Synthesis and Regioselective Functionalization of Tetrafluorobenzo-[α]-Fused BOPYPY Dyes.

The synthesis of a new bis-BF2 tetrafluorobenzo-[α]-fused BOPYPY dye from 4,5,6,7-tetrafluoroisoindole and 2-hydrazinopyrazine is reported. The regioselectivity of nucleophilic substitution reactions at the periphery of the tetrafluorinated BOPYPY and its α-bromo derivative were investigated using N-, O-, S-, and C-based nucleophiles. Among the aromatic fluorine atoms, the F2 atom is consistently regioselectively substituted, except when the α-position contains a thiophenol group; in this case, F4 is substituted instead due to stabilizing π-π-stacking between the two aromatic groups. The α-bromo BOPYPY derivative also reacts under Stille cross-coupling reaction conditions to produce the corresponding α-substituted product. The spectroscopic properties of these new fluorinated BOPYPYs were investigated and compared with nonfluorinated analogs.

Paul A. Castelfranco (1921-2021): a scientist par excellence, a man of lasting faith, and ever a humanist.

We present here the life and the work of Paul A. Castelfranco (1921-2021), a very special person who was not only a top chemist of chlorophyll biosynthesis, but also made major contributions on fatty acid oxidation, acetate metabolism and cellular organization. He led an extraordinary and exemplary life as a human being. We present here both his personal life as well as his scientific life, which is followed by reminiscences by William Breidenbach, Kevin Smith, Alan Stemler, Ann Castelfranco, and John Castelfranco. As the subtitle of this Tribute implies, till the end Paul was a scientist par excellence, an intellectual with unlimited curiosity, a humanist, and a man of enduring religious faith. We all miss him dearly.

Palladium Complexes of N-Methylcorroles.

Alkylation of one of the inner-core nitrogen atoms is one possible approach to obtain dianionic corrole ligands, suitable for the coordination of divalent metal ions, such as PdII . Inner-core N-methylation can be obtained by treating the corrole with CH3 I, but the reaction conditions should be optimized to limit the formation of the dimethylated derivative. Two regioisomers, the N-21 and the N-22 methyl derivatives are obtained from the reaction, with the first product achieved in a higher amount. Structural characterization of the reaction products evidenced the distortion induced by the introduction of the methyl groups; the N-methylcorroles are chiral compounds, and the enantiomers were separated by chromatography, with their absolute configuration assigned by ECD computation. Palladium insertion was achieved in the case of monosubstituted corroles, but not with the dimethylated macrocycle; X-ray characterization of the complexes showed the distortion of the macrocycles. The Pd complexes do not show luminescence emission, but are able to produce singlet oxygen upon irradiation. The PdII complexes were also inserted in human serum albumin (HSA) and dispersed in water; in this case, the protein protects the corroles from photobleaching, and a switch from the type II to the type I mechanism in reactive oxygen species (ROS) production is observed.

Amino Acid Derivatives of Chlorin-e6-A Review.

Details of the structural elucidation of the clinically useful photodynamic therapy sensitizer NPe6 (15) are presented. NPe6, also designated as Laserphyrin, Talaporfin, and LS-11, is a second-generation photosensitizer derived from chlorophyll-a, currently used in Japan for the treatment of human lung, esophageal, and brain cancers. After the initial misidentification of the structure of this chlorin-e6 aspartic acid conjugate as (13), NMR and other synthetic procedures described herein arrived at the correct structure (15), confirmed using single crystal X-ray crystallography. Interesting new features of chlorin-e6 chemistry (including the intramolecular formation of an anhydride (24)) are reported, allowing chemists to regioselectively conjugate amino acids to each available carboxylic acid on positions 131 (formic), 152 (acetic), and 173 (propionic) of chlorin e6 (14). Cellular investigations of several amino acid conjugates of chlorin-e6 revealed that the 131-aspartylchlorin-e6 derivative is more phototoxic than its 152- and 173-regioisomers, in part due to its nearly linear molecular conformation.

Investigations on the Synthesis, Reactivity, and Properties of Perfluoro-α-Benzo-Fused BOPHY Fluorophores.

