Self-assembly of an anion receptor with metal-dependent kinase inhibition and potent in vitro anti-cancer properties.

One topical area of supramolecular chemistry is the binding of anionic species but despite the importance of anions in diverse cellular processes and for cancer development, anion receptors or 'binders' have received little attention as potential anti-cancer therapeutics. Here we report self-assembling trimetallic cryptands (e.g. [L2(Metal)3]6+ where Metal = Cu2+, Zn2+ or Mn2+) which can encapsulate a range of anions and which show metal-dependent differences in chemical and biological reactivities. In cell studies, both [L2Cu3]6+ and [L2Zn3]6+ complexes are highly toxic to a range of human cancer cell lines and they show significant metal-dependent selective activity towards cancer cells compared to healthy, non-cancerous cells (by up to 2000-fold). The addition of different anions to the complexes (e.g. PO43-, SO42- or PhOPO32-) further alters activity and selectivity allowing the activity to be modulated via a self-assembly process. The activity is attributed to the ability to either bind or hydrolyse phosphate esters and mechanistic studies show differential and selective inhibition of multiple kinases by both [L2Cu3]6+ and [L2Zn3]6+ complexes but via different mechanisms.

Self-Assembled Anion-Binding Cryptand for the Selective Liquid-Liquid Extraction of Phosphate Anions.

The ligands L1 and L2 form trinuclear self-assembled complexes with Cu2+ (i.e. [(L1 )2 Cu3 ]6+ or [(L2 )2 Cu3 ]6+ ) both of which act as a host to a variety of anions. Inclusion of long aliphatic chains on these ligands allows the assemblies to extract anions from aqueous media into organic solvents. Phosphate can be removed from water efficiently and highly selectively, even in the presence of other anions.

A ligand strand that displays anion-dependant reactivity with acetonitrile; formation of either a mononuclear complex or head-to-tail circular helicate.

The ligand L2,2 contains two bidentate domains separated by a 3,3-diamino-2,2'-biphenyl spacer unit and with Cu(ClO4)2 a mononuclear species is formed (e.g. [Cu(L2,2)]2+). Upon coordination with Cu(triflate)2 the ligand undergoes reaction with an acetonitrile solvent, producing a different ligand with unsymmetrical bidentate and tridentate domains (L2,3). This new ligand results in the formation of a tetranuclear head-to-tail circular helicate [Cu4(L2,3)4]8+ showing that in the presence of the triflate anion the ligand denticity is changed.

Self-Assembly of an Anion-Binding Cryptand for the Selective Encapsulation, Sequestration, and Precipitation of Phosphate from Aqueous Systems.

The self-assembled trimetallic species [L2 Cu3 ]6+ contains a cavity that acts as a host to many different anions. By using X-ray crystallography, ESI-MS, and UV/Vis spectroscopy we show that these anions are encapsulated both in the solid state and aqueous systems. Upon encapsulation, the anions Br- , I- , CO32- , SiF62- , IO63- , VO43- , WO42- , CrO42- , SO42- , AsO43- , and PO43- are all precipitated from aqueous solution and can be removed by filtration. Furthermore, the cavity can be tuned to be selective to either phosphate or sulfate anions by variation of the pH. Phosphate anions can be removed from water, even in the presence of other common anions, reducing the concentration from 1000 to <0.1 ppm and recovering approximately 99 % of the phosphate anions.

Dihydrogen phosphate-containing dinuclear double assemblies that demonstrate phosphate reactivity to the tetrafluoroborate anion.

The ligands L1 and L2 both form dinuclear assemblies with Cu(ii) and these react with dihydrogen phosphate so that the anion is incorporated within the assembly (e.g. [Cu2L2(H2PO4)]3+). However, in the presence of tetrafluoroborate anions the phosphate undergoes reaction with the anion forming [Cu3(L1)3(O3POBF3)]3+ and [Cu2(L2)2(O2P(OBF3)2)]+.

Ruthenium-Containing Linear Helicates and Mesocates with Tuneable p53-Selective Cytotoxicity in Colorectal Cancer Cells.

