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1.  Development of cyclobutene- and cyclobutane-functionalized fatty acids with inhibitory activity against Mycobacterium tuberculosis 
ChemMedChem  2014;9(8):1838-1849.
Eleven fatty acid analogs incorporating four-membered carbocycles (cyclobutenes, cyclobutanes, cyclobutanones, and cyclobutanols) were investigated for the ability to inhibit growth of Mycobacterium smegmatis (Msm) and Mycobacterium tuberculosis (Mtb). A number of the analogs displayed inhibitory activity against both mycobacterial species in minimal media. Several of the molecules displayed potent levels of inhibition against Mtb with MIC values equal to or below those obtained with the anti-tuberculosis drugs D-cycloserine and isoniazid. In contrast, two of the analogs displaying the greatest activity against Mtb failed to inhibit E. coli growth under either set of conditions. Thus, the active molecules identified here (1, 2, 6, and 8) may provide the basis for development of anti-mycobacterial agents against Mtb.
doi:10.1002/cmdc.201402067
PMCID: PMC4142477  PMID: 24902951
cyclobutane; cyclobutene; fatty acid; mycobacteria; tuberculosis
2.  Discovery, synthesis and characterization of a highly mAChR selective M5 orthosteric antagonist, VU0488130 (ML381): a novel molecular probe 
ChemMedChem  2014;9(8):1677-1682.
Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs or M1-M5), M5 is the least explored and understood due to a lack of mAChR subtype selective ligands. We recently performed a high-throughput functional screen and identified a number of weak antagonist hits that were selective for M5. An iterative parallel synthesis and detailed molecular pharmacologic profiling effort, led to the discovery of the first highly selective, CNS penetrant M5 orthosteric antagonist tool compound, with submicromolar potency (hM5 IC50 = 450 nM, hM5 Ki = 340 nM, M1-M4 IC50s >30 μM), enantiospecific inhibition and an acceptable DMPK profile for in vitro and electrophysiology studies.
doi:10.1002/cmdc.201402051
PMCID: PMC4116439  PMID: 24692176
muscarinic; M5; antagonist; orthosteric; acetylcholine
3.  Optimisation of Tetrahydroisoquinoline-Based Chimeric Microtubule Disruptors 
ChemMedChem  2014;9(8):1783-1793.
Tetrahydroisoquinoline (THIQ)-based “chimeric” microtubule disruptors were optimised through modification of the N-benzyl motif, in concert with changes at C3 and C7, resulting in the identification of compounds with improved in vitro antiproliferative activities (e.g. 15: GI50 20 nM in DU-145). The broad anticancer activity of these novel structures was confirmed in the NCI 60-cell line assay, with 12e,f displaying MGM values in the 40 nM region. In addition, their profiles as inhibitors of tubulin polymerisation and colchicine binding to tubulin were confirmed. Compound 15, for example, inhibited tubulin polymerisation with an IC50 of 1.8 μM, close to that of the clinical drug combretastatin A-4, and also proved effective at blocking colchicine binding. Additionally, compound 20b was identified as the only phenol in the series to date showing both better in vitro antiproliferative properties than its corresponding sulfamate and excellent antitubulin data (IC50 = 1.6 μM). Compound 12f was selected for in vivo evaluation at the NCI in the hollow fibre assay and showed very good activity and wide tissue distribution, illustrating the value of this template for further development.
doi:10.1002/cmdc.201402025
PMCID: PMC4145847  PMID: 24819406
chimeras; colchicine binding; microtubule disruptors; tetrahydroisoquinolines; tubulin assembly
4.  Selective Targeting of the TPX2 Site of Importin-α Using Fragment-Based Ligand Design 
Chemmedchem  2015;10(7):1232-1239.