The synthesis and reactivity of 3,8-dibromo-dodecafluoro-benzo-fused BOPHY 2 are reported, via SN Ar with O-, N- S- and C-nucleophiles, and in Pd(0)-catalyzed cross-coupling reactions (Suzuki and Stille). The resulting perfluoro-BOPHY derivatives were investigated for their reactivity in the presence of various nucleophiles. BOPHY 3 displays reversible color change and fluorescence quenching in the presence of bases (Et3 N, DBU), whereas BOPHY 7 reacts preferentially at the α-pyrrolic positions, and BOPHY 8 undergoes regioselective fluorine substitution in the presence of thiols. The structural and electronic features of the fluorinated BOPHYs were studied by TD-DFT computations. In addition, their spectroscopic and cellular properties were investigated; BOPHY 10 shows the most red-shifted absorption/emission (λmax 659/699 nm) and 7 the highest fluorescence (Φf =0.95), while all compounds studied showed low cytotoxicity toward human HEp2 cells and were efficiently internalized.

'We have goals but [it is difficult]'. Barriers to antiretroviral therapy adherence among women using alcohol and other drugs living with HIV in South Africa.

BACKGROUND: Women living with HIV who misuse alcohol and live in economically disadvantaged settings in South Africa experience a multitude of contextual barriers as they navigate the HIV care continuum. The Women's Health CoOp (WHC), a brief, woman-focused, behavioural, evidence-based intervention, has been shown to be effective in reducing heavy drinking and improving HIV-related outcomes among this key population. However, these women face other broader socioecological barriers to antiretroviral therapy (ART) adherence. METHODS: The WHC was implemented in a modified, stepped-wedge implementation science trial in public health clinics and substance use treatment programmes in Cape Town, South Africa. A qualitative substudy was conducted to explore barriers to HIV treatment adherence among women enrolled in this trial. Eight focus group discussions were conducted with 69 participants 6 months after completion of the WHC workshops. Focus groups were audio-recorded (with consent), transcribed verbatim and analysed using a thematic approach. RESULTS: The mean age of the participants was 33 years and the mean self-reported number of drinks per day was 13. The main contextual factors influencing participants' ART adherence were intrapersonal-level factors (substance use, financial constraints, food insecurity; community-level factors (anticipated and enacted stigma, community violence) and institutional-level factors (patient-provider relationships, health facility barriers, environmental stigma). CONCLUSION: Comprehensive interventions addressing the contextual barriers and unique challenges faced by women who misuse alcohol in low-resource settings that intersect with HIV treatment nonadherence should be implemented in tandem with successful biobehavioural HIV interventions for long-term effectiveness and sustainability. PATIENT OR PUBLIC CONTRIBUTION: Our South African community collaborative board has been involved throughout this study; participants and clinic staff voices have been essential in our interpretation of these findings.

Syntheses and Investigations of Conformationally Restricted, Linker-Free α-Amino Acid-BODIPYs via Boron Functionalization.

A series of α-amino acid-BODIPY derivatives were synthesized using commercially available N-Boc-l-amino acids, via boron functionalization under mild conditions. The mono-linear, mono-spiro, and di-amino acid-BODIPY derivatives were obtained using an excess of basic (histidine, lysine, and arginine), acidic (aspartic acid), polar (tyrosine, serine), and nonpolar (methionine) amino acid residues, in yields that ranged from 37 to 66%. The conformationally restricted mono-spiro- and di-amino acid-BODIPYs display strong absorptions in the visible spectral region with high molar extinction coefficients and significantly enhanced fluorescence quantum yields compared with the parent BF2-BODIPY. Cellular uptake and cytotoxicity studies using the human HEp2 cell line show that both the presence of an N,O-bidentate spiro-ring and basic amino acids (His and Arg) increase cytotoxicity and enhance cellular uptake. Among the series of BODIPYs tested, the spiro-Arg- and spiro-His-BODIPYs were found to be the most cytotoxic (IC50 ∼ 22 µM), while the spiro-His-BODIPY was the most efficiently internalized, localizing preferentially in the cell lysosomes, ER, and mitochondria.

Serious Mental Illness in Nursing Homes: Roles and Perceived Competence of Social Services Directors.

Providing nursing home psychosocial care to persons with serious mental illnesses (SMI) requires understanding of comorbidities and attention to resident rights, needs and preferences. This quantitative study reports how 924 social service directors (SSDs) taking part in the National Nursing Home Social Service Director survey identified their roles and competence, stratified by the percentage of residents with SMI. More than 70% of SSDs, across all categories of homes, reported the social services department was "always" involved in conducting depression screening, biopsychosocial assessments and PASRR planning. SSDs in homes with lower concentrations of residents with SMI reported less involvement in anxiety screening. Those employed in homes with higher concentrations of residents with SMI reported lower involvement conducting staff interventions for resident aggression or making referrals. More than one-fifth of SSDs lacked confidence in their ability to compare/contrast dementia, depression, and delirium or to develop care plans for residents with SMI. SSDs' perceived competence in developing care plans for residents with SMI was associated with education and involvement in care planning. About one-quarter of social services directors reported not being prepared to train a colleague on how to develop care plans for residents with SMI. Training in SMI could enhance psychosocial care.

