Identification of 3-hydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-ones as isoform-selective PKC-zeta inhibitors and potential therapeutics for psychostimulant abuse.
ABSTRACT: From a screen of small molecule libraries to identify potential therapeutics for psychostimulant abuse, 3-hydroxy-2-(3-hydroxyphenyl)-4H-1-benzopyran-4-ones were shown to be isoform-selective PKC-zeta inhibitors.
Project description:In the title compound, C(18)H(16)O(6), the dimethoxy-phenyl ring is rotated by 61.8?(1)° from the plane of the benzopyran system. The mol-ecule is stabilized by an intra-molecular O-H?O hydrogen bond.
Project description:In the title compound, C(19)H(18)O(6), also known as 3,4',5,7-tetra-methoxy-flavone, the dihedral angle between the benzopyran-4-one group and the attached benzene ring is 11.23?(8)°. An intra-molecular C-H?O hydrogen bond generates an S(6) ring motif. In the crystal, mol-ecules are linked into a two-dimensional network parallel to (01) by inter-molecular C-H?O hydrogen bonds, which generate R(4) (4)(20), R(4) (4)(12) and R(2) (2)(14) ring motifs. Adjacent networks interact by ?-? inter-actions between the pyran ring and its methoxy-phenyl substituent [centroid-centroid distance = 3.5267?(8)?Å].
Project description:In the title compound (alternatively called 4',5,7-trimethoxy-flavone methanol solvate hydrate), C(18)H(16)O(5)·CH(3)OH·H(2)O, the flavone mol-ecule is almost planar, the inter-planar angle between the planes of the benzopyran-4-one group and the attached benzene ring being 4.69?(9)°. In the crystal, the flavone mol-ecule makes inter-molecular C-H?O hydrogen bonds to adjacent inversion-related flavone mol-ecules, generating R(2) (2)(8) and R(2) (2)(14) rings and an infinite ribbon. The inversion-related ribbons are stabilized through the inter-stitial water and methanol mol-ecules via inter-molecular O-H?O hydrogen bonds, generating R(4) (2)(8) and R(2) (1)(6) rings and C(2) (2)(4) chains, and are further sustained by ?-? inter-actions with an inter-planar spacing of 3.365?(2)Å.
Project description:Endometrial hyperplasia is a precursor to the most common gynecologic cancer diagnosed in women. Apart from estrogenic induction, aberrant activation of the Wnt/?-catenin signal is well known to correlate with endometrial hyperplasia and its carcinoma. The benzopyran compound 2-(piperidinoethoxyphenyl)-3-(4-hydroxyphenyl)-2H-benzo (b) pyran(K-1), a potent antiestrogenic agent, has been shown to have apoptosis-inducing activity in rat uterine hyperplasia. The current study was undertaken to explore the effect of the benzopyran compound K-1 on growth and Wnt signaling in human endometrial hyperplasial cells. Primary culture of atypical endometrial hyperplasial cells was characterized by the epithelial cell marker cytokeratin-7. Results revealed that compound K-1 reduced the viability of primary endometrial hyperplasial cells and expression of ER?, PR, PCNA, Wnt7a, FZD6, pGsk3? and ?-catenin without affecting the growth of the primary culture of normal endometrial cells. The ?-catenin target genes CyclinD1 and c-myc were also found to be reduced, whereas the expression of axin2 and Wnt/?-catenin signaling inhibitor Dkk-1 was found to be upregulated, which caused the reduced interaction of Wnt7a and FZD6. Nuclear accumulation of ?-catenin was found to be decreased by compound K-1. K-1 also suppressed the pPI3K/pAkt survival pathway and induced the cleavage of caspases and PARP, thus subsequently causing the apoptosis of endometrial hyperplasial cells. In conclusion, compound K-1 suppressed the growth of human primary endometrial hyperplasial cells through discontinued Wnt/?-catenin signaling and induced apoptosis via inhibiting the PI3K/Akt survival pathway.