Protein–protein interactions are difficult therapeutic targets, and inhibiting pathologically relevant interactions without disrupting other essential ones presents an additional challenge. Herein we report how this might be achieved for the potential anticancer target, the TPX2–importin-α interaction. Importin-α is a nuclear transport protein that regulates the spindle assembly protein TPX2. It has two binding sites—major and minor—to which partners bind. Most nuclear transport cargoes use the major site, whereas TPX2 binds principally to the minor site. Fragment-based approaches were used to identify small molecules that bind importin-α, and crystallographic studies identified a lead series that was observed to bind specifically to the minor site, representing the first ligands specific for this site. Structure-guided synthesis informed the elaboration of these fragments to explore the source of ligand selectivity between the minor and major sites. These ligands are starting points for the development of inhibitors of this protein–protein interaction.
doi:10.1002/cmdc.201500014
PMCID: PMC4515083  PMID: 25899172
cancer; fragment-based ligand design; nuclear transporters; protein–protein interactions; structure-guided ligand design
5.  Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases 
Chemmedchem  2015;10(7):1163-1173.
Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease–anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.
doi:10.1002/cmdc.201500131
PMCID: PMC4515084  PMID: 26083237
biginelli reaction; biological activity; elastase inhibitors; proteases; pyrimidinones
6.  Drug Screening Boosted by Hyperpolarized Long-Lived States in NMR 
Chemmedchem  2014;9(11):2509-2515.
Transverse and longitudinal relaxation times (T1ρ and T1) have been widely exploited in NMR to probe the binding of ligands and putative drugs to target proteins. We have shown recently that long-lived states (LLS) can be more sensitive to ligand binding. LLS can be excited if the ligand comprises at least two coupled spins. Herein we broaden the scope of ligand screening by LLS to arbitrary ligands by covalent attachment of a functional group, which comprises a pair of coupled protons that are isolated from neighboring magnetic nuclei. The resulting functionalized ligands have longitudinal relaxation times T1(1H) that are sufficiently long to allow the powerful combination of LLS with dissolution dynamic nuclear polarization (D-DNP). Hyperpolarized weak “spy ligands” can be displaced by high-affinity competitors. Hyperpolarized LLS allow one to decrease both protein and ligand concentrations to micromolar levels and to significantly increase sample throughput.
doi:10.1002/cmdc.201402214
PMCID: PMC4506523  PMID: 25196781
drug discovery; dynamic nuclear polarization; long-lived states; NMR spectroscopy
7.  Synthesis, Anti-tubulin and Antiproliferative SAR of Steroidomimetic Dihydroisoquinolinones 
Chemmedchem  2014;9(4):798-812.
A SAR translation strategy adopted for the discovery of tetrahydroisoquinolinone (THIQ)-based steroidomimetic microtubule disruptors has been extended to dihydroisoquinolinone (DHIQ)-based compounds. A steroid A,B-ring-mimicking DHIQ core was connected to methoxyaryl D-ring mimics through methylene, carbonyl, and sulfonyl linkers, and the resulting compounds were evaluated against two cancer cell lines. The carbonyl-linked DHIQs in particular exhibit significant in vitro antiproliferative activities (e.g., 6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydroisoquinolin-1(2H)-one (16 g): GI50 51 nm in DU-145 cells). The broad anticancer activity of DHIQ 16 g was confirmed in the NCI 60-cell line assay giving a mean activity of 33 nm. Furthermore, 6-hydroxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (16 f) and 16 g and their sulfamate derivatives 17 f and 17 g (2-(3,5-dimethoxybenzoyl)-7-methoxy-6-sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one and 7-methoxy-2-(3,4,5-trimethoxybenzoyl)-6-sulfamoyloxy-3,4-dihydroisoquinolin-1(2H)-one, respectively) show excellent activity against the polymerization of tubulin, close to that of the clinical combretastatin A-4, and bind competitively at the colchicine binding site of tubulin. Compounds 16 f and 17 f were also shown to demonstrate in vitro anti-angiogenic activity. Additionally, X-ray and computational analyses of 17 f reveal that electrostatic repulsion between the two adjacent carbonyl groups, through conformational biasing, dictates the adoption of a “steroid-like” conformation that may partially explain the excellent in vitro activities.
doi:10.1002/cmdc.201400017
PMCID: PMC4506528
colchicine; dihydroisoquinolinones; electrostatic repulsion; microtubules; tubulin
8.  Design, Synthesis and Biological Evaluation of 4-Amino-N-(4-aminophenyl)benzamide Analogues of Quinoline-Based SGI-1027 as Inhibitors of DNA Methylation 
Chemmedchem  2014;9(3):590-601.
