The microtubule-stabilizing agent, epothilone D, reduces axonal dysfunction, neurotoxicity, cognitive deficits, and Alzheimer-like pathology in an interventional study with aged tau transgenic mice.

Neurodegenerative tauopathies, such as Alzheimer's disease (AD), are characterized by insoluble deposits of hyperphosphorylated tau protein within brain neurons. Increased phosphorylation and decreased solubility has been proposed to diminish normal tau stabilization of microtubules (MTs), thereby leading to neuronal dysfunction. Earlier studies have provided evidence that small molecule MT-stabilizing drugs that are used in the treatment of cancer may have utility in the treatment of tauopathies. However, it has not been established whether treatment with a small molecule MT-stabilizing compound will provide benefit in a transgenic model with pre-existing tau pathology, as would be seen in human patients with clinical symptoms. Accordingly, we describe here an interventional study of the brain-penetrant MT-stabilizing agent, epothilone D (EpoD), in aged PS19 mice with existing tau pathology and related behavioral deficits. EpoD treatment reduced axonal dystrophy and increased axonal MT density in the aged PS19 mice, which led to improved fast axonal transport and cognitive performance. Moreover, the EpoD-treated PS19 mice had less forebrain tau pathology and increased hippocampal neuronal integrity, with no dose-limiting side effects. These data reveal that brain-penetrant MT-stabilizing drugs hold promise for the treatment of AD and related tauopathies, and that EpoD could be a candidate for clinical testing.

Epothilone D improves microtubule density, axonal integrity, and cognition in a transgenic mouse model of tauopathy.

Neurons in the brains of those with Alzheimer's disease (AD) and many frontotemporal dementias (FTDs) contain neurofibrillary tangles comprised of hyperphosphorylated tau protein. Tau normally stabilizes microtubules (MTs), and tau misfolding could lead to a loss of this function with consequent MT destabilization and neuronal dysfunction. Accordingly, a possible therapeutic strategy for AD and related "tauopathies" is treatment with a MT-stabilizing anti-cancer drug such as paclitaxel. However, paclitaxel and related taxanes have poor blood-brain barrier permeability and thus are unsuitable for diseases of the brain. We demonstrate here that the MT-stabilizing agent, epothilone D (EpoD), is brain-penetrant and we subsequently evaluated whether EpoD can compensate for tau loss-of-function in PS19 tau transgenic mice that develop forebrain tau inclusions, axonal degeneration and MT deficits. Treatment of 3-month-old male PS19 mice with low doses of EpoD once weekly for a 3 month period significantly improved CNS MT density and axonal integrity without inducing notable side-effects. Moreover, EpoD treatment reduced cognitive deficits that were observed in the PS19 mice. These results suggest that certain brain-penetrant MT-stabilizing agents might provide a viable therapeutic strategy for the treatment of AD and FTDs.

Mechanistic insight into stereoselective carbolithiation.

This article addresses the mechanistic features of asymmetric carbolithiation of ß-methylstyrenes. While often the presence of functional groups is required to obtain high enantioselectivities in carbolithiation reactions, simple ß-methylstyrene also gives high selectivities in (-)-sparteine-mediated addition of alkyl lithium compounds. Computational studies on the carbolithiation of ß-methylstyrene with (-)-sparteine show that the observed selectivities are the result of repulsion effects in the diastereomeric transition states between the (-)-sparteine⋅alkyl lithium adduct and the ß-methylstyrene, upon approximation of the two reactants. In contrast, for the ortho-amino ß-methylstyrene (E)-benzyl(2-propenylphenyl)amine (4) X-ray structure analyses of intermediate lithium amides indicate a carbolithiation mechanism in which one side of the double bond is shielded by the amide moiety, leaving only one side free for approach of the chiral alkyl lithium adduct.

The characterization of microtubule-stabilizing drugs as possible therapeutic agents for Alzheimer's disease and related tauopathies.

