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1.
Pharmaceutics ; 13(11)2021 Nov 22.
Article in English | MEDLINE | ID: mdl-34834395

ABSTRACT

The highly secure blood-brain barrier (BBB) restricts drug access to the brain, limiting the molecular toolkit for treating central nervous system (CNS) diseases to small, lipophilic drugs. Development of a safe and effective BBB modulator would revolutionise the treatment of CNS diseases and future drug development in the area. Naturally, the field has garnered a great deal of attention, leading to a vast and diverse range of BBB modulators. In this review, we summarise and compare the various classes of BBB modulators developed over the last five decades-their recent advancements, advantages and disadvantages, while providing some insight into their future as BBB modulators.

2.
J Psychol ; 155(3): 356-374, 2021.
Article in English | MEDLINE | ID: mdl-33705255

ABSTRACT

Employees with caregiving responsibilities often experience work-life interference (WLI), particularly when caring for either disabled persons and/or children. This study examines sample of 288 working Australians from the AWALI national survey data, who care for at least one family member or friend with long-term physical or mental illness, disability, or aging-related problems. We investigated the role of unpaid work at home in predicting WLI, based on a model that included indirect association via inferred causes for working unpaid hours at home and a conditional direct relationship based on number of children. The findings supported our prediction that unpaid work at home is positively associated with WLI but its effect is moderated by number of children. There was a conditional direct effect where employees with care responsibilities experienced a stronger relationship between unpaid hours and WLI when having more children. Further, when the perceived reason for unpaid work was excessively demanding work, the relationship with WLI was stronger. Implications for workers with multiple caregiving responsibilities are discussed.


Subject(s)
Caregivers , Employment , Work-Life Balance , Australia , Caregivers/psychology , Child , Disabled Persons , Humans
3.
Bioorg Med Chem ; 28(23): 115774, 2020 12 01.
Article in English | MEDLINE | ID: mdl-32992251

ABSTRACT

A series of lysine-based vinyl sulfone peptidomimetics were synthesised and evaluated for anti-trypanosomal activity against bloodstream forms of T. brucei. This focused set of compounds, varying in the P3 position, were accessed in a divergent manner from a common intermediate (ammonium salt 8). Several P3 analogues exhibited sub-micromolar EC50 values, with thiourea 14, urea 15 and amide 21 representing the most potent anti-trypanosomal derivatives of the series. In order to establish an in vitro selectivity index the most active anti-trypanosomal compounds were also assessed for their impact on cell viability and cytotoxity effects in mammalian cells. Encouragingly, all compounds only reduced cellular metabolic activity in mammalian cells to a modest level and little, or no cytotoxicity, was observed with the series.


Subject(s)
Sulfones/chemistry , Trypanocidal Agents/chemical synthesis , Cell Line , Cell Proliferation/drug effects , Drug Design , Humans , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacology , Thiourea/chemistry , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects
4.
Molecules ; 25(4)2020 Feb 14.
Article in English | MEDLINE | ID: mdl-32075008

ABSTRACT

Haemostatic disorders are both complex and costly in relation to both their treatment and subsequent management. As leading causes of mortality worldwide, there is an ever-increasing drive to improve the diagnosis and prevention of haemostatic disorders. The field of microfluidic and Lab on a Chip (LOC) technologies is rapidly advancing and the important role of miniaturised diagnostics is becoming more evident in the healthcare system, with particular importance in near patient testing (NPT) and point of care (POC) settings. Microfluidic technologies present innovative solutions to diagnostic and clinical challenges which have the knock-on effect of improving health care and quality of life. In this review, both advanced microfluidic devices (R&D) and commercially available devices for the diagnosis and monitoring of haemostasis-related disorders and antithrombotic therapies, respectively, are discussed. Innovative design specifications, fabrication techniques, and modes of detection in addition to the materials used in developing micro-channels are reviewed in the context of application to the field of haemostasis.


Subject(s)
Biosensing Techniques , Hemostasis , Hemostatic Disorders/diagnosis , Microfluidics/methods , Hemostatic Disorders/pathology , Humans , Lab-On-A-Chip Devices , Point-of-Care Systems , Quality of Life
5.
Bioorg Med Chem ; 28(5): 115261, 2020 03 01.
Article in English | MEDLINE | ID: mdl-31987694

ABSTRACT

4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and ß with low nanomolar affinity and <20-fold selectivity for α over ß and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERß (compound 42; 170-fold selectivity).


