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1.  Anti-tumor agent calixarene 0118 targets human galectin-1 as an allosteric inhibitor of carbohydrate binding 
Journal of medicinal chemistry  2012;55(11):5121-5129.
Calix[4]arene compound 0118 is an angiostatic agent that inhibits tumor growth in mice. Although 0118 is a topomimetic of galectin-1-targeting angiostatic amphipathic peptide anginex, we had yet to prove that 0118 targets galectin-1. Galectin-1 is involved in pathological disorders like tumor endothelial cell adhesion and migration and therefore presents a relevant target for therapeutic intervention against cancer. Here, 15N-1H HSQC NMR spectroscopy demonstrates that 0118 indeed targets galectin-1 at a site away from the lectin’s carbohydrate binding site, and thereby attenuates lactose binding to the lectin. Flow cytometry and agglutination assays show that 0118 attenuates binding of galectin-1 to cell surface glycans, and the inhibition of cell proliferation by 0118 is found to be correlated with the cellular expression of the lectin. In general, our data indicate that 0118 targets galectin-1 as an allosteric inhibitor of glycan/carbohydrate binding. This work contributes to the clinical development of anti-tumor calixarene compound 0118.
doi:10.1021/jm300014q
PMCID: PMC4242090  PMID: 22575017
NMR; protein; lectin; glycan; galactose
2.  Synthesis and Biological Evaluation of 1-Arylsulfonyl-5-(N-hydroxyacrylamide)indoles as Potent Histone Deacetylase Inhibitors with Antitumor Activity in Vivo 
Journal of medicinal chemistry  2012;55(8):3777-3791.
A series of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indoles has been identified as a new class of histone deacetylase inhibitors. Compounds 8, 11, 12, 13, and 14 demonstrated stronger antiproliferative activities than 1 (SAHA) with GI50 values ranging from 0.36 to 1.21 μM against Hep3B, MDA-MB-231, PC-3, and A549 human cancer cell lines. Lead compound 8 showed remarkable HDAC 1, 2, and 6 isoenzymes inhibitory activities with IC50 values of 12.3, 4.0, 1.0 nM, respectively, which are comparable to 1. In in vivo efficacy evaluation against lung A549 xenograft model, 8 displayed better antitumor activity than compound 1.
doi:10.1021/jm300197a
PMCID: PMC4201585  PMID: 22439863
3.  Novel cGMP efflux inhibitors – Identified by virtual ligand screening (VLS) and confirmed by experimental studies 
Journal of medicinal chemistry  2012;55(7):3049-3057.
Elevated intracellular levels of cyclic guanosine monophosphate (cGMP) may induce apoptosis, and at least some cancer cells seem to escape this effect by increased efflux of cGMP, as clinical studies have shown that extracellular cGMP levels are elevated in various types of cancer. The human ATP binding cassette (ABC) transporter ABCC5 transports cGMP out of cells, and inhibition of ABCC5 may have cytotoxic effects. Sildenafil inhibits cGMP efflux by binding to ABCC5, and in order to search for potential novel ABCC5 inhibitors, we have identified sildenafil derivates using structural and computational guidance and tested them for the cGMP efflux effect. Eleven compounds from virtual ligand screening (VLS) were tested in vitro, using inside-out vesicles (IOV), for inhibition of cGMP efflux. 7 of 11 compounds predicted by VLS to bind to ABCC5 were more potent than sildenafil, and the two most potent showed Ki-values of 50 #x02013;100 nM.
doi:10.1021/jm2014666
PMCID: PMC4181661  PMID: 22380603
4.  Pharmacophore-Based Virtual Screening and Biological Evaluation of Small Molecule Inhibitors for Protein Arginine Methylation 
Journal of medicinal chemistry  2012;55(18):7978-7987.
