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Teenage pregnancy is a complex issue that can have negative socioeconomic and health outcomes. About 11% of births worldwide are by adolescents aged between 15 and 19 years and middle- and low-income countries account for more than 90% of these births. Despite the downward trend in international adolescent pregnancy rates, 10 million unplanned adolescent pregnancies occur annually. Adolescents are also at increase risks of poor obstetric outcomes including preterm delivery, low birth weight, eclampsia, postpartum hemorrhage, anemia, and infant, as well as maternal morbidity. Important additional considerations include increased risk of depression, poor social support, and the need for a multidisciplinary approach to their obstetric care. We look to highlight both the unique socioeconomic and medical factors to consider when caring for these patients and demonstrate that these factors are intertwined.

Cross sectional analysis has shown an association between Obstructive Sleep Apnea (OSA) severity and Aβ burden using amyloid-PET among Mild Cognitive Impairment (MCI) patients. However, whether OSA accelerates longitudinal increases in amyloid beta (Aβ) burden in MCI patients is presently unclear. Study participants included a total of 798 subjects with a diagnosis of MCI and were a subset of the ADNI cohort (adni.loni.usc.edu). OSA was self-reported and participants were labeled either as OSA+ or OSA−. Aβ burden was determined by florbetapir SUVRs. To test whether OSA is associated with the rate of change in Aβ data longitudinally, multilevel mixed effects linear regression was used to fit the models with randomly varying intercepts and slopes allowing dependence on OSA status. The final model was adjusted for age, sex, body mass index, education, CPAP use status, history of respiratory disease, hypertension, diabetes, and history of cardiovascular disease. A significant variation in the change (slope) in Aβ volumes over time was seen (p

Increasing evidence links cognitive-decline and Alzheimer's disease (AD) to various sleep disorders, including obstructive sleep apnea (OSA). With increasing age, there are substantial differences in OSA's prevalence, associated comorbidities and phenotypic presentation. An important question for sleep and AD researchers is whether OSA's heterogeneity results in varying cognitive-outcomes in older-adults compared to middle-aged adults. In this review, we systematically integrated research examining OSA and cognition, mild cognitive-impairment (MCI) and AD/AD biomarkers; including the effects of continuous positive airway pressure (CPAP) treatment, particularly focusing on characterizing the heterogeneity of OSA and its cognitive-outcomes. Broadly, in middle-aged adults, OSA is often associated with mild impairment in attention, memory and executive function. In older-adults, OSA is not associated with any particular pattern of cognitive-impairment at cross-section; however, OSA is associated with the development of MCI or AD with symptomatic patients who have a higher likelihood of associated disturbed sleep/cognitive-impairment driving these findings. CPAP treatment may be effective in improving cognition in OSA patients with AD. Recent trends demonstrate links between OSA and AD-biomarkers of neurodegeneration across all age-groups. These distinct patterns provide the foundation for envisioning better characterization of OSA and the need for more sensitive/novel sleep-dependent cognitive assessments to assess OSA-related cognitive-impairment.

Study Objectives To determine the effect of self-reported clinical diagnosis of obstructive sleep apnea (OSA) on longitudinal changes in brain amyloid PET and CSF biomarkers (Aβ42, T-tau, and P-tau) in cognitively normal (NL), mild cognitive impairment (MCI), and Alzheimer’s disease (AD) elderly. Methods Longitudinal study with mean follow-up time of 2.52 ± 0.51 years. Data were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Participants included 516 NL, 798 MCI, and 325 AD elderly. Main outcomes were annual rate of change in brain amyloid burden (i.e. longitudinal increases in florbetapir PET uptake or decreases in CSF Aβ42 levels); and tau protein aggregation (i.e. longitudinal increases in CSF total tau [T-tau] and phosphorylated tau [P-tau]). Adjusted multilevel mixed effects linear regression models with randomly varying intercepts and slopes was used to test whether the rate of biomarker change differed between participants with and without OSA. Results In NL and MCI groups, OSA+ subjects experienced faster annual increase in florbetapir uptake (B = .06, 95% CI = .02, .11 and B = .08, 95% CI = .05, .12, respectively) and decrease in CSF Aβ42 levels (B = −2.71, 95% CI = −3.11, −2.35 and B = −2.62, 95% CI = −3.23, −2.03, respectively); as well as increases in CSF T-tau (B = 3.68, 95% CI = 3.31, 4.07 and B = 2.21, 95% CI = 1.58, 2.86, respectively) and P-tau (B = 1.221, 95% CI = 1.02, 1.42 and B = 1.74, 95% CI = 1.22, 2.27, respectively); compared with OSA− participants. No significant variations in the biomarker changes over time were seen in the AD group. Conclusions In both NL and MCI, elderly, clinical interventions aimed to treat OSA are needed to test if OSA treatment may affect the progression of cognitive impairment due to AD.

