraquat, and dipyridyl isomers

In this work, we present a computational investigation on diquat, paraquat, and six dipyridyl isomers (2,2′-dipyridyl, 2,3′-dipyridyl, 2,4′-dipyridyl, 3,3′-dipyridyl, 3,4′-dipyridyl, and 4,4′-dipyridyl). Ground state properties such as equilibrium structures, relative energetics, transition states for cis–trans interconversion, and vibrational frequencies were determined for all the isomers at the MP2 level of theory with the cc-pVTZ basis set in the gas-phase; the MP2/cc-pVTZ and MP2/6-311+G(d,p) levels of theory in water were employed for diquat and paraquat. The trans structures are the most stable ones among the compounds that present such isomeric forms, with relative energies of 6.24 kcal/mol, 0.61 kcal/mol, and 0.12 kcal/mol lower than the cis counterparts in 2,2′-dipyridyl, 2,3′-dipyridyl, and 3,3′-dipyridyl, respectively. The transition state lies at 7.65 kcal/mol above the trans form in the case of 2,2′-dipyridyl, 3.68 kcal/mol for 2,3′-dipyridyl, and 2.02 kcal/mol for 3,3′-dipyridyl, indicating that the interconversion is feasible in the cases of 2,3′-dipyridyl and 3,3′-dipyridyl and unlikely to occur in 2,2′-dipyridyl at room temperature. Vertical excitation energies and respective generalized oscillator strengths (GOS) were determined using time-dependent density functional theory (CAM-B3LYP/cc-pVTZ and PBE0/cc-pVTZ) and EOM-CCSD/cc-pVTZ. In terms of excitation (and independent of computational method), all the isomers except 4,4′-dipyridyl, presented excited electronic states that are both bright (with GOS > 0.1) and energetically accessible at UV–vis wavelengths. Two bright states were found for diquat and paraquat in the UV region. Therefore, we expect that photoinduced degradation of both compounds can benefit from the utilization of techniques combining more than one source of radiation.

Trans Manhood: The Intersections of Masculinities, Queerness, and the South

Using qualitative interviews with trans men across the Southeastern United States, this article examines how regional constructions of masculinities and manhood shape how trans men understand and do gender in this region of the country. This analysis is situated at the intersections of three areas of study—southern studies, masculinities studies, and trans studies—and demonstrates how trans masculinities in the South broaden the conversations occurring in each. The key finding in this study is that trans men, despite not being assigned male-bodied at birth and despite not being socialized as boys/men through childhood, understand and do masculinities and manhood in similar ways to their southern cis counterparts. Through three primary mechanisms, southern trans men uphold southern gender ideology and performances of masculinities. These mechanisms include (a) understanding gender as binary and essential; (b) performing stereotypical versions of southern manhood; and, (c) maintaining mastery, honor, and independence.

Pharmacokinetics of iso-α-acids in volunteers following the consumption of beer.

Hop-derived iso-α-acid (IAA) ingredient congeners are specific to beer. Concentrations of IAAs were determined in blood of five volunteers over 6 h following the consumption of small volumes of beer containing relatively high (Pale Ale beer) or low (wheat beer) concentrations of IAAs. IAAs were quickly absorbed with peak trans-IAA concentrations at 0.5 h followed by a drop of generally 10-fold at 2 h and low or not detectable trans-IAA levels at 6 h. However, the qualitative monitoring showed that the cis-IAAs were detected at all time-points. Preliminary pharmacokinetics of these compounds in humans shows relatively small interindividual differences and an estimated short half-life of ∼30 min. Comparison of 0.5 and 2 h blood specimens demonstrated that the trans isomers were eliminated faster than the cis counterparts. Preliminary urine analysis showed only unmodified 'co' analytes detectable throughout the 6 h. In authentic forensic casework where typically large amounts of conventionally hopped beer are consumed, this approach may provide a novel method to target ingredient congeners consistent with beer ingestion.