Protein arginine methyltransferases (PRMTs) are proved to play vital roles in chromatin remodeling, RNA metabolism and signal transduction. Aberrant regulation of PRMT activity is associated with various pathological states such as cancer and cardiovascular disorders. Development and application of small molecule PRMT inhibitors will provide new avenues for therapeutic discovery. We combined pharmacophore-based virtual screening methods with radioactive methylation assays, six hits were identified as inhibitors against the predominant arginine methyltransferase PRMT1 within micromolar potency. Two potent compounds, A9 and A36, exhibitting the inhibitory effect by directly targeting substrate H4 other than PRMT1 and displayed even higher inhibition activity than the well-known PRMT inhibitors AMI-1 and stilbamidine. A9 significantly inhibits proliferation of castrate-resistant prostate cancer cells. Together, A9 may be a potential inhibitor against advanced hormone-independent cancers and the work will provide clues for the future development of specific compounds that block the interaction of PRMTs with their targets.
doi:10.1021/jm300521m
PMCID: PMC4150255  PMID: 22928876
arginine methylation; PRMT1; inhibitor; pharmacophore; virtual screening
5.  Chemical Proteomics-Based Analysis of Off-target Binding Profiles for Rosiglitazone and Pioglitazone: Clues for Assessing Potential for Cardiotoxicity 
Journal of medicinal chemistry  2012;55(19):8260-8271.
Drugs typically exert desired and undesired biological effects by virtue of binding interactions with protein target(s) and off-target(s), providing evidence for drug efficacy and toxicity. Pioglitazone and rosiglitazone possess a common functional core, glitazone, which is considered a privileged scaffold upon which to build a drug selective for a given target – in this case PPARγ. Herein, we report a retrospective analysis of two variants of the glitazone scaffold, pioglitazone and rosiglitazone, in an effort to identify off-target binding events in the rat heart to explain recently reported cardiovascular risk associated with the drugs. Our results suggest glitazone has affinity for dehydrogenases, consistent with known binding preferences for related rhodanine cores. Both drugs bound ion channels and modulators, with implications in congestive heart failure, arrhythmia, and peripheral edema. Additional proteins involved in glucose homeostasis, synaptic transduction, and mitochondrial energy production were detected and potentially contribute to drug efficacy and cardiotoxicity.
doi:10.1021/jm301204r
PMCID: PMC4113394  PMID: 22970990
Peroxisome proliferator-activated receptor; thiazolidinediones; rosiglitazone; pioglitazone; glitazone
6.  A New Positron Emission Tomography (PET) Radioligand for Imaging Sigma-1 Receptors in Living Subjects 
Journal of medicinal chemistry  2012;55(19):8272-8282.
Sigma-1 receptor (S1R) radioligands have the potential to detect and monitor various neurological diseases. Herein we report the synthesis, radiofluorination and evaluation of a new S1R ligand 6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ([18F]FTC-146, [18F]13). [18F]13 was synthesized by nucleophilic fluorination, affording a product with >99% radiochemical purity (RCP) and specific activity (SA) of 2.6 ± 1.2 Ci/Amol (n = 13) at end of synthesis (EOS). Positron emission tomography (PET) and ex vivo autoradiography studies of [18F]13 in mice showed high uptake of the radioligand in S1R rich regions of the brain. Pre treatment with 1 mg/kg haloperidol (2), non radioactive 13, or BD1047 (18) reduced the binding of [18F]13 in the brain at 60 min by 80%, 82% and 81% respectively, suggesting that [18F]13 accumulation in mouse brain represents specific binding to S1Rs. These results indicate that [18F]13 is a promising candidate radiotracer for further evaluation as a tool for studying S1Rs in living subjects.
doi:10.1021/jm300371c
PMCID: PMC4106900  PMID: 22853801
7.  A Synthetic Chalcone as a Potent Inducer of Glutathione Biosynthesis 
Journal of medicinal chemistry  2012;55(3):1382-1388.
Chalcones continue to attract considerable interest due to their anti-inflammatory and antiangiogenic properties. We recently reported the ability of 2′,5′-dihydroxychalcone (2′,5′-DHC) to induce both breast cancer resistance protein-mediated export of glutathione (GSH) and c-Jun N-terminal kinase-mediated increased intracellular GSH levels. Herein, we report a structure–activity relationship study of a series of 30 synthetic chalcone derivatives with hydroxyl, methoxyl, and halogen (F and Cl) substituents and their ability to increase intracellular GSH levels. This effect was drastically improved with one or two electrowithdrawing groups on phenyl ring B and up to three methoxyl and/or hydroxyl groups on phenyl ring A. The optimal structure, 2-chloro-4′,6′-dimethoxy-2′-hydroxychalcone, induced both a potent NF-E2-related factor 2-mediated transcriptional response and an increased formation of glutamate cysteine ligase holoenzyme, as shown using a human breast cancer cell line stably expressing a luciferase reporter gene driven by antioxidant response elements.
doi:10.1021/jm2016073
PMCID: PMC4026013  PMID: 22239485
8.  Unsymmetric Mono- and Dinuclear Platinum(IV) Complexes Featuring an Ethylene Glycol Moiety: Synthesis, Characterization, and Biological Activity 
Journal of medicinal chemistry  2012;55(24):11052-11061.
