Selected nitrostyrene compounds demonstrate potent activity in chronic lymphocytic leukaemia cells, including those with poor prognostic markers.

The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG­3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro­apoptotic effects of the compounds were found to be reactive oxygen species and caspase­dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3­kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co­cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.

Synthesis and antiproliferative action of a novel series of maprotiline analogues.

The synthesis of a diverse library of compounds structurally related to maprotiline, a norepinephrine reuptake transporter (NET) selective antidepressant which has recently been identified as a novel in vitro antiproliferative agent against Burkitt's lymphoma (BL) cell lines is reported. A series of 9,10-dihydro-9,10-ethanoanthracenes were synthesised with modifications to the bridge of the dihydroethanoanthracene structure and with alterations to the basic side chain. A number of compounds were found to reduce cell viability to a greater extent than maprotiline in BL cell lines. In addition a related series of novel 9-substituted anthracene compounds were investigated as intermediates in the synthesis of 9,10-dihydro-9,10-ethanoanthracenes. These compounds proved the most active from the screen and were found to exert a potent caspase-dependant apoptotic effect in the BL cell lines, while having minimal effect on the viability of peripheral blood mononuclear cells (PBMCs). Compounds also displayed activity in multi-drug resistant (MDR) cells.

Designed multiple ligands for cancer therapy.

The concept of a single chemical entity with desirable activity at more than one biological target is an attractive one. Increasingly, multiple complex biochemical pathways are implicated in a variety of diseases including cancer. Successful treatment of these conditions often depends on pharmaceutical intervention at multiple pathways, with a combination of different drugs. Designed multiple ligands (DMLs) are drugs which act at multiple biomolecular targets. Numerous terms have been used to describe such ligands, including multiple-target directed ligands, heterodimers, promiscuous drugs and pan-agonists. However, although there are many reported examples of multiple-targeting anti-cancer agents, no review of these has been presented to date. A huge variety of biological signalling-pathways, proteins and enzymes are currently targeted and implicated in the pathogenesis of cancer. This review will provide an overview of reported designed multiple ligands for cancer and an exploration of the advantages and drawbacks of such compounds. The review also provides brief commentaries on the biological processes and proteins that are currently targeted in cancer therapy and the potential for dual or triple targeting of these with designed multiple ligands.

Targeting tumors using estrogen receptor ligand conjugates.

When treating cancer, cytotoxic agents are intended to exert their effect on rapidly proliferating cancer cells. However, often cancer chemotherapies lack specificity which can lead to toxicity and undesirable side affects. Many approaches have been designed to target tumors. Selective chemotherapies can be established by focusing on distinctive physiological, morphological and environmental differences between tumor and healthy tissue. For example, agents targeting nuclear receptors over-expressed in tumors can hone in on malignant tissue and result in improved chemotherapeutic treatments. In hormone-dependent cancers, such as certain breast cancers, a number of structurally varied estrogen receptor ligand conjugates have been investigated attempting to take advantage of the presence of over-expressed estrogen receptor. Estrogen receptor ligand conjugates containing a variety of cytotoxic agents, photodynamic therapeutic agents and radioligands have been reported. In addition, studies to improve the pharmaceutical properties of certain estrogen receptor ligand conjugates have shown promising results. In this review, developments in these specific types of estrogen receptor targeting approaches are discussed which highlight the potential advantages of these conjugates in the discovery of more effective cancer chemotherapy agents.

Recent developments in the design of anti-depressive therapies: targeting the serotonin transporter.

The serotonin transporter protein (SERT) has been the target for the development of several modern antidepressants with an objective of achieving selectivity over other monoamine transporters, thereby minimising side effects observed in the older generation of tricyclic antidepressants. The clinical selective serotonin reuptake inhibitors (SSRIs) have been shown to be among the most effective therapies in the treatment of depression. However they have clinical disadvantages over other classes of antidepressant drugs such as slow onset of action nausea and sleep disruption. The negative feedback loop attributed to the presynaptic 5-HT(1A) receptors has been implicated in the "time lag" observed in many patients between the administration of the SSRI and its observed therapeutic action. In recent years the focus has been on developing compounds with dual affinity for serotonergic auto-receptors along with an inhibitory activity at SERT. These structurally diverse products promise to be the next generation of anti-depressant medicines. This review presents an analysis of the recently reported structural classes with SSRI activity and rationalises the unique relationship between their molecular properties and biological activities. Specific emphasis is placed on the development of molecular structures with dual serotonergic activity. Recent advances in the design and synthesis of single molecular entities possessing 5-HT reuptake inhibition together with 5-HT(1A), 5-HT(1B), 5-HT(1D), 5-HT(2A), DAT, NET, alpha (2)-adrenoceptor and acetylcholinesterase antagonism are reviewed. The structural studies to identify proposed SERT binding sites together with the role of structure and ligand based design in the development of more effective SSRIs are summarised.

Advances in the science of estrogen receptor modulation.

This work details recent advances in the science of estrogen receptor (ER) modulation, with emphasis on the discovery of novel ligands for the ER ligand binding domain (LBD). A detailed examination of structural studies of the ERs is presented with analysis of the impact of such works on contemporary ligand design and the molecular pharmacology of the ER. The various classes of ER modulators are discussed on the basis of stuctural similarities including selective estrogen receptor modulators (SERMs) and 'pure' non-steroidal antiestrogens. Additionally we review the emergence of a novel selective class of modulator which we have termed the selective estrogen receptor subtype modulators (SERSMs) and, in a departure from LBD strategies we examine the discovery of novel peptide inhibitors of the ER which inhibit transcriptional activiation of agonist liganded receptor through interaction with coactivator recruitment proteins, and offer unique insight to the mechanism of action of all classes of ER modulators. Through examination of patent and classical literature we present a thorough and informative cross-section of the contemporary state of the art in this exciting field of pharmaceutical research.