1‐Methyl‐5‐(trifluoromethyl)azafulvenium Methide, an Intermediate That Undergoes Reaction through “Unusual” cis‐exo‐1,3‐ and trans‐exo‐1,7‐Cycloadditions

AbstractThe generation and reactivity of a new 1‐methyl‐5‐(trifluoromethyl)azafulvenium methide are described. Under microwave‐induced pyrolysis conditions this intermediate could be trapped by dipolarophiles, acting either as a 4π or as an 8π dipole. Quantum chemical calculations carried out at the DFT level of theory allowed the rationalization of the results observed in the cycloaddition of 1‐methyl‐5‐(trifluoromethyl)azafulvenium methide and N‐substituted maleimides. The study revealed that for 1,7‐cycloadducts the major products are obtained in the trans configuration through the unusual exo‐cycloaddition mode, whereas for 1,3‐cycloadducts the cis counterparts are obtained from this unexpected approach. In addition, under flash vacuum pyrolysis or conventional thermolysis conditions 1‐methyl‐5‐(trifluoromethyl)azafulvenium methide undergoes an allowed suprafacial sigmatropic [1,8]H shift leading to the formation of 2‐methyl‐3‐(trifluoromethyl)‐1‐vinyl‐1H‐pyrrole.

Reactivity and Biological Properties of a Series of Cytotoxic PtI2(amine)2 Complexes, Either cis or trans Configured

Six diiodido-diamine platinum(II) complexes, either cis or trans configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the trans isomers being, generally, more effective than their cis counterparts. Cell cycle analysis revealed different modes of action for these new Pt(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that trans complexes preferentially release their iodide ligands upon biomolecule binding, while the cis isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles.

Dendrimer-based synthesis of Pt catalysts for hydrocarbon conversion

Well-defined platinum-based catalysts were prepared using fourth-generation hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers as templates. Nanoparticles with an average of 40 Pt atoms and an average diameter of 1.5 nm were produced this way, and dispersed on a homemade sol–gel silica support. Different treatments were tested for the activation of the resulting catalyst, including heating in vacuum or in oxygen or hydrogen atmospheres. A combination of electron microscopy, infrared absorption spectroscopy, X-ray photoelectron spectroscopy, and catalytic kinetic measurements were used to investigate the effect of those treatments on the decomposition and elimination of the material associated with the dendrimer and on the activity and selectivity of the resulting catalysts. Neither heating in vacuum nor burning with oxygen was deemed acceptable, because much graphitic material is deposited with the former treatment and metal oxidation is induced by the latter. Hydrogen pretreatments, on the other hand, lead to fairly active catalysts with high selectivity for the conversion of trans olefins to their cis counterparts.

Regio-, Stereo-, and Enantioselectivity in Hydrocarbon Conversion on Metal Surfaces

Selectivity is one of the most important criteria for the design of new catalytic processes. More selective catalysis could be both cheaper and greener because it does not waste reactants, does not require expensive separation procedures, and generates fewer toxic byproducts. Traditionally, control of selectivity in heterogeneous catalysis has been hampered by both a lack of understanding of the molecular details that define such selectivity and the limited range of synthetic tools available to make catalysts with the specific properties required. However, progress in surface science as well as in nanotechnology and self-assembly are providing greater molecular understanding and a wider synthetic range to address these limitations. In this Account, we describe our studies using model systems to pinpoint the mechanistic factors that define selectivity in a number of increasingly subtle hydrocarbon dehydrogenation and hydrogenation reactions. The first examples show how the electronic properties of a metal surface affect the regioselectivity of hydrogen elimination from alkyl species adsorbed on that surface. Nickel preferentially promotes the extraction of hydrogen atoms from the carbon directly bonded to the surface, a step that leads to undesirable cracking reactions, whereas platinum allows for dehydrogenation farther down the hydrocarbon chain, facilitating a more desirable isomerization processes. In a second set of examples, we address the issue of selectivity in alkene isomerizations involving either double-bond migrations or cis-trans interconversions. In those reactions, the key mechanistic steps require hydrogen abstraction from a beta-carbon of the hydrocarbon chain (the second when counting away from the surface), and selectivity is defined by steric considerations around the different hydrogens available at those positions. We observed that close-packed surfaces of platinum have the unique ability to promote the thermodynamically unfavorable but highly desirable conversion of trans-alkenes to their cis counterparts, and we prepared new shape-controlled catalysts to take advantage of that valuable behavior. Finally, we discuss the more subtle issue of enantioselectivity. Hydrogenation of prochiral reactants such as asymmetric ketones can produce chiral compounds, but regular metal catalysts are achiral and therefore yield racemic mixtures. Fortunately, the adsorption of chiral modifiers onto a catalytic surface can bestow chirality on it. With cinchona alkaloids, individual molecules can provide the required chiral environment on the surface for such enantioselectivity. Simpler molecules may also bestow chirality on surfaces, even if that may require their assembly into chiral supramolecular structures held together by the surface. In both cases, a specific surface chiral site is produced with the help of molecular adsorbates. The examples discussed in this Account highlight the need to design and prepare heterogeneous catalysts with sophisticated surface sites in order to promote reactions selectively. Perhaps more importantly, they also hint at some of the tools available to accomplish that task.