Quinoline derivative SGI-1027 (N-(4-(2-amino-6-methylpyrimidin-4-ylamino)phenyl)-4-(quinolin-4-ylamino)benzamide) was first described in 2009 as a potent inhibitor of DNA methyltransferase (DNMT) 1, 3A and 3B. Based on molecular modeling studies, performed using the crystal structure of Haemophilus haemolyticus cytosine-5 DNA methyltransferase (MHhaI C5 DNMT), which suggested that the quinoline and the aminopyridimine moieties of SGI-1027 are important for interaction with the substrates and protein, we designed and synthesized 25 derivatives. Among them, four compounds—namely the derivatives 12, 16, 31 and 32—exhibited activities comparable to that of the parent compound. Further evaluation revealed that these compounds were more potent against human DNMT3A than against human DNMT1 and induced the re-expression of a reporter gene, controlled by a methylated cytomegalovirus (CMV) promoter, in leukemia KG-1 cells. These compounds possessed cytotoxicity against leukemia KG-1 cells in the micromolar range, comparable with the cytotoxicity of the reference compound, SGI-1027. Structure–activity relationships were elucidated from the results. First, the presence of a methylene or carbonyl group to conjugate the quinoline moiety decreased the activity. Second, the size and nature of the aromatic or heterocycle subsitutents effects inhibition activity: tricyclic moieties, such as acridine, were found to decrease activity, while bicyclic substituents, such as quinoline, were well tolerated. The best combination was found to be a bicyclic substituent on one side of the compound, and a one-ring moiety on the other side. Finally, the orientation of the central amide bond was found to have little effect on the biological activity. This study provides new insights in to the structure–activity relationships of SGI-1027 and its derivative.
doi:10.1002/cmdc.201300420
PMCID: PMC4506529  PMID: 24678024
cytotoxicity; DNA methyltransferases; epigenetics; gene re-expression; inhibitors
9.  Small-Molecule Inhibitors That Target Protein–Protein Interactions in the RAD51 Family of Recombinases 
Chemmedchem  2014;10(2):296-303.
The development of small molecules that inhibit protein–protein interactions continues to be a challenge in chemical biology and drug discovery. Herein we report the development of indole-based fragments that bind in a shallow surface pocket of a humanised surrogate of RAD51. RAD51 is an ATP-dependent recombinase that plays a key role in the repair of double-strand DNA breaks. It both self-associates, forming filament structures with DNA, and interacts with the BRCA2 protein through a common “FxxA” tetrapeptide motif. We elaborated previously identified fragment hits that target the FxxA motif site and developed small-molecule inhibitors that are approximately 500-fold more potent than the initial fragments. The lead compounds were shown to compete with the BRCA2-derived Ac-FHTA-NH2 peptide and the self-association peptide of RAD51, but they had no effect on ATP binding. This study is the first reported elaboration of small-molecular-weight fragments against this challenging target.
doi:10.1002/cmdc.201402428
PMCID: PMC4506530  PMID: 25470112
biophysics; BRCA2; homologous recombination; inhibitors; protein–protein interactions; RAD51
10.  Merging Allosteric and Active Site Binding Motifs: De novo Generation of Target Selectivity and Potency via Natural-Product-Derived Fragments 
Chemmedchem  2014;10(3):451-454.
The de novo design of molecules from scratch with tailored biological activity is still the major intellectual challenge in chemical biology and drug discovery. Herein we validate natural-product-derived fragments (NPDFs) as excellent molecular seeds for the targeted de novo discovery of lead structures for the modulation of therapeutically relevant proteins. The application of this de novo approach delivered, in synergy with the combination of allosteric and active site binding motifs, highly selective and ligand-efficient non-zinc-binding (3: 4-{[5-(2-{[(3-methoxyphenyl)methyl]carbamoyl}eth-1-yn-1-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl]methyl}benzoic acid) as well as zinc-binding (4: 4-({5-[2-({[3-(3-carboxypropoxy)phenyl]methyl}carbamoyl)eth-1-yn-1-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}methyl)benzoic acid) uracil-based MMP-13 inhibitors presenting IC50 values of 11 nm (3: LE=0.35) and 6 nm (4: LE=0.31).
