Non-Invasive Bracing of Acromioclavicular Joint Dislocations is not Superior to Early Functional Rehabilitation and not Inferior to Surgical Stabilization in Rockwood type III and V Injuries.

BACKGROUND: Treatment of acromioclavicular joint (ACJ) separations remains controversial. Yet, conservative treatment has become more common even for high-grade injuries. Available conservative treatment does to date however not address the loss of anatomical joint integrity in Rockwood (RW) III and V injuries. In a recent case report, we outlined the concept of restoring ACJ integrity by non-invasively bracing a RW V injury. AIM: The purpose of this study was to prospectively evaluate the clinical and radiological efficacy of a modern Kenny-Howard splint like brace and compare it to early functional rehabilitation or surgery for RW III and V injuries after a minimum of 12 months. METHODS: Patients with acute RW III injuries (n=18) and patients with RW V injuries who refused surgery (n=7) were prospectively enrolled and treated with an ACJ brace and followed up clinically and radiologically for 12 months. Endpoint results were compared to injury grade-, sex-, age-, and follow-up-period-matched patients treated with early functional rehabilitation (n=23) and surgical TightRope stabilization (n=23). Clinical outcomes included Constant Score (CS), Subjective Shoulder Value (SSV), Taft Score (TS), and modified Acromioclavicular Joint Instability Score (mAJIS) and radiological outcome included coracoclavicular (CC) index. RESULTS: CS, SSV, TS, and mAJIS improved in RW III and CS and SSV in RW V patients treated with the ACJ brace. Significance was only reached in RW III patients (p < 0.001). Radiological indices did not improve over time in RW III and V patients. No differences were found when comparing functional and cosmetic outcomes (CS, SSV, TS, mAJIS) after a minimum of 12 months between bracing, surgery, and early functional rehabilitation in RW III and V patients. The CC index was most improved in patients treated by surgery compared to bracing after a minimum of 12 months (p=0.0011 for RW III). CONCLUSION: Brace treatment led to comparable clinical and cosmetic outcomes as early functional rehabilitation or surgery in patients with high grade ACJ injuries after a minimum of 12 months. However, no sustainably improved reduction of the ACJ resulted from bracing, when compared to early functional rehabilitation, thus questioning its utility. While surgery ensured radiological improvement compared to bracing, no benefit was seen over early functional rehabilitation.

Advanced therapies in orthopaedics.

Advanced therapies are expected to play a crucial role in supporting repair after injury, halting the degeneration of musculoskeletal tissue to enable and promote physical activity. Despite advancements, the progress in developing advanced therapies in orthopaedics lags behind specialties like oncology, since innovative regenerative treatment strategies fall short of their expectations in musculoskeletal clinical trials. Researchers should focus on understanding the mechanism of action behind the investigated target before conducting clinical trials. Strategic research networks are needed that not only enhance scientific exchange among like-minded researchers but need to include early on commercial views, companies and venture perspectives, regulatory insights and reimbursement perspectives. Only in such collaborations essential roadblocks towards clinical trials and go-to-patients be overcome.

Transcript-dependent effects of the CALCA gene on the progression of post-traumatic osteoarthritis in mice.

Osteoarthritis represents a chronic degenerative joint disease with exceptional clinical relevance. Polymorphisms of the CALCA gene, giving rise to either a procalcitonin/calcitonin (PCT/CT) or a calcitonin gene-related peptide alpha (αCGRP) transcript by alternative splicing, were reported to be associated with the development of osteoarthritis. The objective of this study was to investigate the role of both PCT/CT and αCGRP transcripts in a mouse model of post-traumatic osteoarthritis (ptOA). WT, αCGRP-/- and CALCA-/- mice were subjected to anterior cruciate ligament transection (ACLT) to induce ptOA of the knee. Mice were sacrificed 4 and 8 weeks post-surgery, followed by micro-CT and histological evaluation. Here we show that the expression of both PCT/CT and αCGRP transcripts is induced in ptOA knees. CALCA-/- mice show increased cartilage degeneration and subchondral bone loss with elevated osteoclast numbers compared to αCGRP-/- and WT mice. Osteophyte formation is reduced to the same extent in CALCA-/- and αCGRP-/- mice compared to WT controls, while a reduced synovitis score is noticed exclusively in mice lacking CALCA. Our data show that expression of the PCT/CT transcript protects from the progression of ptOA, while αCGRP promotes osteophyte formation, suggesting that CALCA-encoded peptides may represent novel targets for the treatment of ptOA.