The ligands L1 and L2 both form separable dinuclear double-stranded helicate and mesocate complexes with RuII . In contrast to clinically approved platinates, the helicate isomer of [Ru2 (L1 )2 ]4+ was preferentially cytotoxic to isogenic cells (HCT116 p53-/- ), which lack the critical tumour suppressor gene. The mesocate isomer shows the reverse selectivity, with the achiral isomer being preferentially cytotoxic towards HCT116 p53+/+ . Other structurally similar RuII -containing dinuclear complexes showed very little cytotoxic activity. This study demonstrates that alterations in ligand or isomer can have profound effects on cytotoxicity towards cancer cells of different p53 status and suggests that selectivity can be "tuned" to either genotype. In the search for compounds that can target difficult-to-treat tumours that lack the p53 tumour suppressor gene, [Ru2 (L1 )2 ]4+ is a promising compound for further development.

Structural Strength Benefits Observed at the Hip of Premenarcheal Gymnasts Are Maintained Into Young Adulthood 10 Years After Retirement From the Sport.

PURPOSE: Premenarcheal female gymnasts have been consistently found to have greater bone mass and structural advantages. However, little is known about whether these structural advantages are maintained after the loading stimulus is removed. Therefore, the purpose of this study was to investigate the structural properties at the hip after long-term retirement from gymnastics. METHODS: Structural properties were derived from dual-energy X-ray absorptiometry scans using the hip structural analysis program for the same 24 gymnasts and 21 nongymnasts both in adolescence (8-15 y) and adulthood (22-30 y). Structural measures were obtained at the narrow neck, intertrochanter, and femoral shaft and included cross-sectional area, section modulus, and buckling ratio. Multivariate analysis of covariance was used to assess differences between groups in bone measures while controlling for size, age, maturity, and physical activity. RESULTS: Gymnasts were found to have structural advantages at the narrow neck in adolescence (16% greater cross-sectional area, 17% greater section modulus, and 25% lower buckling ratio) and 14 years later (13% greater cross-sectional area and 26% lower buckling ratio). Benefits were also found at the intertrochanter and femoral shaft sites in adolescence and adulthood. CONCLUSION: Ten years after retirement from gymnastics, former gymnasts' maintained significantly better hip bone structure than females who did not participate in gymnastics during growth.

Catalytic sp3 -sp3 Functionalisation of Sulfonamides: Late-Stage Modification of Drug-Like Molecules.

A new application of Pd-catalysed allylation is reported that enables the synthesis of a range of branched sp3 -functionalised sulfonamides, a compound class for which few reported methods exist. By reacting benzyl sulfonamides with allylic acetates in the presence of Pd0 catalysts and base at room temperature, direct allylation was efficiently performed, yielding products that are analogues of structural motifs seen in biologically active small molecules. The reaction was performed under mild conditions and could be applied to nanomolar sigma-receptor binders, thus enabling a late-stage functionalisation and efficient expansion of drug-like chemical space.

Formation of a dimer of trinuclear helicates which encapsulates an array of six hydrogen-bonded anions.

The amine-containing ligand L, composed of two bidentate pyridyl-thiazole moieties linked by a 1,3-diaminophenylene unit, reacts with copper(II) ions to form a dinuclear double helicate [Cu2 L2 ](4+) . Reaction of [Cu2 L2 ](4+) with dihydrogen phosphate (0.5 equivalents) gives the unsaturated dinuclear double helicate [Cu2 L2 (OPO3 H2 )](3+) . [Cu2 L2 (OPO3 H2 )](3+) further reacts with another 0.5 equivalents of dihydrogen phosphate to give a trinuclear circular helicate which then self-assembles into a hexameric cluster [{Cu3 L3 (OPO3 H2 )3 }](26+) .

Former premenarcheal gymnasts exhibit site-specific skeletal benefits in adulthood after long-term retirement.

Young female gymnasts have greater bone strength compared to controls; although possibly due to selection into gymnastics, it is thought that their loading activity during growth increases their bone mass, influencing both bone geometry and architecture. If such bone mass and geometric adaptations are maintained, this may potentially decrease the risk of osteoporosis and risk of fracture later in life. However, there is limited evidence of the persisting benefit of gymnastic exercise during growth on adult bone geometric parameters. Therefore, the purpose of this study was to determine whether adult bone geometry, volumetric density, and estimated strength were greater in retired gymnasts compared to controls, 10 years after retirement from the sport. Bone geometric and densitometric parameters, measured by peripheral quantitative computed tomography (pQCT) at the radius and tibia, were compared between 25 retired female gymnasts and 22 controls, age range 22 to 30 years, by multivariate analysis of covariance (covariates: age, height, and muscle cross-sectional area). Retired gymnasts had significantly greater adjusted total and trabecular area (16%), total and trabecular bone mineral content (BMC) (18% and 22%, respectively), and estimated strength (21%) at the distal radius (p < 0.05) than controls. Adjusted total and cortical area and BMC, medullary area, and estimated strength were also significantly greater (13% to 46%) in retired gymnasts at the 30% and 65% radial shaft sites (p < 0.05). At the distal tibia, retired gymnasts had 12% to 13% greater total and trabecular BMC and volumetric bone mineral density as well as 21% greater estimated strength; total and cortical BMC and estimated strength were also greater at the tibial shaft (8%, 11%, and 10%, respectively) (p < 0.05). Former female gymnasts have significantly better geometric and densitometric properties, as well as estimated strength, at the radius and tibia 10 years after retirement from gymnastics compared to females who did not participate in gymnastics in childhood and adolescence.