doi:10.1002/cmdc.201402478
PMCID: PMC4506557  PMID: 25487909
de novo drug design; enzyme inhibitors; fragment-based drug discovery; natural products; structure–activity relationships; water-mediated interactions
11.  Comparative Cytotoxicity of Artemisinin and Cisplatin and Their Interactions with Chlorogenic Acids in MCF7 Breast Cancer Cells 
Chemmedchem  2014;9(12):2791-2797.
In parts of Africa and Asia, self-medication with a hot water infusion of Artemisia annua (Artemisia tea) is a common practice for a number of ailments including malaria and cancer. In our earlier work, such an extract showed better potency than artemisinin alone against both chloroquine-sensitive and -resistant parasites. In this study, in vitro tests of the infusion in MCF7 cells showed high IC50 values (>200 μm). The combination of artemisinin and 3-caffeoylquinic acid (3CA), two major components in the extract, was strongly antagonistic and gave a near total loss of cytotoxicity for artemisinin. We observed that the interaction of 3CAs with another cytotoxic compound, cisplatin, showed potentiation of activity by 2.5-fold. The chelation of cellular iron by 3CA is hypothesized as a possible explanation for the loss of artemisinin activity.
doi:10.1002/cmdc.201402285
PMCID: PMC4506560  PMID: 25209896
antagonism; Artemisia tea; artemisinin; chlorogenic acid; cisplatin; synergy
12.  Crystal Structure of Human Soluble Adenylate Cyclase Reveals a Distinct, Highly Flexible Allosteric Bicarbonate Binding Pocket 
Chemmedchem  2014;9(4):823-832.
Soluble adenylate cyclases catalyse the synthesis of the second messenger cAMP through the cyclisation of ATP and are the only known enzymes to be directly activated by bicarbonate. Here, we report the first crystal structure of the human enzyme that reveals a pseudosymmetrical arrangement of two catalytic domains to produce a single competent active site and a novel discrete bicarbonate binding pocket. Crystal structures of the apo protein, the protein in complex with α,β-methylene adenosine 5′-triphosphate (AMPCPP) and calcium, with the allosteric activator bicarbonate, and also with a number of inhibitors identified using fragment screening, all show a flexible active site that undergoes significant conformational changes on binding of ligands. The resulting nanomolar-potent inhibitors that were developed bind at both the substrate binding pocket and the allosteric site, and can be used as chemical probes to further elucidate the function of this protein.
doi:10.1002/cmdc.201300480
PMCID: PMC4506562  PMID: 24616449
allosterism; drug discovery; enzyme regulation; fragment screening; structural biology
13.  Targeting a Dynamic Protein–Protein Interaction: Fragment Screening against the Malaria Myosin A Motor Complex 
Chemmedchem  2014;10(1):134-143.
Motility is a vital feature of the complex life cycle of Plasmodium falciparum, the apicomplexan parasite that causes human malaria. Processes such as host cell invasion are thought to be powered by a conserved actomyosin motor (containing myosin A or myoA), correct localization of which is dependent on a tight interaction with myosin A tail domain interacting protein (MTIP) at the inner membrane of the parasite. Although disruption of this protein–protein interaction represents an attractive means to investigate the putative roles of myoA-based motility and to inhibit the parasitic life cycle, no small molecules have been identified that bind to MTIP. Furthermore, it has not been possible to obtain a crystal structure of the free protein, which is highly dynamic and unstable in the absence of its natural myoA tail partner. Herein we report the de novo identification of the first molecules that bind to and stabilize MTIP via a fragment-based, integrated biophysical approach and structural investigations to examine the binding modes of hit compounds. The challenges of targeting such a dynamic system with traditional fragment screening workflows are addressed throughout.
doi:10.1002/cmdc.201402357
PMCID: PMC4506568  PMID: 25367834
differential scanning fluorimetry; fragment screening; malaria; myosins; NMR; protein–protein interactions
14.  A Cell-Permeable Ester Derivative of the JmjC Histone Demethylase Inhibitor IOX1 
Chemmedchem  2014;9(3):566-571.