Nesting behavior is associated with body weight and grip strength loss in mice suffering from experimental arthritis.

Objective animal health evaluation is essential to determine welfare and discomfort in preclinical in vivo research. Body condition scores, body weight, and grimace scales are commonly used to evaluate well-being in murine rheumatoid arthritis (RA) and osteoarthritis experiments. However, nest-building, a natural behavior in mice, has not yet been evaluated in wild type (WT) or genetically modified rodents suffering from collagen antibody-induced arthritis (CAIA). To address this, we analyzed nesting behavior in WT mice, calcitonin gene-related peptide alpha-deficient (αCGRP-/-) mice, and calcitonin receptor-deficient (Calcr-/-) mice suffering from experimental RA compared to healthy control (CTRL) groups of the same genotypes. CAIA was induced in 10-12-week-old male mice, and clinical parameters (body weight, grip strength, clinical arthritis score, ankle size) as well as nesting behavior were assessed over 10 or 48 days. A slight positive association between the nest score and body weight and grip strength was found for animals suffering from CAIA. For the clinical arthritis score and ankle size, no significant associations were observed. Mixed model analyses confirmed these associations. This study demonstrates that clinical effects of RA, such as loss of body weight and grip strength, might negatively affect nesting behavior in mice. Assessing nesting behavior in mice with arthritis could be an additional, non-invasive and thus valuable health parameter in future experiments to monitor welfare and discomfort in mice. During severe disease stages, pre-formed nest-building material may be provided to animals suffering from arthritis.

The dual pro-inflammatory and bone-protective role of calcitonin gene-related peptide alpha in age-related osteoarthritis.

BACKGROUND: The vasoactive neuropeptide calcitonin gene-related peptide alpha (αCGRP) enhances nociception in primary knee osteoarthritis (OA) and has been shown to disrupt cartilage and joint integrity in experimental rheumatoid arthritis (RA). Little is known about how αCGRP may alter articular structures in primary OA. We investigated whether αCGRP modulates local inflammation and concomitant cartilage and bone changes in a murine model of age-dependent OA. METHODS: Sixteen- to 18-month-old αCGRP-deficient mice (αCGRP-/-aged) were compared to, first, age-matched wild type (WTaged) and, second, young 4- to 5-month-old non-OA αCGRP-deficient (αCGRP-/-CTRL) and non-OA WT animals (WTCTRL). αCGRP levels were measured in serum. Knee and hip joint inflammation, cartilage degradation, and bone alterations were assessed by histology (OARSI histopathological grading score), gene expression analysis, and µ-computed tomography. RESULTS: WTaged mice exhibited elevated αCGRP serum levels compared to young WTCTRL animals. Marked signs of OA-induced cartilage destruction were seen in WTaged animals, while αCGRP-/-aged mice were mostly protected from this effect. Age-dependent OA was accompanied by an increased gene expression of pro-inflammatory Tnfa, Il1b, and Il6 and catabolic Mmp13, Adamts5, Ctsk, Tnfs11 (Rankl), and Cxcl12/Cxcr4 in WTaged but not in αCGRP-/-aged mice. αCGRP-deficiency however further aggravated subchondral bone sclerosis of the medial tibial plateau and accelerated bone loss in the epi- and metaphyseal trabecular tibial bone in age-dependent OA. CONCLUSIONS: Similar to its function in experimental RA, αCGRP exerts a dual pro-inflammatory and bone-protective function in murine primary OA. Although anti-CGRP treatment was previously not successful in reducing pain in OA clinically, these data underline a crucial pathophysiological role of αCGRP in age-related OA.

Design and Additive Manufacturing of a Continuous Servo Pneumatic Actuator.