Project description:A new trisazo dye has been synthesized by coupling the diazonium ion of 3-amino-4H thieno[3,4-c]benzopyran-4-one with 2-tert-butyl-4-methoxyphenol. The newly prepared trisazo dye was characterized by its physical, elemental, and spectroscopic data. 2D-NMR (COSY, HSQC, and HMBC) techniques were used to secure the structural assignments. The new trisazo dye (compound 7) along with precursors 3, 4, and 6 was screened by microdilution susceptibility assay for antibacterial and antifungal activities towards eight bacterial strains and three yeasts selected on the basis of their relevance as human pathogens. The results showed that compound 7 (MIC = 2-128??g/mL) was the most active as compared with its precursors. The most resistant microorganisms were V. cholerae NB2 and V. cholerae SG24, whereas the most sensitive microorganism was C. neoformans. The overall results of this study indicated that compound 7 had the greatest potential value against both yeasts and multidrug-resistant bacteria, so further investigation is warranted.
Project description:A great deal of research has focused on investigating neurobiological alterations induced by chronic psychostimulant use in an effort to describe, understand, and treat the pathology of psychostimulant addiction. It has been known for several decades that dopamine neurotransmission in the nucleus accumbens is integrally involved in the selection and execution of motivated and goal-directed behaviors, and that psychostimulants act on this system to exert many of their effects. As such, a large body of work has focused on defining the consequences of psychostimulant use on dopamine signaling in the striatum as it relates to addictive behaviors. Here, we review presynaptic dopamine terminal alterations observed following self-administration of cocaine and amphetamine, as well as possible mechanisms by which these alterations occur and their impact on the progression of addiction.
Project description:Treatment of psychostimulant addiction has been a major, and not fully met, challenge. For opioid addiction, there is strong evidence for the effectiveness of several medications. For psychostimulants, there is no corresponding form of agonist maintenance that has met criteria for regulatory approval or generally accepted use. Stimulant-use disorders remain prevalent and can result in both short-term and long-term adverse consequences. The mainstay of treatment remains behavioral interventions. In this paper, we discuss those interventions and some promising candidates in the search for pharmacological interventions. This article is part of the Special Issue entitled 'CNS Stimulants'.
Project description:We designed a series of specifically deuterated benzopyran analogues as new COX-2 inhibitors with the aim of improving their pharmacokinetic properties. As expected, the deuterated compounds retained potency and selectivity for COX-2. The new molecules possess improved pharmacokinetic profiles in rats compared to their nondeuterated congeners. Most importantly, the new compounds showed pharmacodynamic efficacy in several murine models of inflammation and pain. The benzopyran derivatives were separated into their enantiomers, and the activity was found to reside with the S-isomers. To streamline the synthesis of the desired S-isomers, an organocatalytic asymmetric domino oxa-Michael/aldol condensation reaction was developed for their preparation.
Project description:Four new hydroporphyrins [the o, m and p isomers of 5,10,15,20-tetra(hydroxyphenyl)chlorin and 5,10,15,20-tetra(m-hydroxyphenyl)bacteriochlorin] related to the tetra(hydroxyphenyl)porphyrins have been prepared. They show the expected strong absorption bands in the red region of the visible spectrum and are found to be very effective tumour photosensitizers.
Project description:N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a-g can exist in conformations where the 3-hydroxyphenyl substituent is either axial or equatorial, similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl equatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single-crystal X-ray analysis of 6a shows that the 3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling studies also suggest that the equatorial conformation has lower potential energy relative to that of the axial conformation. Evaluation of 6a-g in the [(35)S]GTP-gamma-S in vitro functional assay showed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a K(e) of 0.27 nM at the kappa opioid receptor with 154- and 46-fold selectivity relative to those of the micro and delta receptors, respectively, possessed the best combination of kappa potency and selectivity.