The 2-oxoglutarate (2OG)-dependent Jumonji C domain (JmjC) family is the largest family of histone lysine demethylases. There is interest in developing small-molecule probes that modulate JmjC activity to investigate their biological roles. 5-Carboxy-8-hydroxyquinoline (IOX1) is the most potent broad-spectrum inhibitor of 2OG oxygenases, including the JmjC demethylases, reported to date; however, it suffers from low cell permeability. Here, we describe structure–activity relationship studies leading to the discovery of an n-octyl ester form of IOX1 with improved cellular potency (EC50 value of 100 to 4 μm). These findings are supported by in vitro inhibition and selectivity studies, docking studies, activity versus toxicity analysis in cell cultures, and intracellular uptake measurements. The n-octyl ester was found to have improved cell permeability; it was found to inhibit some JmjC demethylases in its intact ester form and to be more selective than IOX1. The n-octyl ester of IOX1 should find utility as a starting point for the development of JmjC inhibitors and as a use as a cell-permeable tool compound for studies investigating the roles of 2OG oxygenases in epigenetic regulation.
doi:10.1002/cmdc.201300428
PMCID: PMC4503230  PMID: 24504543
2-oxoglutarate (2OG) oxygenases; cell permeability; epigenetics; inhibitors; jmjc histone demethylases; structure–activity relationships
15.  Development and screening of a series of antibody-conjugated and silica coated iron-oxide nanoparticles for targeting the Prostate Specific Membrane Antigen 
ChemMedChem  2014;9(7):1356-1360.
The Prostate Specific Membrane Antigen (PSMA) is an established target for the delivery of cancer therapeutic and imaging agents due to its high expression on the surface of prostate cancer cells and within the neovasculature of other solid tumors. Here we describe the synthesis and screening of antibody-conjugated silica-coated iron oxide nanoparticles for PSMA-specific cell targeting. The humanized anti-PSMA antibody, HuJ591, was conjugated to a series of nanoparticles with varying densities of polyethylene glycol and primary amine groups. Customized assays utilizing iron spectral absorbance and Enzyme-Linked Immunoassay (ELISA) were developed to screen microgram quantities of nanoparticle formulations for immunoreactivity and cell targeting ability. Antibody and PSMA-specific targeting of the optimized nanoparticle was evaluated using an isogenic PSMA-positive and PSMA-negative cell line pair. Specific nanoparticle targeting was confirmed by iron quantification with inductively coupled plasma mass spectrometry (ICP-MS). These methods and nanoparticles support the promise of targeted theranostic agents for future treatment of prostate and other cancers.
doi:10.1002/cmdc.201300549
PMCID: PMC4082462  PMID: 24591351
Nanoparticle; PSMA; Iron-oxide; cancer; targeting
16.  Design, Synthesis and Bio-evaluation of an EphA2-based Targeted Delivery System 
ChemMedChem  2014;9(7):1403-1412.
We recently described a new targeted delivery system based on specific EphA2 receptor targeting peptides conjugated with the chemotherapeutic agent paclitaxel. In this manuscript we investigate the chemical determinants responsible for the stability and degradation of these agents in plasma. Introducing modifications in both the peptide and the linker between the peptide and paclitaxel, resulted in drug conjugates that are both long-lived in rat plasma and that markedly reduced tumor size in a prostate cancer xenograft model compared to paclitaxel alone treatment. These studies identify critical rate-limiting degradation sites on the peptide-drug conjugates, enabling the design of agents with increased stability and efficacy. These results provide support for our central hypothesis that peptide-drug conjugates targeting the EphA2 receptor represent an innovative and potentially effective strategy to selectively deliver cytotoxic drugs to cancer cells.
doi:10.1002/cmdc.201400067
PMCID: PMC4082471  PMID: 24677792
Targeted delivery; drug discovery; EphA2; ephrin; chemotherapy
17.  Optimization of antiviral potency and lipophilicity of halogenated 2,6-diarylpyridinamines (DAPAs) as a novel class of HIV-1 NNRTIs 
ChemMedChem  2014;9(7):1546-1555.