Despite an emerging interest in soft and rigid pneumatic lightweight robots, the pneumatic rotary actuators available to date either are unsuitable for servo pneumatic applications or provide a limited angular range. This study describes the functional principle, design, and manufacturing of a servo pneumatic rotary actuator that is suitable for continuous rotary motion and positioning. It contains nine radially arranged linear bellows actuators with rollers that push forward a cam profile. Proportional valves and a rotary encoder are used to control the bellows pressures in relation to the rotation angle. Introducing freely programmable servo pneumatic commutation increases versatility and allows the number of mechanical components to be reduced in comparison to state-of-the-art designs. The actuator presented is designed to be manufacturable using a combination of standard components, selective laser sintering, elastomer molding with novel multi-part cores and basic tools. Having a diameter of 110 mm and a width of 41 mm, our prototype weighs less than 500 g, produces a torque of 0.53 Nm at 1 bar pressure and a static positioning accuracy of 0.31° with no limit of angular motion. By providing a description of design, basic kinematic equations, manufacturing techniques, and a proof of concept, we enable the reader to envision and explore future applications.

Inactivation of the gene encoding procalcitonin prevents antibody-mediated arthritis.

BACKGROUND: Procalcitonin (PCT) is applied as a sensitive biomarker to exclude bacterial infections in patients with rheumatoid arthritis (RA) flare-ups. Beyond its diagnostic value, little is known about the pathophysiological role of PCT in RA. METHODS: Collagen antibody-induced arthritis (CAIA) was induced in Calca-deficient mice (Calca-/-), lacking PCT (n = 15), and wild-type (WT) mice (n = 13), while control (CTRL) animals (n = 8 for each genotype) received phosphate-buffered saline. Arthritis severity and grip strength were assessed daily for 10 or 48 days. Articular inflammation, cartilage degradation, and bone lesions were assessed by histology, gene expression analysis, and µ-computed tomography. RESULTS: Serum PCT levels and intra-articular PCT expression increased following CAIA induction. While WT animals developed a full arthritic phenotype, Calca-deficient mice were protected from clinical and histological signs of arthritis and grip strength was preserved. Cartilage turnover markers and Tnfa were exclusively elevated in WT mice. Calca-deficient animals expressed increased levels of Il1b. Decreased bone surface and increased subchondral bone porosity were observed in WT mice, while Calca-deficiency preserved bone integrity. CONCLUSION: The inactivation of Calca and thereby PCT provided full protection from joint inflammation and arthritic bone loss in mice exposed to CAIA. Together with our previous findings on the pathophysiological function of Calca-derived peptides, these data indicate an independent pro-inflammatory role of PCT in RA.

Standardized protocol and outcome measurements for the collagen antibody-induced arthritis mouse model.

The murine collagen antibody-induced arthritis (CAIA) model resembles various features of human rheumatoid arthritis and is based on the intraperitoneal or intravenous injection of autoantibodies against type II collagen. Here, we present a standardized protocol for the intraperitoneal injection of arthritis-inducing autoantibodies in mice, followed by a description of daily arthritis assessments. We then detail the steps to harvest joint and bone tissues for histological, radiological, and molecular analyses. We highlight animal welfare and 3R considerations for experimental arthritis studies. For complete details on the use and execution of this protocol, please refer to Maleitzke et al. (2021, 2022).

Source and hub of inflammation: The infrapatellar fat pad and its interactions with articular tissues during knee osteoarthritis.

Knee osteoarthritis, the most prevalent degenerative joint disorder worldwide, is driven by chronic low-grade inflammation and subsequent cartilage degradation. Clinical data on the role of the Hoffa or infrapatellar fat pad in knee osteoarthritis are, however, scarce. The infrapatellar fat pad is a richly innervated intracapsular, extrasynovial adipose tissue, and an abundant source of adipokines and proinflammatory and catabolic cytokines, which may contribute to chronic synovial inflammation, cartilage destruction, and subchondral bone remodeling during knee osteoarthritis. How the infrapatellar fat pad interacts with neighboring tissues is poorly understood. Here, we review available literature with regard to the infrapatellar fat pad's interactions with cartilage, synovium, bone, menisci, ligaments, and nervous tissue during the development and progression of knee osteoarthritis. Signaling cascades are described with a focus on immune cell populations, pro- and anti-inflammatory cytokines, adipokines, mesenchymal stromal cells, and molecules derived from conditioned media from the infrapatellar fat pad. Understanding the complex interplay between the infrapatellar fat pad and its neighboring articular tissues may help to better understand and treat the multifactorial pathogenesis of osteoarthritis.