Chemical library screening approaches that focus exclusively on catalytic events may overlook unique effects of protein-protein interactions that can be exploited for development of specific inhibitors. Phosphotyrosyl (pTyr) residues embedded in peptide motifs comprise minimal recognition elements that determine the substrate specificity of protein tyrosine phosphatases (PTPases). We incorporated aminooxy-containing amino acid residues into a 7-residue epidermal growth factor receptor (EGFR) derived phosphotyrosine-containing peptide and subjected the peptides to solution-phase oxime diversification by reacting with aldehyde-bearing druglike functionalities. The pTyr residue remained unmodified. The resulting derivatized peptide library was printed in microarrays on nitrocellulose-coated glass surfaces for assessment of PTPase catalytic activity or on gold monolayers for analysis of kinetic interactions by surface plasmon resonance (SPR). Focusing on amino acid positions and chemical features, we first analyzed dephosphorylation of the peptide pTyr residues within the microarrayed library by the human dual-specificity phosphatases (DUSP) DUSP14 and DUSP22, as well as by PTPases from poxviruses (VH1) and Yersinia pestis (YopH). In order to identify the highest affinity oxime motifs, the binding interactions of the most active derivatized phosphopeptides were examined by SPR using noncatalytic PTPase mutants. On the basis of high-affinity oxime fragments identified by the two-step catalytic and SPR-based microarray screens, low-molecular-weight nonphosphate-containing peptides were designed to inhibit PTP catalysis at low micromolar concentrations.

Study Objectives: To determine the effect of self-reported clinical diagnosis of obstructive sleep apnea (OSA) on longitudinal changes in brain amyloid PET and CSF biomarkers (A beta 42, T-tau, and P-tau) in cognitively normal (NL), mild cognitive impairment (MCI), and Alzheimer's disease (AD) elderly. Methods: Longitudinal study with mean follow-up time of 2.52 +/- 0.51 years. Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants included 516 NL, 798 MCI, and 325 AD elderly. Main outcomes were annual rate of change in brain amyloid burden (i.e. longitudinal increases in florbetapir PET uptake or decreases in CSF A beta 42 levels); and tau protein aggregation (i.e. longitudinal increases in CSF total tau [T-tau] and phosphorylated tau [P-tau]). Adjusted multilevel mixed effects linear regression models with randomly varying intercepts and slopes was used to test whether the rate of biomarker change differed between participants with and without OSA. Results: In NL and MCI groups, OSA+ subjects experienced faster annual increase in florbetapir uptake (B =.06, 95% CI =.02,.11 and B =.08, 95% CI =.05, .12, respectively) and decrease in CSF A beta 42 levels (B = -2.71, 95% CI = -3.11, -2.35 and B = -2.62, 95% CI = -3.23, -2.03, respectively); as well as increases in CSF T-tau (B = 3.68, 95% CI = 3.31, 4.07 and B = 2.21, 95% CI = 1.58, 2.86, respectively) and P-tau (B = 1.221, 95% CI = 1.02, 1.42 and B = 1.74, 95% CI = 1.22, 2.27, respectively); compared with OSA- participants. No significant variations in the biomarker changes over time were seen in the AD group. Conclusions: In both NL and MCI, elderly, clinical interventions aimed to treat OSA are needed to test if OSA treatment may affect the progression of cognitive impairment due to AD.