Nineteen new halogenated diarylpyridinamine (DAPA) analogues (6a-n and 8a-e) modified on the phenoxy C-ring were synthesized and evaluated for anti-HIV activity and certain drug-like properties. Ten compounds showed high anti-HIV activity (EC50 < 10 nM). Particularly, (E)-6-(2”-bromo-4”-cyanovinyl-6“-methoxy)phenoxy-N2-(4′-cyanophenyl)pyridin-2,3-diamine (8c) displayed low nanomolar antiviral potency (3–7 nM) against wild-type and resistant viral strains with E138K or K101E mutation, associated with resistance to rilvipirine (1b). Compound 8c exhibited much lower resistance fold changes (RFC 1.1–2.1) than 1b (RFC 11.8–13.0). Compound 8c also exhibited better metabolic stability (in vitro half-life) than 1b in human liver microsomes (HLM), possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE > 0.3, LLE >5, LELP <10). With balanced potency and drug-like properties, 8c merits further development as an anti-HIV drug candidate.
doi:10.1002/cmdc.201400075
PMCID: PMC4085996  PMID: 24895029
anti-HIV activity; antiviral agents; diarylpyridinamine; drug-like properties; lipophiliicity
18.  Efficient Acid-catalyzed 18F/19F Fluoride Exchange of BODIPY Dyes 
ChemMedChem  2014;9(7):1368-1373.
Fluorine containing fluorochromes represent important validation agents for PET imaging agents as they can be easily rapidly validated in cells by fluorescence imaging. In particular, the 18F-labeled BODIPY-FL fluorophore has emerged as an important platform but little is known about alternative 18F-labeling strategies or labeling on red shifted fluorophores. Here we explore the acid-catalyzed 18F/19F exchange on a range of commercially available N-hydroxysuccinimidyl ester and maleimide BODIPY fluorophores. We show this method to be a simple and efficient 18F-labeling strategy for a diverse span of fluorescent compounds, including a BODIPY modified PARP-1 inhibitor, and amine- and thiol-reactive BODIPY fluorophores.
doi:10.1002/cmdc.201300506
PMCID: PMC4145401  PMID: 24596307
18F-Fluorine; Molecular Imaging; BODIPY; Fluorescence; Positron emission tomography (PET)
19.  3–Aminoazetidin–2–one Derivatives as N–Acylethanolamine Acid Amidase (NAAA) Inhibitors Suitable for Systemic Administration 
ChemMedChem  2014;9(7):1602-1614.
N Acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that catalyzes the hydrolysis of endogenous lipid mediators such as palmitoylethanolamide (PEA). PEA has been shown to exert anti–inflammatory and antinociceptive effects in animals by engaging peroxisome proliferator–activated receptor–α (PPAR–α). Thus preventing PEA degradation by inhibiting NAAA may provide a novel approach for the treatment of pain and inflammatory states. Recently, 3–aminooxetan–2–one compounds were identified as a class of highly potent NAAA inhibitors. The utility of these compounds is limited, however, by their low chemical and plasma stabilities. In the present study, we synthesized and tested a series of N–(2–oxoazetidin–3–yl)amides as a novel class of NAAA inhibitors with good potency and improved physicochemical properties, suitable for systemic administration. Moreover, we elucidated the main structural features of 3–aminoazetidin–2–one derivatives that are critical for NAAA inhibition.
doi:10.1002/cmdc.201300546
PMCID: PMC4224963  PMID: 24828120
β-lactams; NAAA; inhibitors; stability; structure-activity relationship
20.  Suppression of Problematic Compound Oligomerization by Cosolubilization of Nondetergent Sulfobetaines 
Chemmedchem  2015;10(4):736-741.