Higher premenarcheal bone mass in elite gymnasts is maintained into young adulthood after long-term retirement from sport: a 14-year follow-up.

Sports that impact-load the skeleton during childhood and adolescence increase determinants of bone strength such as bone mineral content and density; however, it is unclear if this benefit is maintained after retirement from the sport. The purpose of this study was to assess whether the previously reported higher bone mass in a group of premenarcheal gymnasts was still apparent 10 years after the cessation of participation and withdrawal of the gymnastics loading stimulus. In 1995, 30 gymnasts 8 to 15 years of age were measured and compared with 30 age-matched nongymnasts. Twenty-five former gymnasts and 22 nongymnasts were measured again 14 years later (2009 to 2010). Gymnasts had been retired from gymnastics training and competition for an average of 10 years. Total body (TB), lumbar spine (LS), and femoral neck (FN) bone mineral content (BMC) was assessed at both measurement occasions by dual-energy X-ray absorptiometry (DXA). Multivariate analysis of covariance (MANCOVA) was used to compare former gymnasts' and nongymnasts' BMC while controlling for differences in body size and maturation (covariates: age, height, weight, and years from menarche [1995] or age at menarche [2009 to 2010]). Premenarcheal gymnasts (measured in 1995) had significantly greater size-adjusted TB, LS, and FN BMC (p < 0.05) (15%, 17%, and 12%, respectively) than nongymnasts. Ten years after retirement, gymnasts had maintained similar size-adjusted TB, LS, and FN BMC differences (p < 0.05) (13%, 19%, and 13%, respectively) when compared with nongymnasts. Bone mass benefits in premenarcheal gymnasts were still apparent even after long-term (10 years) removal of the gymnastics loading stimulus.

Bone mineral accrual from 8 to 30 years of age: an estimation of peak bone mass.

Bone area (BA) and bone mineral content (BMC) were measured from childhood to young adulthood at the total body (TB), lumbar spine (LS), total hip (TH), and femoral neck (FN). BA and BMC values were expressed as a percentage of young-adult values to determine if and when values reached a plateau. Data were aligned on biological ages [years from peak height velocity (PHV)] to control for maturity. TB BA increased significantly from -4 to +4 years from PHV, with TB BMC reaching a plateau, on average, 2 years later at +6 years from PHV (equates to 18 and 20 years of age in girls and boys, respectively). LS BA increased significantly from -4 years from PHV to +3 years from PHV, whereas LS BMC increased until +4 from PHV. FN BA increased between -4 and +1 years from PHV, with FN BMC reaching a plateau, on average, 1 year later at +2 years from PHV. In the circumpubertal years (-2 to +2 years from PHV): 39% of the young-adult BMC was accrued at the TB in both males and females; 43% and 46% was accrued in males and females at the LS and TH, respectively; 33% (males and females) was accrued at the FN. In summary, we provide strong evidence that BA plateaus 1 to 2 years earlier than BMC. Depending on the skeletal site, peak bone mass occurs by the end of the second or early in the third decade of life. The data substantiate the importance of the circumpubertal years for accruing bone mineral.

Effect of maturational timing on bone mineral content accrual from childhood to adulthood: evidence from 15 years of longitudinal data.