The indole-substituted titanocene dichloride derivative Titanocene T, which is completely water-soluble and shows micromolar activity against the human renal cancer cells Caki-1, was tested in vivo an against xenografted human renal cell tumors in mice. Titanocene T was then given at 25 and 50 mg/kg, seven times every four days during three weeks to two groups (n=6) of Caki-1 tumor-bearing female NMRI: nu/nu mice, while the control group was treated with solvent only. At both doses Titanocene T induced a moderate to good tumor growth reduction with respect to the solvent-treated control group, with an optimal T/C value of 51% and 32% and showed neither mortality nor toxicity. Immunohistochemical analysis revealed that the expression of the proliferation marker Ki-67 was reduced in the high-dosage group. Furthermore, anti-angiogenic activity was identified by CD31 staining; the number of micro vessels in a defined tumor area decreased by 27% and 29% due to Titanocene T treatment.

We have developed competitive and direct binding methods to examine small-molecule inhibitors of protein tyrosine phosphatase activity. Focusing on the Yersinia pestis outer protein H, a potent bacterial protein tyrosine phosphatase, we describe how an understanding of the kinetic interactions involving Yersinia pestis outer protein H, peptide substrates, and small-molecule inhibitors of protein tyrosine phosphatase activity can be beneficial for inhibitor screening, and we further translate these results into a microarray assay for high-throughput screening.

From the reaction of various 6-indolylfulvenes (1a−f) with Super Hydride (LiBEt3H), followed by transmetalation with titanium tetrachloride (TiCl4), six indolyl-substituted titanocenes, bis[(1-methylindol-2-yl)cyclopentadienyl]titanium(IV) dichloride (3a), bis[(1-methyl-5-methoxyindol-2-yl)cyclopentadienyl]titanium(IV) dichloride (3b), a dihydrochloride derivative of bis[(1-methyl-3-dimethylaminomethylindol-2-yl)cyclopentadienyl]titanium(IV) dichloride (3c), bis[(1-methylindol-3-yl)cyclopentadienyl]titanium(IV) dichloride (3d), bis[(1-methyl-5-methoxyindol-3-yl)cyclopentadienyl]titanium(IV) dichloride (3e), and bis[(1-methylmethoxyindol-3-yl)cyclopentadienyl]titanium(IV) dichloride (3f), were obtained. The six titanocenes 3a−f were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines in order to determine their IC50 values. Titanocenes 3a−f were found to have IC50 values of 47 (±9), 15 (±2), 8.2 (±1.9), 21 (±5), 11 (±1), and 170 (±40) μM, respectively.

The para-methoxybenzyl-substituted vanadocene dichloride (Vanadocene Y) (1) and its diselenocyanate (Selenocyanato-Vanadocene Y) (2) were tested in vitro in an anti-angiogenesis assay against human umbilical vein endothelial cells (HUVEC) delivering IC50 values of 0.92 ± 0.03 μM (1) and 37 ± 11 μM (2). In a cytotoxicity assay against the human renal cancer cells, CAKI-1, the compounds demonstrated IC50 values of 0.55 ± 0.09 μM (1) and 0.25 ± 0.03 μM (2). Then both compounds were given at their maximum tolerable dose, MTD, of 20 mg/kg/d (1) or 40 mg/kg/d (2) on four consecutive days or at 50% of the MTD on five consecutive days per week for three weeks to overall four cohorts of eight CAKI-1 tumor-bearing female NMRI:nu/nu mice each, while a further cohort was treated with solvent only. Both MTD-treated mouse cohorts showed a statistically significant tumor growth reduction with respect to the solvent-treated control group with an optimal T/C value of 47% on day 39 of the experiment. Immunohistological analysis revealed that the expression of the proliferation marker Ki-67 was reduced due to long-term treatment with 2.