Tau, a protein that is enriched in neurons of the central nervous system (CNS), is thought to play a critical role in the stabilization of microtubules (MTs). Several neurodegenerative disorders referred to as tauopathies, including Alzheimer's disease and certain types of frontotemporal lobar degeneration, are characterized by the intracellular accumulation of hyperphosphorylated tau fibrils. Tau deposition into insoluble aggregates is believed to result in a loss of tau function that leads to MT destabilization, and this could cause neurodegeneration as intact MTs are required for axonal transport and normal neuron function. This tau loss-of-function hypothesis has been validated in a tau transgenic mouse model with spinal cord tau inclusions, where the MT-stabilizing agent, paclitaxel, increased spinal nerve MT density and improved motor function after drug absorption at neuromuscular junctions. Unfortunately, paclitaxel is a P-glycoprotein substrate and has poor blood-brain barrier permeability, making it unsuitable for the treatment of human tauopathies. We therefore examined several MT-stabilizing compounds from the taxane and epothilone natural product families to assess their membrane permeability and to determine whether they act as substrates or inhibitors of P-glycoprotein. Moreover, we compared brain and plasma levels of the compounds after administration to mice. Finally, we assessed whether brain-penetrant compounds could stabilize mouse CNS MTs. We found that several epothilones have significantly greater brain penetration than the taxanes. Furthermore, certain epothilones cause an increase in CNS MT stabilization, with epothilone D demonstrating a favorable pharmacokinetic and pharmacodynamic profile which suggests this agent merits further study as a potential tauopathy drug candidate.

Phorboxazole Synthetic Studies: Design, Synthesis and Biological Evaluation of Phorboxazole A and Hemi-Phorboxazole A Related Analogues.

The design, synthesis and biological evaluation of a new phorboxazole analogue, comprising an acetal replacement for the C-ring tetrahdropyran of the natural product and carrying a potency-enhancing C(45-46) vinyl chloride side chain, is described. In addition, the synthesis of (+)-hemi-phorboxazole A and a series of related hemi-phorboxazole A analogues has been achieved. The new acetal ring replacement analogue displayed activity comparable to that of the parent natural product against HCT-116 (colon) cells (IC(50) 2.25 ng/mL). Equally important, the phorboxazole analogue and two related hemiphorboxazole A congeners exhibited significant antifungal activity when assayed against pathogenic Candida albicans strains.

Identification of aminothienopyridazine inhibitors of tau assembly by quantitative high-throughput screening.

Inclusions comprised of fibrils of the microtubule- (MT-) associated protein tau are found in the brains of those with Alzheimer's disease (AD) and other neurodegenerative tauopathies. The pathology that is observed in these diseases is believed to result from the formation of toxic tau oligomers or fibrils and/or from the loss of normal tau function due to its sequestration into insoluble deposits. Hence, small molecules that prevent tau oligomerization and/or fibrillization might have therapeutic value. Indeed, examples of such compounds have been published, but nearly all have properties that render them unsuitable as drug candidates. For these reasons, we conducted quantitative high-throughput screening (qHTS) of approximately 292000 compounds to identify drug-like inhibitors of tau assembly. The fibrillization of a truncated tau fragment that contains four MT-binding domains was monitored in an assay that employed complementary thioflavin T fluorescence and fluorescence polarization methods. Previously described classes of inhibitors as well as new scaffolds were identified, including novel aminothienopyridazines (ATPZs). A number of ATPZ analogues were synthesized, and structure-activity relationships were defined. Further characterization of representative ATPZ compounds showed they do not interfere with tau-mediated MT assembly, and they are significantly more effective at preventing the fibrillization of tau than the Abeta(1-42) peptide which forms AD senile plaques. Thus, the ATPZ molecules described here represent a novel class of tau assembly inhibitors that merit further development for testing in animal models of AD-like tau pathology.

Selective vinyl C-H lithiation of cis-stilbenes.

A stereochemistry-controlled suppression of carbolithiation facilitated a regioselective vinyl C-H lithiation of cis-stilbenes allowing routine regio- and stereoselective access to polysubstituted alkenes and heterocycles. This unique selectivity was obtained for numerous directing groups and could be rationalized with DFT computational studies and an experimental mechanistic illustration of a unique anion migration.