Subject(s)
Antineoplastic Agents/pharmacology , Benzopyrans/pharmacology , Receptors, Estrogen/antagonists & inhibitors , Antineoplastic Agents/chemistry , Benzopyrans/chemistry , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Humans , MCF-7 Cells , Models, Molecular , Molecular Structure
6.
J Med Chem ; 61(2): 514-534, 2018 01 25.
Article in English | MEDLINE | ID: mdl-28426931

ABSTRACT

Estrogen receptor α (ERα) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were synthesized: series I containing an acrylic acid, series II with an acrylamide, and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ERα selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERß expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ERß. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, while compound 22 will be a useful experimental probe for helping to elucidate the role of ERß in cancer cells.


Subject(s)
Benzoxepins/chemistry , Estrogen Receptor alpha/metabolism , Estrogen Receptor beta/metabolism , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Crystallography, X-Ray , Estrogen Receptor alpha/chemistry , Estrogen Receptor beta/chemistry , Humans , Ligands , MCF-7 Cells , Models, Molecular , Molecular Docking Simulation , Proteolysis/drug effects , Selective Estrogen Receptor Modulators/chemical synthesis , Structure-Activity Relationship
7.
J Enzyme Inhib Med Chem ; 31(sup3): 117-130, 2016.
Article in English | MEDLINE | ID: mdl-27476825

ABSTRACT

The estrogen receptors (ERα and ERß) which are ligand inducible nuclear receptors are recognized as pharmaceutical targets for diseases such as osteoporosis and breast cancer. There is an increasing interest in the discovery of subtype Selective Estrogen Receptor Modulators (SERMs). A series of novel ß-lactam compounds with estrogen receptor modulator properties have been synthesized. The antiproliferative effects of these compounds on human MCF-7 breast tumor cells are reported, together with binding affinity for the ERα and ERß receptors. The most potent compound 15g demonstrated antiproliferative effects on MCF-7 breast tumor cells (IC50 = 186 nM) and ERα binding (IC50 = 4.3 nM) with 75-fold ERα/ß receptor binding selectivity. The effect of positioning of the characteristic amine containing substituted aryl ring (on C-4 or N-1 of the ß-lactam scaffold) on the antiproliferative activity and ER-binding properties of the ß-lactam compounds is rationalized in a molecular modeling study.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Estrogen Receptor Modulators/chemistry , Estrogen Receptor Modulators/pharmacology , Estrogen Receptor alpha/antagonists & inhibitors , beta-Lactams/chemistry , Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Estrogen Receptor Modulators/chemical synthesis , Estrogen Receptor beta/antagonists & inhibitors , Humans , MCF-7 Cells , Models, Molecular , Molecular Structure , Structure-Activity Relationship , beta-Lactams/chemical synthesis
8.
J Med Chem ; 57(22): 9370-82, 2014 Nov 26.
Article in English | MEDLINE | ID: mdl-25369367

ABSTRACT

Twelve novel ß-lactams were synthesized and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERß, were determined. ß-Lactams 23 and 26 had the strongest binding affinities for ERα (IC50 values: 40 and 8 nM, respectively) and ERß (IC50 values: 19 and 15 nM). ß-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G2/M phase (mitotic blockade) and depolymerization of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation of the expression of pro-survival proteins Bcl-2 and Mcl-1. Computational modeling predicted binding preferences for the dual ER/tubulin ligand 26. This series is an important addition to the known pool of ER antagonists and ß-lactam 26 is the first reported compound that has dual-targeting properties for both the ER and tubulin.