p-Methoxybenzyl-substituted and benzyl-substituted N-heterocyclic carbene (NHC) [(3a-c) and (6a-c)] precursors were synthesised from the reaction of 1H-imidazole (1a), 4,5-dichloro-1H-imidazole (1b), and 1H-benzimidazole (1c) with p-methoxybenzyl bromide (2) and benzyl bromide (5). These NHC precursors were then treated with silver(I) acetate to yield the NHC-silver complexes [1,3-bis(4-methoxybenzyl)-imidazol-2-ylidene]silver(I) acetate (4a), [4,5-dichloro-1,3-bis(4-methoxybenzyl)imidazol-2-ylidene]silver(I) acetate (4b), [1,3-bis(4-methoxybenzyl)benzimidazol-2-ylidene]-silver(I) acetate (4c), (1,3-dibenzylimidazol-2-ylidene)silver(I) acetate (7a), (1,3-dibenzyl-4,5-dichloroimidazol-2-ylidene)-silver(I) acetate (7b), and (1,3-dibenzylbenzimidazol-2-ylidene)silver(I) acetate (7c), respectively. The NHC precursor 3c, four NHC-silver complexes 4c and 7a-c were characterised by single-crystal X-ray diffraction method. The preliminary antibacterial activity of all the compounds was studied against Gram-negative bacteria Escherichia coli, and Gram-positive bacteria Staphylococcus aureus using the Kirby-Bauer disk-diffusion method. Almost all the NHC-silver complexes have shown high antibacterial activity compared to the NHC precursors. In addition, the NHC-silver complexes had their cytotoxicity investigated through MTT-based preliminary in vitro testing on the Caki-1 cell lines in order to determine their IC 50 values. NHC-silver complexes 4a-c and 7a-c were found to have IC 50 values of 7.3 (+/-6), 12.7 (+/-3), 25.2 (+/-5), 2.5 (+/-3), 10.8 (+/-4) and 12.5 (+/-4) μM respectively on the Caki-1 cell line.

Titanocenes constitute a class of metal-based anticancer agents that seem to display a mode of action distinct from that of platinum complexes and to be more tolerable with a differing spectrum of activity. In the present study, titanocene C (bis-(N,N-dimethylamino-2(N-methylpyrrolyl)-methyl-cyclopentadienyl) titanium(IV) dichloride) was shown to exhibit antiproliferative activity against human tumor cell lines with a mean IC₅₀ value of 48.3 ± 32.5 µM. In particular, high activity was found against small cell lung cancer (SCLC) cell lines with a profile different from cisplatin. Titanocene C induced cell cycle arrest at the G1/0-S interphase. Cross-resistance to either cisplatin or oxoplatin, respectively, was low for titanocene C and absent for titanocene Y in variant HL-60 cell lines. Alterations in gene expression of NCI-H526 SCLC cells induced by titanocene C were investigated using genome-wide expression arrays. Downregulation was found for genes coding for topoisomerases I and IIα, histones of the HIST1H4 cluster, enzymes involved in glycolysis, components of the cytoskeleton and vesicular transport, among others. In contrast, expression of genes involved in apoptosis, stress response, particularly members of the metallothionein gene cluster 1, DNA damage and growth factors was upregulated following exposure to titanocene C. Approximately 50% of those genes downregulated by titanocene C and cisplatin were concordant, including the previously identified markers of cisplatin-sensitivity, tubulin and stathmin, indicating partial overlap of the pathways affected by these metal complexes. The present findings point helicases/topoisomerases and HIST1H4 core histones out as targets of titanocene C and metallothioneins as putative main effectors of drug resistance.

From the reaction of 6-(2-fluoro-4-methoxyphenyl)fulvene (1a), 6-(3-fluoro-4-methoxyphenyl)fulvene (1b) and 6-[4-(trifluoromethoxy)phenyl]fulvene (1c) with LiBEt3H, lithiated cyclopentadienide intermediates (2a–c) were synthesised. These intermediates were then transmetallated to vanadium with VCl4 to yield the benzyl-substituted vanadocenes bis[(2-fluoro-4-methoxybenzyl)cyclopentadienyl]vanadium(IV) dichloride (3a), bis[(3-fluoro-4-methoxybenzyl)cyclopentadienyl]vanadium(IV) dichloride (3b), and bis[(4-trifluoromethoxybenzyl)cyclopentadienyl]vanadium(IV) dichloride (3c). The three vanadocenes 3a–c were characterised by single-crystal X-ray diffraction. All three vanadocenes had their cytotoxicity investigated through MTT-based preliminary in-vitro testing on the LLC-PK and Caki-1 cell lines in order to determine their IC50 values. Vanadocenes 3a–c were found to have IC50 values of 6.0 (+/–4), 35 (+/–7) and 13 (+/–3) μM on the LLC-PK cell line and IC50 values of 78 (+/–11), 18 (+/–16) and 2.2 (+/–0.5) μM on the Caki-1 cell line respectively. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

