Design, synthesis and biological evaluation of a novel bioactive indane scaffold 2-(diphenylmethylene)c-2,3-dihydro-1H-inden-1-one with potential anticancer activity.

Over the past decades, designing of privileged structures has emerged as a useful approach to the discovery and optimisation of novel biologically active molecules, and many have been successfully exploited across and within different target families. Examples include indole, quinolone, isoquinoline, benzofuran and chromone, etc. In the current study, we focus on synthesising a novel hybrid scaffold constituting naturally occurring benzophenone (14) and indanone (22) ring systems, leading to a general structure of 2-(diphenylmethylene)-2,3-dihydro-1H-inden-1-one (23).

Bioactive indanes: insight into the bioactivity of indane dimers related to the lead anti-inflammatory molecule PH46A.

Objectives: PH46A (1) demonstrates significant anti-inflammatory activity in phenotypic models but its mechanism and site of action have been elusive. Current study focused on the bioactivity of PH46 (2) and related novel indane dimers (6-10) to investigate the impact of changes in substitution and stereochemistry at the C-1 and C-2 positions of the PH46 (2) scaffold.

Methods: Cytotoxicity profiles of compounds were established using THP-1 macrophages and SW480 cells.

Bioactive indanes: Development and validation of an LC-MS/MS bioanalytical method for the determination of PH46A, a new potential anti-inflammatory agent, in dog and rat plasma and its application to a pharmacokinetic study in dog.

A new chemical entity, which is a chiral indane dimer, PH46A, has been developed by our research group. As a clinical candidate. PH46A has recently completed Phase I clinical studies in man.

Bioactive Indanes: Proof of Concept Study for Enantioselective Synthetic Routes to PH46A, a New Potential Anti-Inflammatory Agent.

PH46A is a single enantiomer and a member of the 1,2-indane dimer family. It has two contiguous stereogenic centers with , configurations, one of which being a quaternary center, which has been developed as a clinical candidate for the treatment of inflammatory and autoimmune conditions. The current synthetic route to PH46A involves the generation of an unwanted enantiomer (,)-, thus reducing the final yield significantly.

Investigation of the Stereoselective Synthesis of the Indane Dimer PH46A, a New Potential Anti-inflammatory Agent.

PH46A, belonging to a class of 1,2-Indane dimers, has been developed by our research group as a potential therapeutic agent for the treatment of inflammatory and autoimmune diseases. The initial synthetic route to PH46A gave a low overall yield, due in large part to the generation of undesired diastereoisomer and the unwanted enantiomer (,)- during the synthesis. The aim of this work was to carry out a comprehensive investigation into the stereoselective synthesis of PH46A.

The indane diastereoisomers, PH2 and PH5: divergence between their effects in delayed-type hypersensitivity models and a model of colitis.

Objectives: Compounds PH2 and PH5 are distereoisomers of novel indane compounds, synthesised as analogues of secondary metabolites of the fern, Onychium. In this study, we compare their effects on a variety of inflammatory models.

Methods: In an effort to extend our knowledge of their anti-inflammatory profile, we have investigated their activity in two models of delayed-type hypersensitivity (DTH); the methylated bovine serum albumin model (mBSA) and the oxazolone contact hypersensitivity (CHS) model, on IL2 release from Jurkat cells and in the dextran sulphate sodium (DSS) murine model of inflammatory bowel disease.

Antidiabetic Activities of an LC/MS Fingerprinted Aqueous Extract of Fagonia cretica L. in Preclinical Models.

Diabetes mellitus is a chronic disease and one of the most important public health challenges facing mankind. is a medicinal plant used widely in the Punjab in Pakistan. A recent survey has demonstrated that traditional healers and herbalists frequently use this plant to treat diabetes.

Molecular structure studies of (1,2)-2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol.

The single enantiomer (1,2)-2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol (), has recently been synthesized and isolated from its corresponding diastereoisomer (). The molecular and crystal structures of this novel compound have been fully analyzed. The relative and absolute configurations have been determined by using a combination of analytical tools including X-ray crystallography, X-ray Powder Diffraction (XRPD) analysis and Nuclear Magnetic Resonance (NMR) spectroscopy.

2-(Di-phenyl-methyl-idene)-2,3-di-hydro-1H-inden-1-one.

In the title mol-ecule, C22H16O, the indanone ring system is approximately planar with a dihedral angle between the fused rings of 5.13 (14)°. Two benzene rings are linked together at one side of a double bond, sitting on either side of the indanone ring system and making dihedral angles of 70.

(1S)-1-Phenylethanaminium 4-{[(1S,2S)-1-hydroxy-2,3-dihydro-1H,1'H-[2,2'-biinden]-2-yl]methyl}benzoate.

