ROCK inhibitors 2. Improving potency,selectivity and solubility through the application of rationally designed solubilizing groups

Solubilizing groups have been frequently appended to kinase inhibitor drug molecules when solubility is insufficient for pharmaceutical development. Such groups are usually located at substitution sites that have minimal impact on target activity. In this report we describe the incorporation of solubilizing groups in a class of Rho kinase (ROCK) inhibitors that not only confer improved solubility, but also enhance target potency and selectivity against a closely related kinase, PKA.     

ROCK inhibitors 3: Design,synthesis and structure-activity relationships of 7-azaindole-based Rho kinase (ROCK) inhibitors

Rho kinase (ROCK) inhibitors are potential therapeutic agents for the treatment of a variety of disorders including hypertension, glaucoma and erectile dysfunction. Here we disclose a series of potent and selective ROCK inhibitors based on a substituted 7-azaindole scaffold. Substitution of the 3-position of 7-azaindole led to compounds such as 37, which possess excellent ROCK inhibitory potency and high selectivity against the closely related kinase PKA.     

4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: Potent and selective p70S6 kinase inhibitors

We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (K_i <1 nM) of p70S6K, with >100-fold selectivity against PKA, ROCK and GSK3.     

Pygidial gland chemistry and potential alarm-recruitment function in column foraging,but not solitary,Nearctic Messor harvesting ants (Hymenoptera: Formicidae: Myrmicinae)

We investigated the role of the pygidial gland on foraging behavior in two ecologically dominant column foraging Nearctic harvesting ants (Messor pergandei and Messor andrei). Using chemical analyses and behavioral tests, we show that n-tridecane is the major biologically active compound of pygidial gland secretions in both species, and that this chemical functions as a powerful alarm-recruitment pheromone. Another major compound of pygidial gland contents is benzaldehyde; this substance does not release behavioral reactions in M. pergandei workers but might function as a defensive secretion. Six solitary foraging Nearctic Messor and two column foraging Palearctic Messor species, did not have large pygidial gland reservoirs.     

Deposition of iron titanate/titania ceramic composite thin films from a single molecular precursor

A heterobimetallic single molecular precursor, [Fe₂Ti₄(μ-O)₆(TFA)₈(THF)₆] (1) [TFA = trifluoroacetate, THF = tetrahydrofuran], was synthesized by the simple reaction of [Fe₃O(OAc)₆(H₂O)₃]NO₃·4H₂O [OAc = acetato] with tetrakis(2-ethoxyethanalato)titanium(IV) in the presence of trifluoroacetic acid in THF. The synthesized precursor was analyzed by melting point, CHN analysis, FTIR, single crystal X-ray diffraction and thermogravimetric analysis. Complex (1) crystallizes in the orthorhombic space group Pca2₁ with cell dimensions a = 19.2114(14), b = 20.4804(15) and c = 17.2504(12) Å, and the complex undergoes thermal decomposition at 490 °C to give a residual mass corresponding to an Fe₂TiO₅-TiO₂ composite mixture. The synthesized precursor was utilized for deposition of Fe₂TiO₅-TiO₂ composite thin films by aerosol-assisted chemical vapor deposition (AACVD) on glass substrates at 500 °C using argon as the carrier gas. Scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and X-ray powder diffraction (XRD) analyses of the thin films suggest the formation of good quality crystalline thin films of an Fe₂TiO₅-TiO₂ composite with an average grain size of 0.105-0.120 μm.     

Novel thiol-based TACE inhibitors: rational design, synthesis, and SAR of thiol-containing aryl sulfonamides

A series of potent thiol-containing aryl sulfonamide TACE inhibitors was designed and synthesized. The SAR and MMP selectivity of the series were investigated. In particular, compound 4b has shown excellent in vitro potency against the isolated TACE enzyme and good selectivity over MMP-2, -7, -8, -9, and -13. The X-ray structure of 4b bound to TACE was obtained.     

Prolonged breastfeeding reduces risk of breast cancer in Sri Lankan women: A case–control study

Goal: To assess the association between duration of breastfeeding and the risk of breast cancer in Sri Lankan women. Methods: We conducted a case–control study in women aged 30–64 years in selected health care facilities in the Western province. A total of 100 recent cases of breast cancer (histologically confirmed) and 203 controls (age and parity matched) were included. Detailed information regarding breastfeeding, menstruation, reproductive factors, passive smoking and other confounders was collected using a structured questionnaire. Adjusted odds ratios and 95% confidence intervals were calculated using multiple logistic regressions. Principle results: Multivariate analysis found that those women who breastfed for ≥24 months during lifetime had significantly lower risk of breast cancer than those who breastfed for less than 24 months (OR = 0.40; 95%CI = 0.22, 0.73). Compared to 0–11 months of lifetime breastfeeding, there was a 66.3% reduction in breast cancer risk in women who breastfed for 12–23 months, 87.4% reduction in 24–35 months and 94% reduction in 36–47 months categories. The mean duration of breastfeeding per child for ≥12 months was also associated with reduced risk of breast cancer (OR = 0.52; 95%CI = 0.28, 0.94). The significant factors associated with increased risk of breast cancer were: post-menopausal women (OR = 1.74; 95%CI = 1.01, 3.01); having an abortion in the past (OR = 3.42; 95%CI = 1.75, 6.66) and exposure to passive smoking (OR = 2.96, 95%CI = 1.53, 5.75). Major conclusions: Prolonged breastfeeding significantly reduces the risk of breast cancer and this protective effect was supported by a dose–response relationship. Risk due to passive smoking should be emphasized in anti-smoking programmes.     

Novel thiol-based TACE inhibitors. Part 2: Rational design, synthesis, and SAR of thiol-containing aryl sulfones

A series of potent thiol-containing aryl sulfone TACE inhibitors were designed and synthesized. The SAR and MMP selectivity of the series were investigated. In particular, compound 8b showed excellent in vitro potency against the isolated enzyme and good selectivity over MMP-2, -7, -8, -9, and -13. The X-ray structure of 8b in complex with TACE was also obtained.