Numerous small organic compounds exist in equilibrium among monomers, soluble oligomers, and insoluble aggregates in aqueous solution. Compound aggregation is a major reason for false positives in drug screening, and even soluble oligomers can interfere with structural and biochemical analyses. However, an efficient way to manage the equilibrium of aggregation-prone compounds, especially those involved with soluble oligomers, has not been established. In this study, solution NMR spectroscopy was used as a suitable technique to detect compound oligomers in equilibrium, and it was demonstrated that cosolubilization of nondetergent sulfobetaines (NDSBs) can largely suppress compound oligomerization and aggregation by shifting the equilibrium toward the monomers. The rotational correlation time was obtained from the ratio of the selective and nonselective longitudinal NMR relaxation times, which directly and quantitatively reflected the apparent sizes of the compounds in the equilibrium. The rotational correlation time of the aggregation-prone compound SKF86002 (1 mm) was substantially reduced from 0.31 to 0.23 ns by cosolubilization of 100 mm NDSB195. NDSB cosolubilization allowed us to perform successful structural and biochemical experiments with substantially fewer artifacts, which represents a strategy to directly resolve the problematic oligomerization and aggregation of compounds.
doi:10.1002/cmdc.201500057
PMCID: PMC4471626  PMID: 25760302
artifacts; drug discovery; NMR spectroscopy; nondetergent sulfobetaines; oligomerization
21.  Bioisosteric Matrices for Ligands of Serotonin Receptors 
Chemmedchem  2015;10(4):601-605.
The concept of bioisosteric replacement matrices is applied to explore the chemical space of serotonin receptor ligands, aiming to determine the most efficient ways of manipulating the affinity for all 5-HT receptor subtypes. Analysis of a collection of over 1 million bioisosteres of compounds with measured activity towards serotonin receptors revealed that an average of 31 % of the ligands for each target are mutual bioisosteres. In addition, the collected dataset allowed the development of bioisosteric matrices—qualitative and quantitative descriptions of the biological effects of each predefined type of bioisosteric substitution, providing favored paths of modifying the compounds. The concept exemplified here for serotonin receptor ligands can likely be more broadly applied to other target classes, thus representing a useful guide for medicinal chemists designing novel ligands.
doi:10.1002/cmdc.201402563
PMCID: PMC4471634  PMID: 25772514
bioisosterism; bioisosteric matrices; bioisosteric substitutions; chemical space; serotonin receptors
22.  Inhibition of Cathepsin Activity in a Cell-Based Assay by a Light-Activated Ruthenium Compound 
ChemMedChem  2014;9(6):1306-1315.
Light-activated inhibition of cathepsin activity was demonstrated with in a cell-based assay. Inhibitors of cathepsin K, Cbz-Leu-NHCH2CN (2) and Cbz-Leu-Ser(OBn)-CN (3), were caged within the complexes cis-[Ru(bpy)2(2)2]Cl2 (4) and cis-[Ru(bpy)2(3)2](BF4)2 (5), where bpy = 2,2′-bipyridine, as 1:1 mixtures of Δ- and Λ stereoisomers. Complexes 4 and 5 were characterized by 1H NMR, IR and UV-vis spectroscopies and electrospray mass spectrometry. Photochemical experiments confirm that 4 releases two molecules of 2 upon exposure to visible light for 15 min, whereas release of 3 by 5 requires longer irradiation times. IC50 determinations against purified cathepsin K under light and dark conditions with 4 and 5 confirm that inhibition is enhanced from 35 to 88-fold, respectively, upon irradiation with visible light. No apparent toxicity was observed for 4 in the absence or presence of irradiation in bone marrow macrophage (BMM) or PC-3 cells, as judged by the MTT assay, at concentrations up to 10 μM. Compound 5 is well tolerated at lower concentrations (<1 μM) but does show growth inhibitory effects at higher concentrations. Confocal microscopy experiments show that 4 reduces intracellular cathepsin activity in osteoclasts with light activation. These results support further development of caged nitrile-based inhibitors as chemical tools for investigating spatial aspects of proteolysis within living systems.
doi:10.1002/cmdc.201400081
PMCID: PMC4095795  PMID: 24729544
cathepsin; enzymes; inhibitors; photochemistry; ruthenium
23.  Platinum compounds for high-resolution in vivo cancer imaging 
ChemMedChem  2014;9(6):1131-1135.