Eight novel mononuclear and two dinuclear platinum(IV) complexes were synthesized and characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, mass spectrometry, and reversed-phase HPLC (log kw) and in one case by X-ray diffraction. Cytotoxicity of the compounds was studied in three human cancer cell lines (CH1, SW480, and A549) by means of the MTT assay, featuring IC50 values to the low micromolar range. Furthermore a selected set of compounds was investigated in additional cancer cell lines (P31 and P31/cis, A2780 and A2780/cis, SW1573, 2R120, and 2R160) with regard to their resistance patterns, offering a distinctly different scheme compared to cisplatin. To gain further insights into the mode of action, drug uptake, DNA synthesis inhibition, cell cycle effects, and induction of apoptosis were determined for two characteristic substances.
doi:10.1021/jm301645g
PMCID: PMC4021451  PMID: 23194425
9.  Investigation of Chalcones as Selective Inhibitors of the Breast Cancer Resistance Protein: Critical Role of Methoxylation in both Inhibition Potency and Cytotoxicity 
Journal of medicinal chemistry  2012;55(7):3193-3200.
ABCG2 plays a major role in anticancer-drug efflux and related tumor multidrug resistance. Potent and selective ABCG2 inhibitors with low cytotoxicity were investigated among a series of 44 chalcones and analogues (1,3-diarylpropenones), by evaluating their inhibitory effect on the transport of mitoxantrone, a known ABCG2 substrate. Six compounds producing complete inhibition with IC50 values below 0.5 µM and high selectivity for ABCG2 were identified. The number and position of methoxy substituents appeared to be critical for both inhibition and cytotoxicity. The best compounds, with potent inhibition and low toxicity, contained an N-methyl-1-indolyl (compound 38) or a 6′-hydroxyl-2′,4′-dimethoxy-1-phenyl (compound 27) moiety (A-ring) and two methoxy groups at positions 2 and 6 of the 3-phenyl moiety (B-ring). Methoxy substitution contributed to inhibition at positions 3 and 5, but had a negative effect at position 4. Finally, methoxy groups at positions 3, 4, and 5 of the B-ring markedly increased cytotoxicity and, therefore, should be avoided.
doi:10.1021/jm2016528
PMCID: PMC3983950  PMID: 22449016
10.  A Bactericidal Guanidinomethyl Biaryl That Alters the Dynamics of Bacterial FtsZ Polymerization 
Journal of medicinal chemistry  2012;55(22):10160-10176.
The prevalence of multidrug resistance among clinically significant bacterial pathogens underscores a critical need for the development of new classes of antibiotics with novel mechanisms of action. Here we describe the synthesis and evaluation of a guanidinomethyl biaryl compound {1-((4′-(tert-butyl)-[1,1′-biphenyl]-3-yl)methyl)guanidine} that targets the bacterial cell division protein FtsZ. In vitro studies with various bacterial FtsZ proteins reveal that the compound alters the dynamics of FtsZ self-polymerization via a stimulatory mechanism, while minimally impacting the polymerization of tubulin, the closest mammalian homologue of FtsZ. The FtsZ binding site of the compound is identified through a combination of computational and mutational approaches. The compound exhibits a broad spectrum of bactericidal activity, including activity against the multidrug-resistant pathogens methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), while also exhibiting a minimal potential to induce resistance. Taken together, our results highlight the compound as a promising new FtsZ-targeting bactericidal agent.
doi:10.1021/jm3012728
PMCID: PMC3969268  PMID: 23050700
11.  Lead Discovery, Chemistry Optimization, and Biological Evaluation Studies of Novel Biamide Derivatives as CB2 Receptor Inverse Agonists and Osteoclast Inhibitors 
Journal of medicinal chemistry  2012;55(22):9973-9987.