Subject(s)
Estrogen Receptor Antagonists/chemistry , Tubulin/chemistry , beta-Lactams/chemistry , Apoptosis , Cell Division , Chemistry, Pharmaceutical/methods , Computer Simulation , Estrogen Receptor alpha/antagonists & inhibitors , Estrogen Receptor alpha/chemistry , Estrogen Receptor beta/antagonists & inhibitors , Estrogen Receptor beta/chemistry , Estrogens/chemistry , G2 Phase , Humans , Inhibitory Concentration 50 , L-Lactate Dehydrogenase/chemistry , Ligands , MCF-7 Cells , Models, Molecular , Myeloid Cell Leukemia Sequence 1 Protein/chemistry , Protein Binding , Proto-Oncogene Proteins c-bcl-2/chemistry , Software , Tetrazolium Salts/chemistry , Thiazoles/chemistry
9.
J Med Chem ; 56(17): 6638-50, 2013 Sep 12.
Article in English | MEDLINE | ID: mdl-23952916

ABSTRACT

A series of vinyl sulfone-containing peptidomimetics were rationally designed, synthesized, and evaluated against Trypanosoma brucei brucei . These electrophilic compounds are likely to exert their antitrypanosomal activity via inhibition of trypanosomal cysteine proteases, TbCatB and rhodesain, through alkylation of a key cysteine residue within the protease active site. The series was designed to present complementary groups to naturally recognized peptide substrates while probing tolerance to a range of substitutions at the P1, P1', and P2 positions. The most potent compound, 29 (EC50 = 70 nM, T. b. brucei whole cell assay), displayed minimal toxicity (>785 times selectivity) when assayed for cytotoxicity against the human promyelocytic leukemia (HL-60) cell line. Cells treated with compound 29, as with K777 (2), exhibited an increase in both the number of multinucleated cells and cells with swollen flagellar pockets. Computational analysis revealed a strong correlation between the hypothetical binding mode in TbCatB/rhodesain and trypanocidal activity in vitro.


Subject(s)
Peptidomimetics , Sulfones/chemistry , Sulfones/pharmacology , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Animals , Drug Design , HL-60 Cells , Humans , Hydrogen Bonding , Models, Molecular , Spectrum Analysis , Trypanosoma brucei brucei/drug effects
10.
J Chem Biol ; 5(2): 63-79, 2012 Apr.
Article in English | MEDLINE | ID: mdl-23284589

ABSTRACT

UNLABELLED: An array of chemical modifications have recently emerged, designed to improve the stability of natural peptides that inherently suffer from short in vivo half-lives, thereby preventing their use as therapeutics. The resultant peptidomimetics resemble native peptides; however, they contain synthetic elements (e.g. non-coded amino acids) which confer improved biophysical properties. An elegant approach towards the identification of peptidomimetics is through screening of large combinatorial chemical libraries incorporating both coded and non-coded amino acids (e.g. ß amino acids). We apply here our recently developed Integrated Chemical Biophysics (ICB) platform, which combines microscale one-bead one-compound screening with fluorescence tagging of retrieved hit beads and subsequent affinity determination of hit compounds in homogenous solution, to the task of identifying novel mixed α, ß peptidomimetic binders for the adaptor protein SLAM-associated protein (SAP), which acts as an intracellular adapter that transduces T and NK cell activation. An enhancement to the ICB process is introduced which enables ranking hit compounds from single-point measurements even if the library compound is <95% pure and without HPLC purification of single-bead-derived substance. Finally, a novel computational protocol enabling binding mode and SAR rationalisation of hit compounds is also described which we now utilise to inform future library design. Application of the full ICB process has allowed identification of a highly interesting motif, Ac-ß(3)-Pro-α-pTyr, as a mimic for the -1 and -2 positions of the natural binding motif and provides a promising starting point for further optimization towards higher-affinity SAP inhibitors with enhanced metabolic stability. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12154-011-0071-9) contains supplementary material, which is available to authorized users.