A higher bone mass may reduce the risk of osteoporosis and fractures. The role of maturational timing for optimizing bone mass is controversial due to the lack of prospective evidence from childhood to adulthood. The purpose of this study was to examine the long term relationship between the onset of maturation and bone mineral content (BMC) development. Two hundred thirty individuals (109 males and 121 females) from the Saskatchewan Pediatric Bone Mineral Accrual Study (PBMAS) were classified into maturity groups based on age of peak height velocity. BMC was serially assessed using dual energy X-ray absorptiometry (DXA). Multilevel models were constructed to examine the independent development of BMC by maturity group. When age, body size, and body composition were controlled early maturing females had on average 3-4%, 62.2 ± 16.8g (p<0.05), more total body BMC than their average maturing peers by 20 years of age. In contrast, late maturing females had 50.7 ± 15.6g less total body BMC. No maturational effects were found at either the lumbar spine or femoral neck (p>0.05) in females. There were no significant differences in BMC development at any site among male maturational groups (p>0.05). In this group of healthy participants, there appears to be a sex-dependent effect on the relationship between maturational timing and total body BMC development. Early, average and late maturing males displayed similar BMC development. Late maturing females had compromised BMC accrual compared to their early and average maturing peers.

The effect of aquatic exercise and education on lowering fall risk in older adults with hip osteoarthritis.

OBJECTIVE: To evaluate the effect of aquatic exercise and education on fall risk factors in older adults with hip osteoarthritis (OA). METHOD: Seventy-nine adults, 65 years of age or older with hip OA and at least 1 fall risk factor, were randomly assigned to 1 of 3 groups: aquatics and education (AE; aquatic exercise twice a wk with once-a-wk group education), aquatics only (A; 2 wk aquatic exercise) and control (C; usual activity). Balance, falls efficacy, dual-task function, functional performance (chair stands), and walking performance were measured pre- and postintervention or control period. RESULTS: There was a significant improvement in fall risk factors (full-factorial MANCOVA, baseline values as covariates; p = .038); AE improved in falls efficacy compared with C and in functional performance compared with A and C. CONCLUSION: The combination of aquatic exercise and education was effective in improving fall risk factors in older adults with arthritis.

Does childhood and adolescence fracture influence bone mineral content in young adulthood?

Previous fracture may predispose an individual to bone fragility because of impaired bone mineral accrual. The primary objective of the study was to investigate the influence of fractures sustained during childhood and (or) adolescence on total body (TB), lumbar spine (LS), femoral neck (FN), and total hip (TH) bone mineral content (BMC) in young adulthood. It was hypothesized that there would be lower TB, LS, FN, and TH BMC in participants who had sustained a pediatric fracture. Participant anthropometrics, physical activity, and BMC (measured with dual energy X-ray absorptiometry) were assessed longitudinally during childhood and adolescence (from 1991 to 1997), and again in young adulthood (2002 to 2006). Sex, adult height, adult lean mass, adult physical activity, and adolescent BMC adjusted TB, LS, FN, and TH BMC in young adulthood, for those who reported 1 or more fractures (n = 42), were compared with those who reported no fractures (n = 101). There were no significant differences (p > 0.05) in adjusted BMC between fracture and nonfracture groups at the TB, LS, FN, and TH sites in young adulthood. These results suggest that fractures sustained during childhood and adolescence may not interfere with bone mass in young adulthood at clinically relevant bone sites.

Assessment of total and central adiposity in Canadian Aboriginal children and their Caucasian peers.

OBJECTIVE: Although Aboriginal children seem to be more susceptible to developing obesity and metabolic disorders than other ethnic groups in Canada, few studies have examined adiposity comprehensively in this population. The purpose of this study was to assess total and central adiposity in Canadian Aboriginal and Caucasian children matched by age, gender and maturity. METHODS: A total of 212 Aboriginal and 204 Caucasian children (8-17 years) were recruited. Heights, weights and waist circumferences were measured and classified using international standards. Dual energy x-ray absorptiometry (DXA) indicated relative total body and trunk fatness. Age of peak height velocity was predicted from somatic growth. Descriptives with independent t-tests and Chi-square analyses were run to detect ethnic differences. ANCOVA was used to assess differences in total body and trunk fatness (covariates height, chronological age and biological age) in girls and boys separately. RESULTS: Overweight/obesity and central adiposity were more prevalent in Aboriginal children compared with Caucasian children (p < 0.05). Ethnic differences in total body and trunk fatness were also significant, with Aboriginal girls and boys presenting, on average, 5.4% and 6.0% more total body fatness and 7.6% and 8.3% more trunk fatness, than Caucasian girls and boys, respectively (p < 0.01). CONCLUSION: Canadian Aboriginal children have greater prevalence of overweight/obesity and central adiposity, and higher relative total body fatness and trunk fatness than their Caucasian peers, which may predispose them to cardiovascular and metabolic disorders at a very young age. Longitudinal research is needed to confirm the associated health risks in this population.

Peak lean tissue mass accrual precedes changes in bone strength indices at the proximal femur during the pubertal growth spurt.