Platinum(II) compounds, principally cisplatin and carboplatin, are commonly used front-line cancer therapeutics. Despite widespread use and the interest of developing new derivatives, including nanoformulations with improved properties, it has been difficult to visualize Pt compounds in live subjects, in real-time, and with subcellular resolution. Here we present four novel cisplatin- and carboplatin-derived fluorescent imaging compounds for quantitative intravital cancer imaging. We conjugate boron dipyromethene FL (BODIPY-FL) to PtII complexes for robust in vivo fluorescence, and show retained DNA-damaging and cytotoxic properties. We image pharmacokinetics and tumor uptake in a xenograft cancer mouse model. Finally, we present a genetic reporter of single-cell DNA damage for in vivo imaging, and simultaneously monitor Pt drug accumulation and resultant DNA damage in individual tumor cells, at subcellular resolution, and in real-time in a live animal model of cancer.
doi:10.1002/cmdc.201300502
PMCID: PMC4037345  PMID: 24504646
intravital imagingagents; pharmacology; fluorescent probes; DNA damage; pharmacokinetics
24.  Insights into the Recognition, Binding and Reactivity of Catalytic Metallodrugs Targeting Stem Loop IIb of Hepatitis C IRES RNA 
ChemMedChem  2014;9(6):1275-1285.
Complex Cu-GGHYrFK-amide (1-Cu) was previously reported as a novel metallotherapeutic that catalytically inactivates stem loop IIb of the Hepatitis C Virus (HCV) Internal Ribosomal Entry Site (IRES) RNA and demonstrates significant antiviral activity in a cellular HCV replicon assay. Herein are described additional studies focused on understanding the cleavage mechanism, as well as the relationship of catalyst configuration to structural recognition and site-selective cleavage of the structured RNA motif. These are advanced by use of a combination of MALDI-TOF mass spectrometry, melting temperature determination, and computational analysis to develop a structural model for binding and reactivity toward SLIIb of the IRES RNA. In addition, the binding, reactivity, and structural chemistry of the all d-amino acid form of this metallopeptide, complex 2-Cu, is reported and compared to complex 1-Cu. In vitro RNA binding and cleavage assays for complex 2-Cu show a KD of 76 ± 3 nM, and Michaelis-Menten parameters of kcat of 0.14 ± 0.01 min−1 and KM of 7.9 ± 1.2 µM, with a turnover number exceeding 40. In a luciferase-based cellular replicon assay Cu-GGhyrfk-amide shows activity similar to the parent peptide, complex 1-Cu, with IC50 of 1.9 ± 0.4 µM and cytotoxicity exceeding 100 µM. RT-PCR experiments confirm a significant reduction in HCV RNA levels in replicon assays for up to nine days when treated with complex 1-Cu in three day dosing increments. This study shows the influence that the α-carbon stereocenter has for this the new class of compounds, while detailed mass spectrometry and computational analysis provide new insights into the mechanisms of recognition, binding, and reactivity.
doi:10.1002/cmdc.201400070
PMCID: PMC4163017  PMID: 24756921
HCV IRES RNA; copper ATCUN motif; RNA cleavage; stem-loop; catalytic; metallodrug
25.  Conjugates of Cisplatin and Cyclooxygenase Inhibitors as Potent Antitumor Agents Overcoming Cisplatin Resistance** 
ChemMedChem  2014;9(6):1150-1153.
Cyclooxygenase-2 (COX-2) is an enzyme involved in tumorigenesis, and inhibitors of the enzyme are increasingly used as adjuvant modulators in anticancer therapies due to their synergistic effects. The enzyme is also reported to cause resistance against antitumor agents, such as cisplatin. Here we report the first covalently linked conjugates of cisplatin and COX inhibitors, which allow concerted transport of both drugs into tumor cells and simultaneous action on intracellular cleavage. These platinum(IV) complexes show highly increased cytotoxicity compared to cisplatin and are even able to overcome cisplatin-related resistance of tumor cells. Furthermore, the conjugates provide tools for the elucidation of the influence of COX inhibitors on the efficacy of antitumor agents.
doi:10.1002/cmdc.201402074
PMCID: PMC4136547  PMID: 24801194
antitumor agents; cyclooxygenase inhibitors; drug delivery; drug design; prodrugs

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