Tuning selectivity in catalysis by controlling particle shape

A catalytic process for the selective formation of cis olefins would help minimize the production of unhealthy trans fats during the partial hydrogenation of edible oils. Here we report on the design of such a process on the basis of studies with model systems. Temperature programmed desorption data on single crystals showed that the isomerization of trans olefins to their cis counterparts is promoted by (111) facets of platinum, and that such selectivity is reversed on more open surfaces. Quantum mechanics calculations suggested that the extra stability of cis olefins seen on hydrogen-saturated Pt(111) surfaces may be due to a lesser degree of surface reconstruction, a factor found to be significant in the adsorption on close-packed platinum surfaces. Kinetic data using catalysts made out of dispersed tetrahedral Pt nanoparticles corroborated the selective promotion of the trans-to-cis isomerization on the (111) facets of the metal. Our work provides an example for how catalytic selectivity may be controlled by controlling the shape of the catalytic particles.

Computer simulation of the dynamics of crosslinked epoxidized oligobutadienes with different microstructures

The influence of the type of crosslinks and oligomer microstructure on the local mobility of crosslinked epoxidized 1,4-oligobutadienes was studied by molecular dynamics simulation. Distribution histograms and time autocorrelation functions of distances between oxygen and carbon atoms from different chains were examined. The chain microstructure has a substantial effect on all types of molecular motion. After crosslinking via double bonds, crosslinked oligomer molecules with the trans configuration of the double bonds turn out to be more flexible than their cis counterparts.

Trans-platinum(II) complexes with cyclohexylamine as expectator ligand induce necrosis in tumour cells by inhibiting DNA synthesis and RNA transcription

Enhanced removal of cisplatin-DNA adducts has been reported as one of main causes of cell resistance to cisplatin. This particular resistance mechanism may be circumvented by platinum complexes that bind differently to DNA. One line of work is focussed on trans platinum complexes, some of which exhibit antitumour activity similar to or even higher than that of their cis counterparts. We synthesised new trans platinum complexes, trans-[PtCl2(cyclohexylamine)(dimethylamine)] and trans-[PtCl2(OH)2(cyclohexylamine)(dimethylamine)], previously evaluated as cytotoxic agents towards different cancer and normal cell lines. These trans platinum compounds were highly effective against a panel of tumoral cell lines either sensitive to or with acquired resistance to cisplatin. In the present work we examined the mechanisms induced by these compounds to cause tumour cells toxicity. We have found that these compounds induced a complete blockade at the S phase of the cell cycle inhibiting total mRNA transcription and precluding p53 activation. In contrast to other DNA-damaging agents, these compounds do not induce senescence-associated permanent arrest. Furthermore, only a small percentage of these cells enter into apoptosis, with most of the population dying by a necrosis-like mechanism.