PURPOSE: We examined the timing of the age and the magnitude of peak lean tissue mass accrual (PLTV) relative to the age and magnitude of two variables of bone strength [peak cross sectional area velocity (PCSAV), and peak section modulus velocity, (PZV)] at the proximal femur in males and females during the adolescent growth spurt. We hypothesized that the age of PLTV would precede the ages of PCSAV and PZV and that there is a positive relationship between the magnitude of PLTV and both PCSAV and PZV in both genders. METHODS: 41 males and 42 females aged 8-18 years were selected from the Saskatchewan Pediatric Bone Mineral Accrual Study (1991-2005). Participants' total body lean tissue mass was assessed annually for 6 consecutive years using DXA. Narrow neck and femoral shaft cross sectional areas (CSA) and section modulus (Z) were determined using the hip structural analysis (HSA) program. Participants were aligned by maturational age (years from peak height velocity). Lean tissue mass, CSA, and Z were converted into whole year velocities and the maturational age of peak tissue velocities was determined using a cubic spline curve fitting procedure. A 2 x 3 (gender x tissue) factorial MANOVA with repeated measures was used to test for differences between age of PLTV and the ages of PCSAV and PZV between genders. Multiple regression analyses were used to examine the relationship between PLTV and both PCSAV and PZV. RESULTS: There were no sex differences in the ages at which tissue peaks occurred when aligned by maturational age. There were significant differences between the age of PLTV and both PCSAV and PZV at the narrow neck (p=0.001) and femoral shaft (p=0.03), where the age of PLTV preceded both PCSAV and PZV when pooled by gender. PLTV was a significant predictor of the magnitude of both PCSAV and PZV at all sites (p<0.05). CONCLUSIONS: These findings support the hypothesis that the age of PLTV precedes the age of PCSA and PZV at the proximal femur. Results support the theory that muscle development is an important factor in affecting bone strength.

Does falls-efficacy predict balance performance in older adults with hip osteoarthritis?

This cross-sectional study evaluated the relationship of falls-efficacy to physical performance of functional balance tasks in older adults with hip osteoarthritis (OA). Older adults with hip OA experience several factors associated with fall risk: loss of movement, loss of strength, and increased fear of falls. Seventy-nine men and women age 65 or older were measured for balance, dual task function, and falls-efficacy. Using hierarchical regression, falls-efficacy was a significant predictor of balance when number of medications, age, use of a walking aid, health status, and physical activity level were controlled for. Understanding the role of falls-efficacy in predicting fall risk helps clinicians develop falls screening and prevention programs.

A longitudinal study of the relationship of physical activity to bone mineral accrual from adolescence to young adulthood.

Physical activity in adolescence is beneficial for increasing bone mineral accrual; however, it's unclear whether these benefits persist into adulthood. This prospective study investigated whether physically active adolescents maintained their higher bone mineral content (BMC) into the third decade of life when compared to their less active peers. Data were from 154 subjects (82 females and 72 males) who participated in the University of Saskatchewan's Pediatric Bone Mineral Accrual Study (1991-1997), entry age 8 to 15 years. Participants returned for follow-up as young adults (2002-2006), follow-up age 23 to 30 years. Dual energy X-ray absorptiometry was used to measure BMC of total body (TB), lumbar spine (LS), total hip (TH) and femoral neck (FN) annually from 1991 to 1997 and from 2002 to 2006. Peak height velocity (PHV) was determined for each child as a measure of maturity. Age and gender-specific activity Z-scores were calculated for each participant based on the mean physical activity scores obtained from bi-annual questionnaire data during childhood and adolescence. Subjects were ranked into three adolescent activity groups: active, average and inactive (top, middle two, and bottom quartiles, respectively). Analysis of covariance (ANCOVA) was used to compare adjusted TB, LS, TH and FN BMC across the three adolescent activity groups at 1 year post PHV and in young adulthood. When compared to the inactive group, active males had 8% greater adjusted BMC at the TB, 13% at the LS and 11% at the TH (p<0.05) in adolescence. Active females also had 8% and 15% more adjusted BMC (p<0.05) at the TB and LS, respectively, during adolescence. In young adulthood the male and female adolescent active groups were still significantly more active than their peers (p>0.05). It was found that active adolescent males had 8-10% more adjusted BMC at the TB, TH and FN (p<0.05) in young adulthood and that active adolescent females had 9% and 10% more adjusted BMC at the TH and FN. These results suggest that the skeletal benefits of physically activity in adolescents are maintained into young adulthood.