N,N′-((4-(Dimethylamino)phenyl)methylene)bis(2-phenylacetamide) was discovered by using 3D pharmacophore database searches and was biologically confirmed as a new class of CB2 inverse agonists. Subsequently, 52 derivatives were designed and synthesized through lead chemistry optimization by modifying the rings A–C and the core structure in further SAR studies. Five compounds were developed and also confirmed as CB2 inverse agonists with the highest CB2 binding affinity (CB2 Ki of 22–85 nM, EC50 of 4–28 nM) and best selectivity (CB1/CB2 of 235- to 909-fold). Furthermore, osteoclastogenesis bioassay indicated that PAM compounds showed great inhibition of osteoclast formation. Especially, compound 26 showed 72% inhibition activity even at the low concentration of 0.1 µM. The cytotoxicity assay suggested that the inhibition of PAM compounds on osteoclastogenesis did not result from its cytotoxicity. Therefore, these PAM derivatives could be used as potential leads for the development of a new type of antiosteoporosis agent.
doi:10.1021/jm301212u
PMCID: PMC3967745  PMID: 23072339
12.  Design of potent and selective hybrid inhibitors of the mitotic kinase Nek2: SAR, structural biology and cellular activity 
Journal of medicinal chemistry  2012;55(7):3228-3241.
We report herein a series of Nek2 inhibitors based on an aminopyridine scaffold. These compounds have been designed by combining key elements of two previously discovered chemical series. Structure based design led to aminopyridine (R )-21, a potent and selective inhibitor able to modulate Nek2 activity in cells.
doi:10.1021/jm201683b
PMCID: PMC3935458  PMID: 22404346
13.  A Remarkable Series of Vinblastine Analogues Displaying Enhanced Activity and an Unprecedented Tubulin Binding Steric Tolerance: C20' Urea Derivatives 
Journal of medicinal chemistry  2012;56(3):628-639.
A systematic series of previously inaccessible key C20' urea and thiourea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH4-mediated alkene functionalization reaction of anhydrovinblastine. Their examination defined key structural features of the urea-based analogues that contribute to their properties and provided derivatives that match or exceed the potency of vinblastine by as much as 10-fold in cell-based functional assays, which is directly related to their relative tubulin binding affinity. In contrast to expectations based on apparent steric constraints of the tubulin binding site surrounding the vinblastine C20' center depicted in an x-ray co-crystal structure, remarkably large C20' urea derivatives are accommodated.
doi:10.1021/jm3015684
PMCID: PMC3574233  PMID: 23244701
14.  Synthesis and Biological Evaluation of Indenoisoquinolines that Inhibit both Tyrosyl-DNA-Phosphodiesterase I (Tdp1) and Topoisomerase I (Top1) 
Journal of medicinal chemistry  2012;56(1):182-200.
Tyrosyl-DNA-phosphodiesterase I (Tdp1) plays a key role in the repair of damaged DNA resulting from the topoisomerase I (Top1) inhibitor camptothecin and a variety of other DNA-damaging anticancer agents. This report documents the design, synthesis, and evaluation of new indenoisoquinolines that are dual inhibitors of both Tdp1 and Top1. Enzyme inhibitory data and cytotoxicity data from human cancer cell cultures were used to establish structure-activity relationship. The potencies of the indenoisoquinolines against Tdp1 ranged from 5 μM to 111 μM, which places the more active compounds among the most potent known inhibitors of this target. The cytotoxicity mean-graph midpoints ranged from 0.02 to 2.34 μM. Dual Tdp1-Top1 inhibitors are of interest because the Top1 and Tdp1 inhibitory activities could theoretically work synergistically to create more effective anticancer agents.
doi:10.1021/jm3014458
PMCID: PMC3542538  PMID: 23259865
15.  Peptide-conjugated pterins as inhibitors of Ricin Toxin A 
Journal of medicinal chemistry  2012;56(1):320-329.
Several 7-peptide-substituted pterins were synthesized and tested as competitive active-site inhibitors of Ricin Toxin A (RTA). Focus began on dipeptide conjugates, and these results further guided the construction of several tripeptide conjugates. The binding of these compounds to RTA was studied via a luminescence-based kinetic assay, as well as through X-ray crystallography. Despite the relatively polar, solvent exposed active site, several hydrophobic interactions, most commonly π-interactions, not predicted by modeling programs, were identified in all of the best-performing inhibitors. Nearly all of these compounds provide IC50’s in the low μM range.
doi:10.1021/jm3016393
PMCID: PMC3552522  PMID: 23214944
Ricin inhibitors; Pterin; RTA; π-interactions
16.  Toward Highly Potent Cancer Agents by Modulating the C-2 Group of the Arylthioindole Class of Tubulin Polymerization Inhibitors 
Journal of medicinal chemistry  2012;56(1):123-149.