In previous work we have found that Cp2TiCl2 and its corresponding derivative of tamoxifen, Titanocene tamoxifen, show an unexpected proliferative effect on hormone dependent breast cancer cells MCF-7. In order to check if this behavior is a general trend for titanocene derivatives we have tested two other titanocene derivatives, Titanocene Y and Titanocene K, on this cell line. Interestingly, these two titanocene complexes behave in a totally different manner. Titanocene K is highly proliferative on MCF-7 cells even at low concentrations (0.5 μM), thus behave almost similarly to Cp2TiCl2. This proliferative effect is also observed in the presence of bovine serum albumin (BSA). In contrast, Titanocene Y alone has almost no effect on MCF-7 at a concentration of 10 μM, but exhibits a significant dose dependent cytotoxic effect of up to 50% when incubated with BSA (20–50 μg/mL). This confirms the crucial role played by the binding to serum proteins in the expression of the in vivo, cytotoxicity of the titanocene complexes. From the hydridolithiation reaction of 6-p-anisylfulvene with LiBEt3H followed by transmetallation with iron dichloride [bis-[(p-methoxy-benzyl)cyclopentadienyl]iron(II)] (Ferrocene Y) was synthesised. This complex, which was characterised by single crystal X-ray diffraction, contains the robust ferrocenyl unit instead of Ti associated with easily leaving groups such as chlorine and shows only a modest cytotoxicity against MCF-7 or MDA-MB-231 cells.

From the reaction of Super Hydride (LiBEt3H) with 6-(4-methoxyphenyl) fulvene (1a), 6-(2-fluoro-4-methoxyphenyl) fulvene (1b), and 6-(4-N,N-dimethylaminophenyl) fulvene (1c) lithiated cyclopentadienide intermediates (2a–c) were synthesised. These intermediates were then transmetallated to zirconium with ZrCl4 to give benzyl-substituted zirconocenes bis-[(4-methoxybenzyl)cyclopentadienyl] zirconium(IV) dichloride (3a), bis-[(2-fluoro-4-methoxybenzyl)cyclopentadienyl] zirconium(IV) dichloride (3b) and bis-[(4-N,N-dimethylaminobenzyl)cyclopentadienyl] zirconium(IV) dichloride (3c). All three zirconocenes were characterised by single crystal X-ray diffraction and preliminary in vitro cell tests were performed with the zirconocene derivatives on the LLC-PK cell line in order to determine their cytotoxicity. Zirconocenes 3b and 3c did not show cytotoxicity up to a concentration of 170 μM, while 3a exhibited an IC50 value of 57 μM against LLC-PK.

From the reaction of 6-(p-methoxyphenyl) fulvene (1a), 6-(p-N,N-dimethylaminophenyl) fulvene (1b) and 6-(3,4-dimethoxyphenyl) fulvene (1c) with LiBEt3H, lithiated cyclopentadienide intermediates (2a–c) were synthesised. These intermediates were then transmetallated to tin with SnCl4 to yield tetra-substituted bis(cyclopentadienyl)tin dichloride complexes (3a–c). Further reaction with tin tetrachloride yielded the benzyl-substituted derivatives bis-[(p-methoxybenzyl)cyclopentadienyl] tin(IV) dichloride (4a), bis-[(p-N,N-dimethylaminobenzyl)cyclopentadienyl] tin(IV) dichloride (4b), and bis-[(3,4-dimethoxyphenyl)cyclopentadienyl] tin(IV) dichloride (4c). Preliminary antibacterial tests were carried out using the Kirby–Bauer disk-diffusion method, in which 4a–c showed little to no activity against the Gram-negative bacterium Escherichia coli, but medium activity against Gram-positive bacteria (MRSA, MSSA). In addition, the organotin complexes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in order to determine their IC50 values. Compound 4c showed no cytotoxic activity, while 4a and 4b were found to have IC50 values of 15 and 205 μM, respectively.