Dementia Care Involvement and Training Needs of Social Services Directors in U.S. Nursing Homes.

This study describes social services directors' involvement in dementia care in U.S. nursing homes, focusing on interest in and needs for dementia care training. Respondents were 924 social service directors from U.S. nursing homes. We found that 87% of social service departments engaged in cognitive assessment; 59% of social services directors were strongly interested in dementia care training, and 23% would need up to 10 hours of preparation time or would not be able to train staff on dementia-related care. Multinomial logistic regression analysis (n = 836) revealed that, in comparison to having no interest in dementia training, age, years of experience in nursing homes, outside mental health contracting, barriers to staffing, and hours needed to prepare dementia training predicted varying interest in dementia care training. These findings demonstrate social services directors' active involvement in dementia care and need for training.

About a Third of Nursing Home Social Services Directors Have Earned a Social Work Degree and License.

Nursing home (NH) residents have high psychosocial needs related to illness, disability, and changing life circumstances. The staff member with the most expertise in addressing psychosocial needs is the social worker. However, federal regulations indicate that only NHs with 120+ beds need hire a social services staff member and that a "qualified social worker" need not have a social work degree. Therefore, two-thirds of NHs are not required to employ a social services staff member and none are required to hire a degreed social worker. This is in stark contrast to NASW professional standards. Reporting findings from this nationally representative sample of 924 social services directors, we describe the NH social services workforce and document that most NHs do hire social services staff, although 42% of social services directors are not social work educated. 37% of NHs have a degreed and licensed social worker at the helm of social services. The odds of hiring a degreed and licensed social workers are higher for larger NHs, especially if not-for-profit and not part of a chain. NH residents deserve psychosocial care planned by staff with such expertise. Quality of psychosocial care impacts quality of life.

Synthesis and Investigation of Linker-Free BODIPY-Gly Conjugates Substituted at the Boron Atom.

An efficient synthesis of boron-functionalized cyclic BODIPY-Gly conjugates, using commercially available N-protected glycine amino acids and a BF2-BODIPY moiety as starting materials, is reported. The existence of two conformers (up and down) is revealed through comprehensive DFT calculations and 1H and 11B NMR analyses. The experimental and computational results indicate that all BODIPYs are stable in aqueous solutions at neutral pH and that Fmoc-BODIPY (4) is more stable than Ac-BODIPY (6) in the presence of trifluoroacetic acid (TFA). In part due to their enhanced rigidity, all BODIPY-Gly conjugates display increased fluorescence quantum yields (0.6 < Φ < 0.9) relative to the corresponding BF2-BODIPY, making them excellent candidates for fluorescence imaging applications.

Single-stage revision anterior cruciate ligament reconstruction using bone grafting for posterior or widening tibial tunnels restores stability of the knee and improves clinical outcomes.

PURPOSE: Revision ACL surgery may be complicated by tunnel malposition and/or tunnel widening and often requires a staged treatment approach that includes bone grafting, a period of several months to allow bone graft incorporation and then definitive revision ACL reconstruction. The purpose of this study was to evaluate the results of a single-staged ACL revision reconstruction technique using a cylindrical dowel bone graft for patients who have existing posteriorly placed and/or widened tibial tunnels in the tibia at a minimum of 2 years follow-up. METHODS: Between 2010 and 2014, patients undergoing single-stage revision ACL reconstruction with the described technique were prospectively enrolled and evaluated. At a minimum of 24 months, patients were evaluated by physical examination, multiple clinical outcome instruments including KOOS, Tegner and Lysholm, and preoperative and postoperative MRIs. RESULTS: At a mean of 35.1 months, 18 consecutive patients had no revision surgery and no subjective knee instability. There were statistically significant improvements in the Tegner (median 2, interquartile range 2.25; p < 0.01), Lysholm (20.0 ± 15.0; p < 0.01), KOOS symptoms scale (12.9 ± 11.8; p < 0.01), KOOS pain scale (15.4 ± 18.7; p < 0.01), KOOS ADL scale (13.5 ± 19.0; p < 0.01), KOOS sports scale (32.8 ± 26.4; p < 0.01), and KOOS QoL scale (18.1 ± 16.9; p < 0.01). Postoperative MRI demonstrated statistically significant anteriorization of the tibial tunnel and a statistically significant decrease in tunnel widening. CONCLUSION: Revision ACL reconstruction utilizing a single-staged tibial tunnel grafting technique resulted in improved knee pain, function, and stability at a minimum of 24-month follow-up. LEVEL OF EVIDENCE: IV.