The calcitonin receptor protects against bone loss and excessive inflammation in collagen antibody-induced arthritis.

Pharmacological application of teleost calcitonin (CT) has been shown to exert chondroprotective and anti-resorptive effects in patients with rheumatoid arthritis (RA). However, the role of endogenous CT that signals through the calcitonin receptor (CTR) remains elusive. Collagen II antibody-induced arthritis (CAIA) was stimulated in wild type (WT) and CTR-deficient (Calcr-/-) mice. Animals were monitored over 10 or 48 days. Joint inflammation, cartilage degradation, and bone erosions were assessed by clinical arthritis score, histology, histomorphometry, gene expression analysis, and µ-computed tomography. CAIA was accompanied by elevated systemic CT levels and CTR expression in the articular cartilage. Inflammation, cartilage degradation, and systemic bone loss were more pronounced in Calcr-/- CAIA mice. Expression of various pro-inflammatory, bone resorption, and catabolic cartilage markers were exclusively increased in Calcr-/- CAIA mice. Endogenous CT signaling through the mammalian CTR has the potential to protect against joint inflammation, cartilage degradation, and excessive bone remodeling in experimental RA.

Proinflammatory and bone protective role of calcitonin gene-related peptide alpha in collagen antibody-induced arthritis.

OBJECTIVES: Calcitonin gene-related peptide alpha (αCGRP) represents an immunomodulatory neuropeptide implicated in pain perception. αCGRP also functions as a critical regulator of bone formation and is overexpressed in patients with rheumatoid arthritis (RA). In the present study, we investigated the role of αCGRP in experimental RA regarding joint inflammation and bone remodelling. METHODS: Collagen II-antibody-induced arthritis (CAIA) was induced in wild type (WT) and αCGRP-deficient (αCGRP-/-) mice. Animals were monitored over 10 and 48 days with daily assessments of the semiquantitative arthritis score and grip strength test. Joint inflammation, cartilage degradation and bone erosions were assessed by histology, gene expression analysis and µCT. RESULTS: CAIA was accompanied by an overexpression of αCGRP in WT joints. αCGRP-/- mice displayed reduced arthritic inflammation and cartilage degradation. Congruently, the expression of TNF-α, IL-1ß, CD80 and MMP13 was induced in WT, but not αCGRP-/- animals. WT mice displayed an increased bone turnover during the acute inflammatory phase, which was not the case in αCGRP-/- mice. Interestingly, WT mice displayed a full recovery from the inflammatory bone disease, whereas αCGRP-/- mice exhibited substantial bone loss over time. CONCLUSION: This study demonstrates a proinflammatory and bone protective role of αCGRP in CAIA. Our data indicate that αCGRP not only enhances joint inflammation, but also controls bone remodelling as part of arthritis resolution. As novel αCGRP inhibitors are currently introduced clinically for the treatment of migraine, their potential impact on RA progression warrants further clinical investigation.

Synthesis, Characterization, and Electrochemistry of Diferrocenyl ß-Diketones, -Diketonates, and Pyrazoles.

The synthesis of FcC(O)CH(R)C(O)Fc (Fc = Fe(η5-C5H4)(η5-C5H5); R = H, 5; nBu, 7; CH2CH2(OCH2CH2)2OMe, 9), [M(κ2O,O'-FcC(O)CHC(O)Fc)n] (M = Ti, n = 3, 10; M = Fe, n = 3, 11; M = BF2, n = 1, 12), and 1-R'-3,5-Fc2-cC3HN2 (R' = H, 13; Me, 14; Ph, 15) is discussed. The solid-state structures of 5, 7, 9, 12, 13, 15, and 16 ([TiCl2(κ2O,O'-PhC(O)CHC(O)Ph)2]) show that 7 and 9 exist in their ß-diketo form. Compound 13 crystallizes as a tetramer based on a hydrogen bond pattern, including one central water molecule. The electrochemical behavior of 5-7 and 9-16 was studied by cyclic and square-wave voltammetry, showing that the ferrocenyls can separately be oxidized reversibly between -50 and 750 mV (5-7, 9, 12-15: two Fc-related events; 10, 11: six events, being partially superimposed). For complex 10, Ti-centered reversible redox processes appear at -985 (TiII/TiIII) and -520 mV (TiIII/TiIV). Spectro-electrochemical UV-Vis/NIR measurements were carried out on 5, 6, and 12, whereby only 12 showed an IVCT (intervalence charge-transfer) band of considerable strength (νmax = 6250 cm-1, Δν½ = 4725 cm-1, εmax = 240 L·mol-1·cm-1), due to the rigid C3O2B cycle, enlarging the coupling strength between the Fc groups.