From the reaction of Super Hydride (LiBEt3H) with 6-(2-fluoro-4-methoxyphenyl)fulvene (1a), 6-(4-trifluoromethoxyphenyl)fulvene (1b), and 6-(3-fluoro-4-methoxyphenyl)fulvene (1c) lithiated cyclopentadienide intermediates 2a–c were synthesised. These intermediates were then transmetallated to titanium with TiCl4 to give the benzyl-substituted titanocenes bis[(2-fluoro-4-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride (3a), bis[(4-trifluoromethoxybenzyl)cyclopentadienyl]titanium(IV) dichloride (3b) andbis[(3-fluoro-4-methoxybenzyl)cyclopentadienyl]titanium(IV)dichloride (3c). The three titanocenes 3a–c were characterised by single-crystal X-ray diffraction. Preliminary in vitro cell tests were performed on the titanocenes on the LLC-PK (long-lasting cells–pig kidney) cell line in order to determine the cytotoxicity of these compounds presented in this paper. The titanocenes 3a and 3b had their cytotoxicity inhibitory concentration (IC50) values determined to be 6.0 and 7.3 μM, respectively. The cytotoxicity value of 3c could not be determined accurately due to solubility problems of the compound under standard test conditions. All three titanocene derivatives show significant cytotoxicity improvement when compared to unsubstituted titanocene dichloride, whereas titanocenes 3a and 3b show threefold cytotoxicity improvement in comparison to previous class leader titanocene Y. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

From the reaction of 6(2-methoxy-phenyl)fulvene ( 1a ), 6(3-methoxy-phenyl)fulvene ( 1b ), 6(3,4-dimethoxy-phenyl)fulvene ( 1c ) and 6(3,4,5-trimethoxy-phenyl)fulvene ( 1d ) with LiBEt 3 H, lithiated cyclopentadienide intermediates 2a – d were synthesised. These intermediates were then transmetallated to titanium with TiCl 4 to give benzyl substituted titanocenes bis-[(2-methoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3a ), bis-[(3-methoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3b ), bis-[(3,4-dimethoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3c ) and bis-[(3,4,5-trimethoxy-benzyl)cyclopentadienyl]titanium(IV) dichloride ( 3d ). The three titanocenes 3a – c were characterised by single crystal X-ray diffraction, while the structure of the fourth titanocene 3d was elucidated through a DFT calculation. All four titanocenes had their cytotoxicity investigated through preliminary in vitro testing on the LLC-PK (pig kidney epithelial) cell line in order to determine their IC 50 values. Titanocenes 3a – d were found to have IC 50 values of 97, 159, 88 and 253 μM, respectively. All four titanocene derivatives show significant cytotoxicity improvement when compared to unsubstituted titanocene dichloride.

From the carbolithiation of 6-morpholino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4 resulting in morpholino-functionalised titanocenes 5a–c. When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 58, 63 and 115 μM for titanocenes 5a–c respectively. The most cytotoxic titanocene 5a with an IC50 value of 58 μM is found to be approximately 20 times less cytotoxic than cis-platin, which showed an IC50 value of 3.3 μM, when tested on the LLC-PK cell line, and 10 times less cytotoxic than its dimethylamino-functionalised analogue (Titanocene C, IC50 = 5.5 μM).

From the carbolithiation of 6-N,N-dimethylamino fulvene (3a) and different lithiated N-heterocyclic compounds (N,N-dimethylaminomethylpyrrole, 1-methylimidazole and 2,4-[bis(N',N'-dimethylaminomethyl)]-N-methyl pyrrole), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4 resulting in dimethylamino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 13, and 63 microM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper (5a) with an IC50 value of 6.8 microM is found to be almost as cytotoxic as cis-platin, which showed an IC50 value of 3.3 microM, when tested on the epithelial pig kidney LLC-PK cell line, and titanocene 5c is approximately 400 times better than titanocene dichloride itself.