Phenylalkylamine abuse among opiate addicts attending a methadone treatment programme in the Republic of Ireland.

Since the early 1990s ring-substituted derivatives of amphetamine have been abused widely in the Republic of Ireland. The main ring-substituted amphetamines being abused include methylenedioxyamphetamine (MDA), methylenedioxymethamphetamine (MDMA) and methylenedioxyethamphetamine (MDEA). A newer illicit synthetic analogue, which has been seized to a lesser extent by Irish police, is N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB). The work presented here involved the determination of the type of ring-substituted amphetamines being abused by a group of recovering opiate abusers participating in a methadone maintenance programme in a Dublin Drug Rehabilitation Centre. Urine samples which tested positive for amphetamines and ring-substituted amphetamines via EMIT immunoassay were subjected to further analysis using GC-MS with MBTFA flash derivatization. It was found that the methylenedioxypropanamines were being abused, as was amphetamine itself. However, no abuse of methylenedioxybutanamines or thioamphetamines was observed.

Flexible estrogen receptor modulators: design, synthesis, and antagonistic effects in human MCF-7 breast cancer cells.

Although many series of estrogen receptor antagonists continue to be produced, the majority are direct structural analogues of existing modulators. To examine the tolerance of the estrogen receptor toward flexible ligands, a series of novel flexible estrogen receptor antagonists were prepared and their antiproliferative effects on human MCF-7 breast tumor cells investigated. Each of these compounds deviated from the traditional triphenylethylene backbone associated with common tamoxifen analogues through the introduction of a flexible methylene (benzylic) spacing group between one of the aryl rings and the ethylene group and through variations in the basic side chain moiety. The compounds prepared, when assayed in conjunction with a tamoxifen standard, demonstrated high potency in antiproliferative assays against an MCF-7 human breast cancer cell line with low cytotoxicity and high binding affinity. A computational study was undertaken to investigate the compounds' potential interactions with specific residues within the human estrogen receptor alpha ligand-binding domain (ER-LBD), predicting these compounds bind in an antiestrogenic fashion within the ER-LBD and interact with those important residues previously identified in the structures of ER-LBD agonist/antagonist cocrystals. These compounds further illustrate the eclectic nature of the estrogen receptor in terms of ligand flexibility tolerance.

Ethyl side-chain modifications in novel flexible antiestrogens--design, synthesis and biological efficacy in assay against the MCF-7 breast tumor cell line.

To examine the efficacy of ethyl side-chain modifications in a family of flexible non-steroidal modulators of the estrogen receptor, a series of novel compounds was prepared and their antiproliferative effects on human MCF-7 breast tumor cells evaluated. These flexible antiestrogens consisted of members wherein the ethyl portion of the parent compound, a flexible analogue of tamoxifen, had been modified so as to introduce halogens or a nitro group, or to extend the side-chain length from ethyl to propyl or butyl. The compounds demonstrated potency at low micromolar concentrations in antiproliferative assays against an MCF-7 human breast cancer cell line with low associated cytotoxicity. Tested compounds exhibited nanomolar binding affinity (Ki) for the estrogen receptor (ER) as determined through displacement of radiolabelled estradiol. Semiempirical calculations predict an inherent lower oxidative potential at the allylic position, similar to that calculated for the established analogue toremifene, indicating a lesser propensity of such compounds towards metabolic oxidative carbocation generation and consequent DNA adduct formation. Computational studies predict these compounds to bind in a typical estrogen antagonist mode within the ER-ligand binding domain (LBD). Ethyl side-chain modification in this compound class is well tolerated within the ER and is not detrimental to compound efficacy, with additional potential anti-carcinogenic properties imbued to the molecule.

An evaluation of the acute in vivo toxicity of benzylidenechroman-4-ones, 1-thiobenzylidenechroman-4-ones and benzylidenetetralones.

A series of new compounds were evaluated for acute in vivo toxicity. Their synthesis and antifungal activity have previously been described by us. The naturally occurring class of compounds to which they belong - the benzylidenechroman-4-ones - have been identified as a potential source of new antifungal agents. These compounds were found to be less toxic, as judged by acute toxicity, than existing commercially available antifungals. A number of conclusions can be drawn about the relationship of structural changes in this series of compounds to increases or decreases in acute toxicity.

Preparation and characterization of lactic/glycolic acid polymers and copolymers.

A range of poly(L-lactic acid) [L-PLA], poly(DL-lactic acid) [DL-PLA], polyglycolic acid [PGA] polymers and PLA-PGA copolymers were synthesized from lactide and glycolide. The effect of lactide type, catalyst concentration, reaction time and reaction temperature was studied. Intrinsic viscosity determination, gel permeation chromatography, laser light scattering, nuclear magnetic resonance and differential scanning calorimetry were used to characterize the polymers formed. It was impossible to determine the molecular weight of most PGA samples due to lack of solubility. The consequences of the results with regard to the production and storage of microencapsulated and related products are discussed.