2-Isoxazolidineethanols: An NMR study of the effect of intramolecular H-bonding on the population of nitrogen invertomers and inversion process

A series of ( βR, 5R)- and ( βR, 5S)-2,5-disubstituted isoxazolidines: 5-(substituent)-β-phenyl-2-isoxazolidineethanols, have been prepared by asymmetric nitrone cycloaddition reactions and their NMR spectra recorded over a wide range of temperatures. The spectra at low temperatures indicate the presence of the ( βR, 5S) diasteromer almost exclusively as a single invertomer having trans disposition of the substituents at N(2) and C(5), while the ( βR, 5R) diasteromer remained as a mixture of two interconverting invertomers in deuterated chloroform. The effect of H-bonding – intramolecular in CDCl 3 and intermolecular in CD 3OD – on the population ratio of the invertomers and nitrogen inversion process has been investigated. The nitrogen inversion barriers are determined using complete line-shape analysis, and their dependence on solvent is discussed. Due to steric factor the trans-invertomers are found to be more stable than their cis counterparts.

Double Helix-to-Double Helix Transformation, Using Platinum(II) Acetylide Complexes as Surrogate Linkers

We describe novel optically active double helices consisting of complementary strands stabilized by amidinium-carboxylate salt bridges. The m-terphenyl groups of each strand are joined by trans-Pt(II) acetylide complexes with pendant PPh(3) ligands as the surrogate linker, which converts to cis counterparts by a ligand exchange reaction with cis-1,2-bis(diphenylphosphino)ethylene, resulting in the formation of double helices with different structures. Subsequent iodine-promoted reductive elimination on the Pt(II) atoms generates the fully organic, enantiomerically pure double helices. [structure: see text]

Effect of 9,10‐Cyclic Acetal Stereochemistry on Feasible Operation of the α‐Ketol Rearrangement in Highly Functionalized Paclitaxel (Taxol) Precursors.

The convergent, stereocontrolled synthesis of enantiopure stereoisomeric 9,10-cyclic acetals, whose designed role was to serve as potential precursors to Taxol, is reported. These advanced intermediates are multiply functionalized and carry a bridgehead α-ketol array which was key to isomerization into the proper framework. In agreement with relative strain energy values obtained by MM3 calculations, a dichotomy was observed between these two families. While the trans-fused acetals failed to undergo bridge migration, their cis counterparts did so efficiently. In fact, isomerization was sufficiently rapid that oxygenation at C2 was now precluded. The operation of several unusual transannular hydride shifts is also detailed.

Effect of 9,10-cyclic acetal stereochemistry on feasible operation of the alpha-ketol rearrangement in highly functionalized paclitaxel (Taxol) precursors.

The convergent, stereocontrolled synthesis of enantiopure stereoisomeric 9,10-cyclic acetals, whose designed role was to serve as potential precursors to Taxol, is reported. These advanced intermediates are multiply functionalized and carry a bridgehead alpha-ketol array which was key to isomerization into the proper framework. In agreement with relative strain energy values obtained by MM3 calculations, a dichotomy was observed between these two families. While the trans-fused acetals failed to undergo bridge migration, their cis counterparts did so efficiently. In fact, isomerization was sufficiently rapid that oxygenation at C2 was now precluded. The operation of several unusual transannular hydride shifts is also detailed.

Supercritical fluid extraction of all-trans-lycopene from tomato.

A procedure is proposed for the supercritical fluid extraction of all-trans-lycopene from tomato using carbon dioxide at 40 degrees C without modifier. The present method minimizes the risk of degradation via isomerization and oxidation of health-promoting ingredients, such as lycopene. The effect of different experimental variables on the solvating power of the supercritical fluid was evaluated in terms of both the selectivity achievable in the process and the yield of the extraction of all-trans-lycopene. Satisfactory separations of the all-trans-lycopene isomers from the cis counterparts were achieved using a C(30) column. The obtained extract contained 88% all-trans-lycopene and 12% cis-lycopene.