Ferrocenyl-Pyrenes, Ferrocenyl-9,10-Phenanthrenediones, and Ferrocenyl-9,10-Dimethoxyphenanthrenes: Charge-Transfer Studies and SWCNT Functionalization.

The synthesis of 1-Fc- (3), 1-Br-6-Fc- (5 a), 2-Br-7-Fc- (7 a), 1,6-Fc2 - (5 b), 2,7-Fc2 -pyrene (7 b), 3,6-Fc2 -9,10-phenanthrenedione (10), and 3,6-Fc2 -9,10-dimethoxyphenanthrene (12; Fc=Fe(η5 -C5 H4 )(η5 -C5 H5 )) is discussed. Of these compounds, 10 and 12 form 1D or 2D coordination polymers in the solid state. (Spectro)Electrochemical studies confirmed reversible Fc/Fc+ redox events between -130 and 160 mV. 1,6- and 2,7-Substitution in 5 a (E°'=-130 mV) and 7 a (E°'=50 mV) influences the redox potentials, whereas the ones of 5 b and 7 b (E°'=20 mV) are independent. Compounds 5 b, 7 b, 10, and 12 show single Fc oxidation processes with redox splittings between 70 and 100 mV. UV/Vis/NIR spectroelectrochemistry confirmed a weak electron transfer between FeII /FeIII in mixed-valent [5 b]+ and [12]+ . DFT calculations showed that 5 b non-covalently interacts with the single-walled carbon nanotube (SWCNT) sidewalls as proven by, for example, disentangling experiments. In addition, CV studies of the as-obtained dispersions confirmed exohedral attachment of 5 b at the SWCNTs.

Ferrocenyl naphthalenes: substituent- and substitution pattern-depending charge transfer studies.

The synthesis of a series of ferrocenyl-functionalized naphthalenes of type 2-Fc-C10H7 (3a), 1-Fc-2-R-C10H6 (3b, R = OMe; 3c, R = Me; 3d, R = H; 3e, R = CH(O)), 1,1'-(C10H7)2Fc' (4), 1-Br-4-Fc-C10H6 (6a), 1-Br-5-Fc-C10H6 (6b), 1-Br-8-Fc-C10H6 (6c), 2-Br-6-Fc-C10H6 (6d), 1,4-Fc2-C10H6 (7a), 1,5-Fc2-C10H6 (7b), 1,8-Fc2-C10H6 (7c) and 2,6-Fc2-C10H6 (7d) (Fc = Fe(η5-C5H4)(η5-C5H5), Fc' = Fe(η5-C5H4)2) is reported. They are accessible either by the Suzuki-Miyaura or Negishi C,C cross-coupling reaction of FcB(OH)2 (1a) or FcZnCl (1b) with the appropriate bromo-naphthalenes 2a-e and 5a-d, respectively. The molecular structures of 3a-c, 3e, 4, 6b-d and 7a-d in the solid state were determined by single-crystal X-ray diffraction analysis. They show inter- (3b,c,e, 6b,d, 7a) and intramolecular (7c) π-interactions in the form of T-shaped or parallel displaced π arrangements (3c,e, 6b), whereby 3e displays a columnar stacking of the condensed aromatic unit with plane distances of 3.485(5) to 3.525(5) Å. The (spectro)electrochemical behaviour of 3-4 and 6-7 in dichloromethane in the presence of the weakly coordinating anion [B(C6F5)4]- is discussed, showing reversible redox events in the range of -140-150 mV vs. FcH/FcH+. The electrochemical response of 3a-e and 4 depends on the electron-withdrawing and -donating groups present. The redox processes of mono Fc-substituted 6a-d are affected by the naphthalene substitution pattern, which also influences the redox separations ΔE of Fc2-naphthalenes 7a-d, confirming a significant effect of the different electron transfer pathways through the aromatic core. The UV/vis/NIR spectra of mixed-valent [7a,b,d]+ show broad and weak absorptions in the NIR region, allowing a classification as weakly coupled class II systems according to Robin and Day.