11.
Nephrol Dial Transplant ; 27(3): 1035-41, 2012 Mar.
Article in English | MEDLINE | ID: mdl-21810765

ABSTRACT

BACKGROUND: Elevated serum uric acid (UA) is associated with gout, hypertension, cardiovascular and renal disease. Hereditary renal hypouricemia type 1 (RHUC1) is caused by mutations in the renal tubular UA transporter URAT1 and can be complicated by nephrolithiasis and exercise-induced acute renal failure (EIARF). We have recently shown that loss-of-function homozygous mutations of another UA transporter, GLUT9, cause a severe type of hereditary renal hypouricemia with similar complications (RHUC2). METHODS: Two unrelated families with renal hypouricemia were clinically characterized. DNA was extracted and SLC22A12 and SLC2A9 coding for URAT1 and GLUT9, respectively, were sequenced. Transport studies into Xenopus laevis oocytes were utilized to evaluate the function of the GLUT9 mutations found. A molecular modeling study was undertaken to structurally characterize and probe the effects of these mutations. RESULTS: Two novel homozygous GLUT9 missense mutations were identified: R171C and T125M. Mean serum UA level of the four homozygous subjects was 0.15 ± 0.06 mg/dL and fractional excretion of UA was 89-150%. None of the affected subjects had nephrolithiasis, EIARF or any other complications. Transport assays revealed that both mutant proteins had a dramatically reduced ability to transport UA. Modeling showed that both R171C and T125M mutations are located within the inner channel that transports UA between the cytoplasmic and extracellular regions. CONCLUSIONS: This is the second report of renal hypouricemia caused by homozygous GLUT9 mutations. Our findings confirm the pivotal role of GLUT9 in UA transport and highlight the similarities and differences between RHUC1 and RHUC2.


Subject(s)
Glucose Transport Proteins, Facilitative/genetics , Homozygote , Mutation/genetics , Renal Tubular Transport, Inborn Errors/genetics , Uric Acid/blood , Urinary Calculi/genetics , Adult , Aged, 80 and over , Animals , Child , Child, Preschool , Female , Humans , Male , Models, Molecular , Molecular Dynamics Simulation , Pedigree , Renal Tubular Transport, Inborn Errors/blood , Urinary Calculi/blood , Xenopus laevis/genetics , Xenopus laevis/metabolism , Young Adult
12.
Bioorg Med Chem ; 19(20): 6055-68, 2011 Oct 15.
Article in English | MEDLINE | ID: mdl-21920765

ABSTRACT

Heat shock protein 90 is an emerging target for oncology therapeutics. Inhibitors of this molecular chaperone, which is responsible for the maintenance of a number of oncogenic proteins, have shown promise in clinical trials and represent a new and exciting area in the treatment of cancer. Heat shock protein 90 inhibitors have huge structural diversity, and here we present the lead identification of novel inhibitors based on ß-lactam and imine templates. ß-Lactam 5 and imines 12 and 18 exhibit binding to heat shock protein 90-α with IC(50) values of 5.6 µM, 14.5 µM, and 22.1 µM, respectively. The binding affinity displayed by these compounds positions them as lead compounds for the design of future inhibitors of heat shock protein 90 based on the ß-lactam and imine templates.


Subject(s)
Antineoplastic Agents/chemistry , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Imines/antagonists & inhibitors , beta-Lactams/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Female , HSP90 Heat-Shock Proteins/chemistry , HSP90 Heat-Shock Proteins/metabolism , Humans , Models, Molecular , Structure-Activity Relationship , beta-Lactams/chemical synthesis , beta-Lactams/chemistry
13.
Eur J Med Chem ; 46(9): 4595-607, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21840628

ABSTRACT

The structure-activity relationships of antiproliferative ß-lactams, focusing on modifications at the 4-position of the ß-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The antiproliferative activity was assessed in MCF-7 cells, where the 4-(4-ethoxy)phenyl substituted compound 26 displayed the most potent activity with an IC(50) value of 0.22 µM. The mechanism of action was demonstrated to be by inhibition of tubulin polymerisation. Cell exposure to combretastatin A-4 and 26 led to arrest of MCF-7 cells in the G2/M phase of the cell cycle and induction of apoptosis. Additionally, mitotic catastrophe for combretastatin A-4 and for 26 was demonstrated in breast cancer cells for the first time, as evidenced by the formation of giant, multinucleated cells.


Subject(s)
Azetidines/pharmacology , Cell Proliferation/drug effects , Microtubules/drug effects , Mitosis/drug effects , Models, Molecular , Cell Line, Tumor , Crystallography, X-Ray , Flow Cytometry , Humans , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Microscopy, Confocal , Microscopy, Fluorescence , Spectrophotometry, Infrared
14.
Bioorg Med Chem ; 19(3): 1328-48, 2011 Feb 01.
Article in English | MEDLINE | ID: mdl-21227702