From the carbolithiation of 6-N,N-dimethylamino fulvene (3a) and different ortho-lithiated indole derivatives (5-methoxy-N-methylindole, N-methylindole and N,N-dimethylaminomethylindole), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4 resulting in dimethylamino-functionalised titanocenes (5a–c). When these titanocenes were tested against LLC-PK cells, the IC50 values obtained were of 37 and 71 μM for titanocenes 5a and 5b respectively. The most cytotoxic titanocene in this paper, 5c showed an IC50 value of 8.4 μM is found to be almost as cytotoxic as cis-platin, which showed an IC50 value of 3.3 μM, when tested on the LLC-PK cell line, and titanocene 5c is approximately 250 times better than titanocene dichloride itself. Bis-(N,N-dimethylamino-2-(N-methylindolyl)methylcyclopentadienyl) titanium (IV) dichloride was synthesised starting from 2-(N-methylindolyl) lithium and 6-N,N-dimethylamino fulvene. Herein, we present the synthesis and DFT structure of the titanocene and two further derivatives followed by MTT-based cytotoxicity tests on LLC-PK cells.

We have developed competitive and direct binding methods to examine small-molecule inhibitors of protein tyrosine phosphatase activity. Focusing on the Yersinia pestis outer protein H, a potent bacterial protein tyrosine phosphatase, we describe how an understanding of the kinetic interactions involving Yersinia pestis outer protein H, peptide substrates, and small-molecule inhibitors of protein tyrosine phosphatase activity can be beneficial for inhibitor screening, and we further translate these results into a microarray assay for high-throughput screening.

Despite the advantages in the outcome of patients with acute lymphoblastic leukemia, 25% of the affected children suffer relapses. As the response to chemotherapy is essentially determined by the development of cellular drug resistance, new drugs that are capable to overcome resistance to conventional chemotherapeutics are urgently needed. With regard to this demand, we investigated the titanium-based anticancer drug Titanocene Y. Treatment with Titanocene Y leads to inhibition of tumour cell proliferation and induces apoptosis in established cell lines of leukemia, lymphoma and melanoma. The extrinsic pathway appears to be responsible, at least in part, for the effect: cell death is partly inhibited in BJAB cells overexpressing a dominant negative Fas-associated death domain (FADD) mutant and via real time PCR we found a significant up-regulation of Fas ligand in the affected cells. Apoptosis is triggered regardless of the expression of anti-apoptotic Bcl-2 and pro-apoptotic smac and the agent is also effective on cells that are multidrug resistant due to overexpression of P-gp. In combination with vincristine impressive synergistic effects could be observed, exposing Titanocene Y as a possible component for polychemotherapy. Taken together, Titanocene Y turns out to be a promising candidate for anti-tumour therapy, especially for the treatment of multidrug resistant malignancies.

While locally advanced prostate cancer is initially treatable with androgen ablation, eventually cells develop a castrate-resistant phenotype. Currently, there are no effective treatments for this form of the disease with Docetaxel only providing a small survival advantage. In this study, the effects of novel derivatives of titanocene dichloride on prostate cancer cell lines has been investigated.Cellular effects were assessed using the crystal violet assay and the clonogenic survival assay. Cell cycle and apoptosis were assessed by propidium iodide staining. DNA damage was analyzed by comet assay and Western analysis. DNA damage response inhibition was achieved by pre-incubation with an ATM/ATR inhibitor; CGK733 and DNA-PK inhibitor; DMNB.These analogs caused a reduction in cell number. In particular titanocene Y and C had significant effects in all cell lines. A reduction in clonogenic survival was found in response to titanocene Y in three cell lines while the PC-3 cells exhibited increased resistance.Further analysis showed no effect on cell cycle however, the analogs were found to induce apoptosis in a dose-dependent manner in all cell lines. These analogs associate with DNA, induce DNA damage and a differential damage response. Inhibition of key regulators of this DNA damage response sensitized the PC-3 cell line to titanocene-induced apoptosis and significantly reduced the clonogenic capacity of the cells.These results demonstrate the mechanism of action of these novel titanocene dichloride analogs and their potential use in castrate-independent advanced prostate cancer.