Anion and solvent dependency of the electronic coupling strength in mixed valent class II systems.

The influence of the coordination and ion pairing properties of electrolyte anions on electronic coupling in cationic class II mixed valent species was studied. In order to cover a range of electronic coupling strengths within the class II regime, weakly coupled 2,5-diferrocenyl-3,4-thiadiazol, moderately coupled 2,5-diferrocenyl thiophene and strongly coupled N-(4-dimethylaminophenyl)-2,5-diferrocenyl-1H-pyrrole were chosen as analytes. The electrochemical properties of these compounds were determined by cyclic and square wave voltammetry using electrolytes with varying ion pairing capabilities, such as [NBu4][Cl], [NBu4][PF6] and [NBu4][BArF] ([NBu4][B(C6F5)4]), as well as solvents with increasing dielectric constants (dichloromethane (εr = 8.93), acetone (εr = 20.56), acetonitrile (εr = 35.94) and propylene carbonate (εr = 64.92)). It is shown that the choice of electrolyte has a considerable impact on the electrostatic and the electron transfer features of the mixed valent compounds when solvents of low polarity and low relative permittivity such as dichloromethane are used. For the use of more polar solvents such as propylene carbonate the electrochemical and spectroscopic properties are almost electrolyte independent. The solvatochromic and ion-related changes in the spectroscopic properties are most pronounced for weakly coupled systems and decrease with an increase in the electron transfer coupling strength.

Diaqua-ß-octaferrocenyltetraphenylporphyrin: a multiredox-active and air-stable 16π non-aromatic species.

Herein the synthesis and properties of the first ß-octaferrocenyltetraphenylporphyrin, {TPPFc8(H2O)2}, in its extraordinary stable and non-aromatic 16π form are reported, showing seven separate reversible redox events. As oxidation progresses, the neighbouring ferrocenyls of the pyrrole subunits display moderate electronic coupling, while electron transfer along the 16π porphyrin cycle was, due to its non-aromatic nature, not observed.

PolyJet-Printed Bellows Actuators: Design, Structural Optimization, and Experimental Investigation.

Pneumatic bellows actuators are exceptionally suitable for Additive Manufacturing (AM) as the required geometrical complexity can easily be obtained and their functionality is not affected by rough surfaces and small dimensional accuracy. This paper is an extended version of a previously published contribution to the RoboSoft2018 conference in Livorno, Italy. The original paper (Dämmer et al., 2018) contains a simulation-driven design approach as well as experimental investigations of the structural and fatigue behavior of pneumatic multi-material PolyJet™ bellows actuators. This extended version is enhanced with investigations on the relaxation behavior of PolyJet bellows actuators. The presented results are useful for researchers and engineers considering the application of PolyJet bellows actuators for pneumatic robots.

Ferrocenyl GNA Nucleosides: A Bridge between Organic and Organometallic Xeno-nucleic Acids.

The enantioselective synthesis and electrochemistry of the first ferrocenyl GNA nucleosides is reported. These compounds were obtained by a Sharpless asymmetric dihydroxylation reaction of [3-(N1-thyminyl)-1-(ferrocenyl)]propene as S,R and R,S enantiomers in about 70 % yield with enantiomeric excesses of >99 % and 71 %, respectively. The absolute configurations of the chiral carbon atoms in the nucleosides were assigned by single-crystal X-ray diffraction analysis of the methyl derivatives in the solid state. The compounds were also studied with circular dichroism (CD) spectroscopy in solution. The enantiomeric relationship between the S,R and R,S isomers was confirmed by the near-mirror-image CD spectra. The redox properties of the nucleosides and their methylated derivatives were investigated using cyclic voltammetry. The cyclic voltammograms revealed reversible redox processes for the entire series of compounds at potentials of -25 mV (for nonmethylated derivatives) and 75 mV (for methylated derivatives) versus the ferrocene/ferrocenium reference redox couple.