Competencies for infant mental health therapists: A survey of expert opinion.

We report on data provided by a nationwide panel of 23 infant mental health (IMH) experts who provided numerical ratings of the relative importance of 143 competencies desirable for licensed mental health therapists working with infants/children birth to 5 years of age and their families/caregivers. The competencies were developed based on prior state and national efforts and our own experience in training IMH therapists. The competencies were grouped conceptually into seven areas: (a) Normal infant and toddler development; (b) Atypical development (perturbations in development); (c) Emotional/behavioral disorders in infants and young children; (d) Assessment; (e) Intervention; (f) Community resources and referrals; and (g) Organization, communication, and collaboration. We calculated means, SDs, 95% confidence intervals to rank order each competency. We conducted reliability analyses and tested for mean differences in ratings for the seven areas. Interrater and intraclass correlations were modest, likely the result of restriction of range in the ratings. The seven areas showed high levels of internal consistency and, with few exceptions, did not significantly differ in the means of their ratings. The utility of the competencies are discussed as a framework for training and professional development for IMH clinicians.

Synthetic applications of carbolithiation transformations.

Carbolithiation reactions are exceptionally versatile transformations which have been utilised in a remarkably diverse and creative manner. In this review we outline the background and scope of these reactions and then focus on their use in organic synthesis with a particular emphasis on literature examples published since 2000.

Applications of enantioselective carbolithiation of ortho-substituted beta-methylstyrenes.

The enantioselective carbolithiation of ortho-substituted (E)-beta-methylstyrenes provides access to chiral lithiated intermediates with broad synthetic potential. Specifically, beta-methylstyrenes with o-aminomethyl, ether, and oxazoline groups have been employed in the synthesis of chiral aromatics and heteroaromatics such as isoquinolines, isoquinolinones, benzofurans, and isobenzofuranones.

Quantification of Head Acceleration during Vestibular Rehabilitation Exercises.

PURPOSE: Vestibular rehabilitation exercises have been proven to reduce symptoms and diminish the risk of falls in those with dizziness and balance impairments. The first purpose of this study is to investigate a new method of measuring head movements during habituation vestibular rehabilitation exercises. The second is to explore the relationship between head acceleration measurements during select traditional vestibular rehabilitation exercises and the variables of age, dizziness, and poor balance confidence. RESEARCH DESIGN: A descriptive, cross-sectional study, in a university setting. STUDY SAMPLE: Fifty-two participants, ranging in age from 20 to 96 yr. All were volunteers, with the majority (34) reporting no history of dizziness or balance confidence. DATA COLLECTION: Head accelerations were calculated from linear and angular displacements as measured by magnetometry. RESULTS: Head accelerations decreased with increasing age, dizziness, and low balance confidence during four habituation exercises. CONCLUSIONS: Head acceleration varies as a function of age, dizziness, and low balance confidence during head movement-based vestibular and balance rehabilitation therapy (habituation) exercises. The magnetometry measurement method used could be applied across the course of treatment to establish predictive measures based on change in acceleration over time. More diverse participant sampling is needed to create normative data.

Development and application of a direct vinyl lithiation of cis-stilbene and a directed vinyl lithiation of an unsymmetrical cis-stilbene.

[reaction: see text] The vinyl deprotonation of cis-stilbene can be readily achieved using s-BuLi in THF at -25 degrees C. The generated 1-lithio-1,2-diphenylethene undergoes an in situ Z-to-E isomerization, and subsequent reaction with electrophiles results in an efficient stereoselective synthesis of trisubstituted alkenes. A directed vinyl lithiation of the unsymmetrical cis-stilbene 2-styryl-phenyl-carbamic acid tert-butyl ester can be achieved regioselectively, thereby expanding this methodology for further synthetic applications in indole chemistry.

The development and evaluation of the intervention model for the Florida Infant Mental Health Pilot Program.