Silicon(IV) Corroles.

Silicon complexes of corrole were obtained for the first time by reaction of the free-base corrole with hexachlorodisilane. The peripheral substituents of corrole strongly influence the nature of the reaction products: ß-octaalkyl corrole was mainly isolated as the µ-oxo dimer, while a hydroxo complex was obtained in the case of 5,10,15-tris-(pentafluorophenyl)corrole. In the case of meso-tritolyl corrole, a mixture of monomer/µ-oxo dimer was obtained. The silicon corrole complexes are more stable toward hydrolysis than the corresponding porphyrin derivatives and are endowed with brilliant luminescence properties. The high affinity of silicon for fluoride ion allowed investigation of the ability of an Si corrole to serve as a sensor for F- detection. The strong color variation due to the interaction with the halide ion makes the Si corrole an interesting material for the naked-eye detection of inorganic fluoride.

Tetrafluorobenzo-Fused BODIPY: A Platform for Regioselective Synthesis of BODIPY Dye Derivatives.

A novel route for the synthesis of unsymmetrical benzo-fused BODIPYs is reported using 4,5,6,7-tetrafluoroisoindole as a precursor. The reactivity of the 3,5-dibromo tetrafluorobenzo-fused BODIPY was investigated under nucleophilic substitution and Pd(0)-catalyzed cross-coupling reaction conditions. In addition to the 3,5-bromines, one α-fluoro group on the benzo-fused ring can also be functionalized, and an unusual homocoupling with formation of a bisBODIPY was observed. This new class of fluorinated BODIPYs could find various applications in medicine and materials.

Lewis-Acid-Catalyzed BODIPY Boron Functionalization Using Trimethylsilyl Nucleophiles.

A novel and straightforward strategy for boron functionalization in boron dipyrromethenes (BODIPYs) is developed. In particular, this synthetic strategy provides new possibilities for the synthesis of sp2 N-substituted (B-NCS and -NCO), benzotriazole- and trifluoroacetamide-substituted BODIPYs that were hitherto unknown. These new BODIPYs display an array of highly desirable photophysical properties (0.04 < Φf < 0.86), paving the road for further investigations in material applications.

Photolytic Reactivity of Organometallic Chromium Bipyridine Complexes.

Known stable [Cr(bpy)2(Ph)2](BPh4) complexes undergo reductive elimination of biphenyl with visible-light photolysis using household incandescent or compact fluorescent light bulbs. A series of [Cr(R-bpy)2(Ar)2](X) complexes (R = H or CMe3; Ar = Ph, C6H4-CMe3, or C6H4-OMe; X = I, BPh4, or PF6) were prepared, and the effect of varying the bipyridine and aryl ligands on the UV-visible spectra and electrochemistry of the chromium(III) complexes was investigated. Photolysis of a mixture of two different bis(aryl) complexes gave only the homocoupled biaryl products by 1H NMR and gas chromatography/mass spectrometry analysis. The initial product of photoinduced reductive elimination of [Cr(bpy)2(Ar)2](PF6) was trapped with bipyridine to generate [Cr(bpy)3](PF6) and with benzoyl peroxide to form [Cr(bpy)2(O2CPh)2](PF6). The latter chromium(III) bis(benzoate) complex was also synthesized by the addition of bipyridine and PhCO2H to Cp2Cr, followed by air oxidation. The neutral Cr(bpy)(S2CNMe2)Ph2 complex also generated biphenyl upon visible-light photolysis. While the treatment of Cr(tBu-bpy)(dpm)Cl2 [dpm = (OCtBu)2CH] with AgO2CPh gave trans-Cr(tBu-bpy)(dpm)(O2CPh)2, reaction of the dichloro precursor with PhMgCl produced anionic [Cr(tBu-bpy)Ph3]- with [Mg(dpm)(THF)4]+ as the countercation, with both complexes characterized by single-crystal X-ray diffraction. Protonolysis of Cr(bpy)Ph3(THF) with 8-hydroxyquinoline produced Cr(bpy)(quin)Ph2, which generated biphenyl under visible-light photolysis, and the initial product of reductive elimination was trapped by bipyridine or benzoyl peroxide. A related Cr(bpy)(quin)2 complex was synthesized by protonolysis of Cr(bpy)[N(SiMe3)2]2 and characterized by single-crystal X-ray diffraction.