Mono-, di- and tetrarhenium Fischer carbene complexes with thienothiophene substituents.

The oxidative cleaving of a rhenium-rhenium bond by bromine in binuclear Fischer carbene complexes proves to be an effective method to prepare mononuclear bromido-carbene complexes. The reaction of mono- and dilithiated thieno[2,3-b]thiophene (2,3-b-TTH2) and thieno[3,2-b]thiophene (3,2-b-TTH2) with [Re2(CO)10] affords dirhenium nonacarbonyl ethoxycarbene complexes, [Re2(CO)9{C(OEt)2,3-b-TTH}] (1a) and [Re2(CO)9{C(OEt)3,2-b-TTH}] (1b), and the tetrarhenium bis(ethoxycarbene) complexes from the dilithiated thiophene substrates, [Re2(CO)9-µ-{C(OEt)-2,3-b-TT-C(OEt)}Re2(CO)9] (2a) and [Re2(CO)9-µ-{C(OEt)-3,2-b-TT-C(OEt)}Re2(CO)9] (2b) featuring bridging thiophene linkers. Rhenium-rhenium bond cleavage by bromine of the monocarbene complexes yielded the scarce class of monorhenium bromido-carbene complexes, cis-[Re(CO)4{C(OEt)2,3-b-TTH}Br] (3a) and cis-[Re(CO)4{C(OEt)3,2-b-TTH}Br] (3b), while the corresponding reaction of the biscarbene tetrarhenium carbonyl complex of thieno[2,3-b]thiophene afforded the cleaving of both metal-metal bonds to give the novel dirhenium biscarbene dibromido complex with a thienothiophene spacer, [Re(CO)4Br-µ-{C(OEt)-2,3-b-TT-C(OEt)}Re(CO)4Br] (4a). A new indirect aminolysis route is described to prepare the chlorido dimethylaminocarbene complex 5acis-[Re(CO)4{C(NMe2)2,3-b-TTH}Cl], with unexpected cleavage of the Re-Re bond. Single crystal X-ray diffraction studies were performed on 1a, 2a, 3a, 5a, 1b and 3b. Spectroscopic and electrochemical methods are employed to investigate the electronic effect of the different conjugation pathways in the different thienothiophenyl carbene substituents, and the replacement of the rhenium pentacarbonyl fragment with a bromido ligand.

Cymantrene, Cyrhetrene and Ferrocene Nucleobase Conjugates: Synthesis, Structure, Computational Study, Electrochemistry and Antitrypanosomal Activity.

A series of 11 cymantrene and cyrhetrene nucleobase conjugates, together with the hitherto unreported N7 isomer of a ferrocene-adenine conjugate were synthesised and characterised. The synthetic approach involved a Michael addition reaction of in-situ-generated acryloylcymantrene, acryloylcyrhetrene and acryloylferrocene with the canonical nucleobases thymine, uracil and adenine. The mechanism of these reactions was investigated by means of density functional theory calculations. The products were characterised by spectroscopic and electrochemical methods. The molecular structure of one cymantrene-adenine conjugate in the solid state was determined by single-crystal X-ray structure analysis, confirming the N9-substitution of the adenine moiety. It was found that the molecule adopts a bent conformation with the adenine and cyclopentadienyl planes in almost perpendicular orientation. The cymantrenyl nucleobases showed an irreversible redox behaviour, which is associated with ligand-exchange reactions of the radical cationic species. The newly synthesised compounds were also tested for their activity against the protozoan parasite Trypanosoma brucei and human myeloid leukaemia HL-60 cells. Some compounds showed promising antitrypanosomal activity, and most of them were non-toxic to HL-60 cells. It was also found that cymantrene and cyrhetrene ketone nucleobases were more active than their alcohol congeners. These findings indicate the potential of cymantrenyl and cyrhetrenyl nucleobase conjugates as possible lead compounds for future antitrypanosomal drug development.