ABSTRACT

Structural derivatives of 4-MTA, an illegal amphetamine analogue have been previously shown to have anticancer effects in vitro. In this study we report the synthesis of a series of novel 1,3-bis(aryl)-2-nitro-1-propene derivatives related in structure to 4-MTA. A number of these compounds containing a classic nitrostyrene structure are shown to have antiproliferative activities in vitro in a range of malignant cell lines, particularly against Burkitt's lymphoma derived cell lines, whilst having no effect on 'normal' peripheral blood mononuclear cells. Such effects appear to be independent of the serotonin transporter, a high affinity target for amphetamines and independent of protein tyrosine phosphatases and tubulin dynamics both of which have been previously associated with nitrostyrene-induced cell death. We demonstrate that a number of these compounds induce caspase activation, PARP cleavage, chromatin condensation and membrane blebbing in a Burkitt's lymphoma derived cell line, consistent with these compounds inducing apoptosis in vitro. Although no specific target has yet been identified for the action of these compounds, the cell death elicited is potent, selective and worthy of further investigation.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Nitro Compounds/chemical synthesis , Serotonin Plasma Membrane Transport Proteins/metabolism , Alkenes/chemistry , Antineoplastic Agents/chemistry , Burkitt Lymphoma/metabolism , Burkitt Lymphoma/pathology , Cell Line, Tumor , Drug Design , Humans , Molecular Structure , Nitro Compounds/chemistry , Nitro Compounds/pharmacology , Serotonin/metabolism
15.
Eur J Med Chem ; 45(12): 5752-66, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20933304

ABSTRACT

The synthesis and study of the structure-activity relationships of a series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (ß-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. The 1,4-diaryl-2-azetidinones are unsubstituted at C-3, or contain methyl substituent(s) at C-3. The most potent compounds 12d and 12e display antiproliferative activity at nanomolar concentrations when evaluated against the MCF-7 and MDA-MB-231 human breast carcinoma cell lines. 12d exerts antimitotic effects through an inhibition of tubulin polymerisation and subsequent G2/M arrest of the cell cycle in human MDA-MB-231 breast cancer cells, with similar activity to that of CA-4. These novel ß-lactam compounds are identified as potentially useful scaffolds for the further development of antitumour agents which target tubulin.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Stilbenes/chemical synthesis , Stilbenes/pharmacology , beta-Lactams/chemistry , Animals , Antineoplastic Agents/chemistry , Cattle , Cell Cycle/drug effects , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Computer Simulation , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Conformation , Stereoisomerism , Stilbenes/chemistry , Structure-Activity Relationship , Tubulin/chemistry , Tubulin/metabolism
16.
ACS Chem Biol ; 5(10): 967-79, 2010 Oct 15.
Article in English | MEDLINE | ID: mdl-20677820

ABSTRACT

In eukaryotic cells, proteins and RNAs are transported between the nucleus and the cytoplasm by nuclear import and export receptors. Over the past decade, small molecules that inhibit the nuclear export receptor CRM1 have been identified, most notably leptomycin B. However, up to now no small molecule inhibitors of nuclear import have been described. Here we have used our automated confocal nanoscanning and bead picking method (CONA) for on-bead screening of a one-bead one-compound library to identify the first such import inhibitor, karyostatin 1A. Karyostatin 1A binds importin ß with high nanomolar affinity and specifically inhibits importin α/ß mediated nuclear import at low micromolar concentrations in vitro and in living cells, without perturbing transportin mediated nuclear import or CRM1 mediated nuclear export. Surface plasmon resonance binding experiments suggest that karyostatin 1A acts by disrupting the interaction between importin ß and the GTPase Ran. As a selective inhibitor of the importin α/ß import pathway, karyostatin 1A will provide a valuable tool for future studies of nucleocytoplasmic trafficking.


Subject(s)
Active Transport, Cell Nucleus/drug effects , Drug Evaluation, Preclinical/methods , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , beta Karyopherins/antagonists & inhibitors , beta Karyopherins/metabolism , HeLa Cells , Humans , Protein Binding/drug effects , beta Karyopherins/chemistry , ran GTP-Binding Protein/metabolism
17.
J Enzyme Inhib Med Chem ; 25(2): 180-94, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20222762

ABSTRACT

We have synthesized a series of polymethoxylated rigid analogs of combretastatin A-4 which contain a benzoxepin ring in place of the usual ethylene bridge present in the natural combretastatin products. The compounds display antiproliferative activity when evaluated against the MCF-7 and MDA human breast carcinoma cell lines. 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-2,3-dihydro-benzoxepine (11g) was found to be the most potent product when evaluated against the MCF-7 breast cancer cell line. A brief computational study of the structure-activity relationship for the synthesized compounds is presented. These 4,5-diarylbenzoxepins are identified as potentially useful scaffolds for the further development of antitumor agents which target tubulin.