6-Substituted fulvenes are interesting and easily accessible starting materials for the synthesis of novel-substituted titanocenes via reductive dimerisation, carbolithiation or hydridolithiation reactions, which are followed by a transmetallation reaction with titanium tetrachloride in the latter two cases. Depending on the substitution pattern, these titanocenes prove to be bioorganometallic anticancer drugs, which have significant potential against advanced or metastatic renal-cell cancer. Patients bearing these stages of kidney cancer have a poor prognosis so far and therefore real progress in the area of metal-based anticancer drugs may come from this simple and effective synthetic approach.

From the carbolithiation of 6-morpholino fulvene (3) and different lithiated nitrogen containing heterocycles (2-N-methylimidazolyl, 2-N-(N,N-dimethylamino)methyl-imidazolyl, and 2-N-methylindolyl), the corresponding lithium cyclopentadienide intermediate (4a-c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl(4) resulting in morpholino-functionalised titanocenes 5a-c. When these titanocenes were tested against LLC-PK cells, the IC(50) values obtained were of 24, 36, and 41 microM respectively. The most cytotoxic titanocene in this paper (5a) with an IC(50) value of 24 microM is found to be almost ten times less cytotoxic than cis-platin, which showed an IC(50) value of 3.3 microM when tested on the epithelial pig kidney LLC-PK cell line, and approximately 2 times less cytotoxic than its dimethylamino-functionalised analogue. Encouragingly however, the IC(50) value obtained for titanocene 5a is approximately 100 times better than titanocene dichloride itself.

From the carbolithiation of 6-N,N-dimethylamino fulvene (3) and 2,4[bis(N,N-dimethylamino)methyl]-N-methylpyrrolyl lithium (2a), N-(N′,N′-dimethylaminomethyl)benzimidazolyl lithium (2b)' or p-(N,N-dimethylamino)methylphenyl lithium (2c), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4' resulting in N,N-dimethylamino-functionalised titanocenes 5a–c. When these titanocenes were tested against a pig kidney epithelial cell line (LLC-PK), the IC50 values obtained were of 23, and 52 μM for titanocenes 5a and 5b, respectively. The most cytotoxic titanocene in this paper, 5c with an IC50 value of 13 μM, was found to be approximately two times less cytotoxic than its analogue Titanocene C (IC50=5.5 μM) and almost four times less cytotoxic than cisplatin, which showed an IC50 value of 3.3 μM when tested on the LLC-PK cell line.

From the carbolithiation of 6-bis-N,N-dimethylamino fulvene (3a) and different ortho-lithiated heterocycles (furan, thiophene and N-methylpyrrole), the corresponding lithium cyclopentadienide intermediate (4a–c) was formed. These three lithiated intermediates underwent a transmetallation reaction with TiCl4 resulting in bis-N,N-dimethylamino-functionalised titanocenes 5a–c. When these titanocenes were tested against LLC-PK cells, the IC50-values obtained were of 240, and 270 μM for titanocenes 5b and 5c, respectively. The most cytotoxic titanocene in this paper, 5a with an IC50-value of 36 μM was found to be approximately six times less cytotoxic than its mono-N,N-dimethylamino substituted analogue Titanocene C (IC50 = 5.5 μM) and almost ten times less cytotoxic than cisplatin, which showed an IC50-value of 3.3 μM, when tested on the LLC-PK cell line. Bis-(bis- (N,N-dimethylamino)-2-(N′-methylpyrrolyl)methylcyclopentadienyl) titanium (IV) dichloride, {η5-C5H4-CH[N(CH3)2]2[C5H3NCH3]}2TiCl2 was synthesised starting from 6-bis-(N,N-dimethylamino) fulvene and 2-N-methylpyrrolyl lithium. Herein, we present the synthesis and DFT structure of the titanocene and two further derivatives followed by MTT-based cytotoxicity tests on pig kidney epithelial (LLC-PK) cells.