The focus of this paper is on the development and evaluation of an intervention model for Florida's Infant and Young Child Mental Health Pilot Program, designed to identify families with children at risk for abuse and neglect, and to provide clinical evaluation and treatment services. The evaluation model, intervention strategies, and results presented in this paper are all part of the Florida pilot project developed as a response to the recommendations of the state's Strategic Plan for Infant Mental Health. Funded by the Florida legislature, the 3-year, multisite pilot was designed to provide earlier identification, better evaluation, and more effective treatment services for high-risk children under the age of three. The target population was children either at risk for out-of-home placement due to abuse and neglect, or those already in the child welfare system or adjudicated dependent by the state. The goals of the pilot project were: 1) to reduce the occurrence and re-occurrence of abuse and neglect; 2) to enhance the child's developmental functioning; 3) to improve the parent-child relationship; 4) to increase expeditious permanency placements; 5) to develop a model for intervention and treatment that could potentially be replicated in different sites; and 6) to document the components of a quality infant mental health intervention model and evaluate its effectiveness.

Regioselective carbolithiation of o-amino-(E)-stilbenes: cascade route to the quinoline scaffold.

[reaction: see text] The regioselective carbolithiation of substituted ortho-amino-(E)-stilbenes can be exploited to initiate cascade reaction sequences that can be utilized as new routes to substituted 3,4-dihydro-1H-quinolin-2-ones, 1,2,3,4-tetrahydroquinolines, 1,4-dihydroquinolines, and quinolines.

Bringing a developmental perspective to early childhood and family interventionists: where to begin.

There is a pressing need to share advances in developmental science with the large, multidisciplinary professional workforce that serves vulnerable infants and toddlers and their families. Foundational knowledge and conceptual frameworks that integrate material regarding the contents and processes of early development and promotion of their use can assist interventionists and the families they serve. This chapter describes an approach that has been developed over the past 10 years and summarizes key contents with sample practical applications. Topic areas include developmental theories, newborn capacities, a model for synthesizing information about early social competence (including self-regulation, early relationships, social skills, and social cognition), and key current topics in developmental psychopathology. Brief considerations of diversity and stigma for work with young children and families are also included.

The relationship between the chemistry and biological activity of the bisphosphonates.

The ability of bisphosphonates ((HO)(2)P(O)CR(1)R(2)P(O)(OH)(2)) to inhibit bone resorption has been known since the 1960s, but it is only recently that a detailed molecular understanding of the relationship between chemical structures and biological activity has begun to emerge. The early development of chemistry in this area was largely empirical and based on modifying R(2) groups in a variety of ways. Apart from the general ability of bisphosphonates to chelate Ca(2+) and thus target the calcium phosphate mineral component of bone, attempts to refine clear structure-activity relationships had led to ambiguous or seemingly contradictory results. However, there was increasing evidence for cellular effects, and eventually the earliest bisphosphonate drugs, such as clodronate (R(1)=R(2)=Cl) and etidronate (R(1)=OH, R(2)=CH(3)), were shown to exert intracellular actions via the formation in vivo of drug derivatives of ATP. The observation that pamidronate, a bisphosphonate with R(1)=OH and R(2)=CH(2)CH(2)NH(2), exhibited higher potency than previously known bisphosphonate drugs represented the first step towards the later recognition of the critical importance of having nitrogen in the R(2) side chain. The synthesis and biological evaluation of a large number of nitrogen-containing bisphosphonates took place particularly in the 1980s, but still with an incomplete understanding of their structure-activity relationships. A major advance was the discovery that the anti-resorptive effects of the nitrogen-containing bisphosphonates (including alendronate, risedronate, ibandronate, and zoledronate) on osteoclasts appear to result from their potency as inhibitors of the enzyme farnesyl pyrophosphate synthase (FPPS), a key branch-point enzyme in the mevalonate pathway. FPPS generates isoprenoid lipids utilized in sterol synthesis and for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Effects on other cellular targets, such as osteocytes, may also be important. Over the years many hundreds of bisphosphonates have been synthesized and studied. Interest in expanding the structural scope of the bisphosphonate class has also motivated new approaches to the chemical synthesis of these compounds. Recent chemical innovations include the synthesis of fluorescently labeled bisphosphonates, which has enabled studies of the biodistribution of these drugs. As a class, bisphosphonates share common properties. However, as with other classes of drugs, there are chemical, biochemical, and pharmacological differences among the individual compounds. Differences in mineral binding affinities among bisphosphonates influence their differential distribution within bone, their biological potency, and their duration of action. The overall pharmacological effects of bisphosphonates on bone, therefore, appear to depend upon these two key properties of affinity for bone mineral and inhibitory effects on osteoclasts. The relative contributions of these properties differ among individual bisphosphonates and help determine their clinical behavior and effectiveness.