Subject(s)
Antineoplastic Agents, Phytogenic , Benzoxepins , Cell Proliferation/drug effects , Drug Design , Stilbenes/chemistry , Tubulin/metabolism , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Benzoxepins/chemical synthesis , Benzoxepins/chemistry , Benzoxepins/pharmacology , Binding Sites , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Humans , Models, Molecular , Molecular Structure , Protein Binding , Structure-Activity Relationship
18.
Mol Inform ; 29(5): 421-30, 2010 May 17.
Article in English | MEDLINE | ID: mdl-27463197

ABSTRACT

A novel tiered Structure-Based (SB) Virtual Screening (VS) workflow called tieredScreen was designed and implemented. The automated protocol utilises diverse computational tools in a synergistic manner to reduce false positives and increase the likelihood of converging on putative active molecules. The performance of the novel VS workflow was validated using the Directory of Useful Decoys (DUD) Estrogen Receptor α (ERα) antagonist dataset, and successfully deployed for the identification of novel antagonists of ERα from a screening collection of ca. 160 000 commercially available compounds. As well as yielding nanomolar (nM) active ligands identified previously through a docking only protocol, from a selection of eight virtual hits suggested by tieredScreen, four novel nM ERα binding chemotypes were identified and biologically validated - demonstrating the applicability of a tiered intervention for virtual screening.

19.
Eur J Med Chem ; 44(12): 4862-88, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19717215

ABSTRACT

The discovery that some serotonin reuptake transporter (SERT) ligands have the potential to act as pro-apoptotic agents in the treatment of cancer adds greatly to their diverse pharmacological application. 4-Methylthioamphetamine (MTA) is a selective ligand for SERT over other monoamine transporters. In this study, a novel library of structurally diverse 4-MTA analogues were synthesised with or without N-alkyl and/or C-alpha methyl or ethyl groups so that their potential SERT-dependent antiproliferative activity could be assessed. Many of the compounds displayed SERT-binding activity as well as cytotoxic activity. While there was no direct correlation between these two effects, a number of derivatives displayed anti-tumour effects in lymphoma, leukaemia and breast cancer cell lines, showing further potential to be developed as possible chemotherapeutic agents.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Phenethylamines/chemical synthesis , Phenethylamines/pharmacology , Serotonin Plasma Membrane Transport Proteins/metabolism , Sulfur , Amphetamines/chemical synthesis , Amphetamines/chemistry , Amphetamines/pharmacology , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Phenethylamines/chemistry , Serotonin Plasma Membrane Transport Proteins/drug effects , Structure-Activity Relationship , Sulfur/chemistry
20.
J Med Chem ; 52(8): 2177-80, 2009 Apr 23.
Article in English | MEDLINE | ID: mdl-19331414

ABSTRACT

We describe the discovery of a novel indazole-based scaffold that represents the "first-in-class" dual Hsp90/tubulin binding compound. Individual known ligands for both targets shared similar 3',4',5'-trimethoxyphenyl cores, and from this it was hypothesized that application of an integrated ligand and structure-based virtual screening (VS) workflow could yield a single scaffold with dual binding affinity. Following validation of the VS protocol, we successfully identified a novel dual inhibitor, sourced from a commercial screening collection of 160 000 compounds.


Subject(s)
Antineoplastic Agents/chemistry , Databases, Factual , HSP90 Heat-Shock Proteins/metabolism , Imidazoles/chemistry , Indazoles/chemistry , Quantitative Structure-Activity Relationship , Tubulin/metabolism , Adenosine Triphosphate/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Binding Sites , Biopolymers , Cell Line, Tumor , Colchicine/metabolism , Estrogen Receptor alpha/metabolism , HSP90 Heat-Shock Proteins/antagonists & inhibitors , HSP90 Heat-Shock Proteins/chemistry , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Indazoles/chemical synthesis , Indazoles/pharmacology , Ligands , Models, Molecular , Principal Component Analysis , Protein Binding , Tubulin/chemistry , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology
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