Syntheses, Spectroscopic Properties, and Computational Study of ( E, Z)-Ethenyl and Ethynyl-Linked BODIPYs.

A series of ( E, Z)-ethenyl- and ethynyl-linked boron dipyrromethene (BODIPY) dimers were synthesized in 23-34% yields by condensation of pyrroles with the corresponding bis-benzaldehydes, followed by oxidation and boron complexation. The BODIPY dimers were characterized by 1H, 13C, and 11B NMR spectroscopy, high-resolution mass spectrometry, and, in the cases of 1b, 2, and 3, by X-ray crystallography. The spectroscopic properties for this series of dimers were investigated in tetrahydrofuran solutions, and very similar absorption and emission profiles were observed for all dimers. Density functional theory calculations show minimal conjugation between the two BODIPY units in the dimers, as a result of the large dihedral angle between the BODIPYs and the linker. The ( E)-ethenyl-linked dimer 1a showed the highest fluorescence quantum yield of all dimers investigated in this study.

Pharmacological Foundations of Cannabis Chemovars.

An advanced Mendelian Cannabis breeding program has been developed utilizing chemical markers to maximize the yield of phytocannabinoids and terpenoids with the aim to improve therapeutic efficacy and safety. Cannabis is often divided into several categories based on cannabinoid content. Type I, Δ9-tetrahydrocannabinol-predominant, is the prevalent offering in both medical and recreational marketplaces. In recent years, the therapeutic benefits of cannabidiol have been better recognized, leading to the promotion of additional chemovars: Type II, Cannabis that contains both Δ9-tetrahydrocannabinol and cannabidiol, and cannabidiol-predominant Type III Cannabis. While high-Δ9-tetrahydrocannabinol and high-myrcene chemovars dominate markets, these may not be optimal for patients who require distinct chemical profiles to achieve symptomatic relief. Type II Cannabis chemovars that display cannabidiol- and terpenoid-rich profiles have the potential to improve both efficacy and minimize adverse events associated with Δ9-tetrahydrocannabinol exposure. Cannabis samples were analyzed for cannabinoid and terpenoid content, and analytical results are presented via PhytoFacts, a patent-pending method of graphically displaying phytocannabinoid and terpenoid content, as well as scent, taste, and subjective therapeutic effect data. Examples from the breeding program are highlighted and include Type I, II, and III Cannabis chemovars, those highly potent in terpenoids in general, or single components, for example, limonene, pinene, terpinolene, and linalool. Additionally, it is demonstrated how Type I - III chemovars have been developed with conserved terpenoid proportions. Specific chemovars may produce enhanced analgesia, anti-inflammatory, anticonvulsant, antidepressant, and anti-anxiety effects, while simultaneously reducing sequelae of Δ9-tetrahydrocannabinol such as panic, toxic psychosis, and short-term memory impairment.

ß-Acrolein-Substituted Corroles: A Route to the Preparation of Functionalized Polyacrolein Microspheres for Chemical Sensor Applications.

An efficient ß-functionalization of [5,10,15-tris-(4-methylphenyl)corrolato]cobalt derivatives through a Vilsmeier-type reaction allows the introduction of an acrolein substituent, which is subsequently copolymerized with pure acrolein. The obtained hybrid microspheres are exploited as nanogravimetric chemical sensors. The sensing properties of the developed sensors are tested through exposure to different volatile organic compounds chosen as model analytes. The results show improved sensor sensitivity of the resulting devices for all the tested analytes with respect to sensors functionalized with either corrole or polyacrolein. The enhanced properties are attributed to the accurate and tunable merging of the properties of both exploited materials.

Enhanced Hypsochromic Shifts, Quantum Yield, and π-π Interactions in a meso,ß-Heteroaryl-Fused BODIPY.

We report the synthesis and investigation of an unprecedented 8-heteroaryl-fused BODIPY 4. This compound exhibits enhanced π-π stacking in the solid state, unusually large blue-shifts in the absorbance and emission spectra, and higher fluorescence quantum yield than its unfused precursor; DFT calculations suggest a small energy gap for 4 and strong electronic communication between the 8-OPh and the BODIPY core.