The title molecular salt, C(8)H(12)N(+)·C(26)H(21)O(3)(-), contains a dimeric indane pharmacophore that demonstrates potent anti-inflammatory activity. The indane group of the anion exhibits some disorder about the α-C atom, which appears common to many structures containing this group. A model to account for the slight disorder was attempted, but this was deemed unsuccessful because applying bond-length constraints to all the bonds about the α-C atom led to instability in the refinement.

6-(methylamino)hexane-1,2,3,4,5-pentanol 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1'H-[2,2-biinden]-2-yl)methyl)benzoate (PH46A): a novel small molecule with efficacy in murine models of colitis.

The indane skeleton is found naturally and in several therapeutic molecules in medicinal chemistry. During our work on the anti-inflammatory activity of naturally occurring and synthetic indanes, we have synthesized a novel indane scaffold that has been optimized for both anti-inflammatory activity and bioavailability. We have evaluated our lead molecule, PH46A, in in vivo models of inflammatory bowel disease (IBD), an area of considerable unmet clinical need; current therapies are often unable to control the course of the disease.

N-Cyclo-pentyl-N-(3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide.

The title mol-ecule, C(16)H(19)NO(2), consists of an indane moiety, which is connected through an N atom to an acetamide group and a cyclo-pentane ring. The N atom adopts planar triangular geometry. Inter-molecular inter-actions, such as π-π stacking or hydrogen bonding, were not observed.

Enhancement of insulin release from the beta-cell line INS-1 by an ethanolic extract of Bauhinia variegata and its major constituent roseoside.

Plants of the genus Bauhinia are used in several countries worldwide for the treatment of diabetes, and several related species have been shown to have hypoglycaemic effects in vivo in both normoglycaemic and alloxan- and streptozotocin-treated animal models. In this study, the insulin-secreting cell line INS-1 was used to examine the effects of the crude ethanolic extract of leaves of B. variegata L.

Diastereoisomers of 2-benzyl-2, 3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol: potential anti-inflammatory agents.

The synthesis and biological activity of the novel diastereoisomers of 2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol is reported. The 2,2-coupled indane dimers were synthesised by coupling of the silyl enol ether of 1-indanone with the dimethyl ketal of 2-indanone. The coupled product was directly alkylated to give the racemic ketone which was reduced to the diastereoisomeric alcohols.

The RBL-2H3 cell line: its provenance and suitability as a model for the mast cell.

The RBL-2H3 cell line is a commonly used histamine-releasing cell line used in inflammation, allergy and immunological research. Quite commonly, it is referred to in research papers as a mast cell line, despite the fact that it is derived from basophils. There is also a lack of consistency, both between different research groups using the same cell line and with both mast cell and basophil physiology.

RBL-2H3 cells are an imprecise model for mast cell mediator release.

Objective: The cell line, RBL-2H3, has been widely used as a mast cell model though much of the data is contradictory. The aim of this study is to assess the RBL-2H3 cell line as an in vitro model for degranulation studies.

Methods: RBL-2H3 cells were stimulated with either dinitrophenylated-IgE, calcium ionophore A23187, compound 48/80, mast cell degranulating peptide or lipopolysaccharide and mediator (histamine, beta-hexosaminidase, interleukin-13 and TNF-alpha) release was analysed.

Inhibition of LFA-1 mediated T-cell motility by naphthoquinones.

An in vitro T-cell migration assay has been established that can be used to study the effects of compounds on the development of T-cell polarisation with HuT-78 T lymphocytes. This assay indicates the ability of compounds tested to inhibit the inflammatory response by decreasing LFA-1-mediated T-cell motility. The effect of a series of naturally occurring quinone isolates on motility has been evaluated in this assay.

Investigation into the mast cell stabilizing activity of nature-identical and synthetic indanones.

As part of an ongoing search for novel molecules with therapeutic potential we examined the mediator release inhibition activity of a number of indanones and their derivatives. The aldol condensation product 18 was approximately twice as potent as disodium cromoglycate as an inhibitor of compound 48/80-stimulated histamine release from rat peritoneal mast cells. The activity of this class of dimeric indanone compound is significantly higher than controls and may represent a new class of mast cell stabilizing agents.

Ionisation characteristics and elimination rates of some aminoindanones determined by capillary electrophoresis.

Capillary electrophoresis (CE) has emerged as an important tool for evaluating the ionisation characteristics of compounds and their corresponding pKa values. A particular strength of CE in this context is that its relative selectivity allows one to measure the extent of ionisation of materials that are impure. In this study, using CE, we have measured the pKa values of a series of anti-inflammatory aminoindanones, which underwent degradation to indenone during the course of the determination.