Hemi-phorboxazole a: structure confirmation, analogue design and biological evaluation.

A synthesis providing totally synthetic (+)-hemi-phorboxazole A (1), proceeding in two steps (85% yield) from known vinyl iodide precursor (+)-2, has been achieved in conjunction with the design, synthesis, and biological evaluation of two hemi-phorboxazole analogues [(+)-3 and (-)-4] featuring ring replacements inscribed within the macrolide. Although hemi-phorboxazole A (1) displayed no activity when tested against Candida albicans and two human cancer cell lines, analogue (-)-4 exhibited significant tumor cell growth inhibitory activity in the nanomolar range against HCT-116 (colon) and SK-BR-3 (breast), while (+)-3 displayed promising antifungal activity against C. albicans.

Asymmetric cascade reaction sequences via chiral lithiated intermediates.

The (-)-sparteine-mediated enantioselective intermolecular carbolithiation of (E)-2-propenylarylamines allows for the generation of chiral lithiated intermediates which have broad synthetic potential. These intermediates have been exploited in a series of further in situ reactions with electrophiles to generate a collection of products each containing a common stereogenic center. The stereogenic center, formed in high enantiomeric ratio in the first carbolithiation step, is carried through the cascade reaction sequence to the final products and is independent of electrophile used. The methodology is demonstrated by the synthesis of structurally diverse chiral anilines, indoles, and indolones all with an er of 92:8 (+/-1). The heterocyclic syntheses involve an enantioselective alkene carbolithiation and subsequent trapping of the intermediate organolithium with a suitable electrophile, followed by an in situ ring closure and dehydration to generate the indole or indolone rings.

Carbolithiation of o-Amino-(E)-stilbenes: diastereoselective electrophile substitution with applications to quinoline synthesis.

A regioselective carbolithiation of o-amino-(E)-stilbenes has been achieved with a series of alkyllithiums when THF is employed as the reaction solvent. The use of other solvents, such as diethyl ether or hydrocarbons, leads to a pronounced loss in regioselectivity. Moreover, high levels of diastereoselectivity have been obtained following reaction of the lithiated intermediate in THF with different electrophiles such as MeOD, CO2, and Bu3SnCl. It was shown that diastereoselectivity was influenced by the ortho-amino substituent and the alkyllithium utilized for carbolithiation with N-Boc substituent and t-BuLi proving optimal. In the case of carbolithiated intermediate 3a, obtained from the reaction of N-Boc substituted stilbene with t-BuLi, 1H and 13C NMR analysis revealed predominantly one diastereoisomer which was stable at room temperature. Application of the carbolithiation/electrophile reaction methodology to the synthesis of six-membered quinoline ring systems is demonstrated with substituted 3,4-dihydroquinolin-2-ones, 1,2,3,4-tetrahydroquinolines, 1,4-dihydroquinolines, and quinolines all prepared by a common cascade route.

Enantioselective carbolithiation initiated cascade reactions.

Enantioselective cascade reactions are very powerful synthetic protocols for the assembly of complex architectures. Our current approach is to exploit a (-)-sparteine-controlled enantioselective carbolithiation of 2-propenylarylamines to provide chiral intermediates, which depending upon choice of electrophile are subsequently in situ converted into products of increasing complexity. The chiral center, formed in high enantiomeric ratio in the first carbolithiation step, is carried through the cascade reaction sequence to the final products and is independent of electrophile used. The scope of the cascade reaction is outlined in terms of reaction conditions, alkyllithiums, and electrophiles.