New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.
doi:10.1021/jm3013097
PMCID: PMC3563301  PMID: 23214452
17.  An optimized RAD51 inhibitor that disrupts homologous recombination without requiring Michael acceptor reactivity 
Journal of medicinal chemistry  2012;56(1):254-263.
Homologous recombination (HR) is an essential process in cells that provides repair of DNA double-strand breaks and lesions that block DNA replication. RAD51 is an evolutionarily conserved protein that is central to HR. Overexpression of RAD51 protein is common in cancer cells and represents a potential therapeutic target in oncology. We previously described a chemical inhibitor of RAD51, called RI-1 (referred to as compound 1 in this report). The chloromaleimide group of this compound is thought to act as a Michael acceptor and react with the thiol group on C319 of RAD51, using a conjugate addition-elimination mechanism. In order to reduce the likelihood of off-target effects and to improve compound stability in biological systems, we developed an analog of compound 1 that lacks maleimide-based reactivity but retains RAD51 inhibitory activity. This compound, 1-(3,4-dichlorophenyl)-3-(4-methoxyphenyl)-4-morpholino-1H-pyrrole-2,5-dione, named RI-2 (referred to as compound 7a in this report), appears to bind reversibly to the same site on the RAD51 protein as does compound 1. Like compound 1, compound 7a specifically inhibits HR repair in human cells.
doi:10.1021/jm301565b
PMCID: PMC3619390  PMID: 23231413
DNA repair; Homologous recombination; RAD51; medicinal chemistry; structure activity relationship
18.  Discovery of potent myeloid cell leukemia 1 (Mcl 1) inhibitors using fragment based methods and structure based design 
Journal of medicinal chemistry  2012;56(1):15-30.
Myeloid cell leukemia-1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of <100 nM with selectivity for Mcl-1 over Bcl-xL and Bcl-2. Structures of merged compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition of small-molecule ligands binding Mcl-1. The compounds represent starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers.
doi:10.1021/jm301448p
PMCID: PMC3646517  PMID: 23244564
Fragment-based screening; apoptosis; cancer; Mcl-1; drug discovery
19.  Coumarin-based Inhibitors of Bacillus anthracis and Staphylococcus aureus Replicative DNA Helicase: Chemical Optimization, Biological Evaluation, and Antibacterial Activities 
Journal of medicinal chemistry  2012;55(24):10896-10908.
The increasing prevalence of drug-resistant bacterial infections demands the development of new antibacterials that are not subject to existing mechanisms of resistance. Previously, we described coumarin-based inhibitors of an underexploited bacterial target, namely, the replicative helicase. Here we report the synthesis and evaluation of optimized coumarin-based inhibitors with 9–18-fold increased potency against S. aureus (Sa) and B. anthracis (Ba) helicases. Compounds 20 and 22 provided the best potency, with IC50 values of 3 and 1 µM, respectively, against the DNA duplex strand-unwinding activities of both B. anthracis and S. aureus helicases without affecting the single strand DNA-stimulated ATPase activity. Selectivity index (SI = CC50/MIC) values against S. aureus and B. anthracis for compound 20 were 33 and 66 and for compound 22 were 20 and 40, respectively. In addition, compounds 20 and 22 demonstrated potent antibacterial activity against multiple ciprofloxacin-resistant MRSA strains with MIC values ranging between 0.5–4.2 µg/mL.
doi:10.1021/jm300922h
PMCID: PMC3531573  PMID: 23231076
20.  Identification, Synthesis, and Biological Evaluation of Metabolites of the Experimental Cancer Treatment Drugs Indotecan (LMP400) and Indimitecan (LMP776) and Investigation of Isomerically Hydroxylated Indenoisoquinoline Analogues as Topoisomerase I Poisons 
Journal of medicinal chemistry  2012;55(24):10844-10862.
Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP76) have been prepared because: 1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and 2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to the synthetic standards. The hydroxylated indotecan and indimitecan metabolites and analogues were tested as Top1 poisons and for antiproliferative activity in a variety of human cancer cell cultures, and in general were found to be very potent. Differences in activity resulting from the placement of the hydroxyl group are explained by molecular modeling analyses.
doi:10.1021/jm300519w
PMCID: PMC3542640  PMID: 23215354
21.  The Effect of the Prosthetic Group on the Pharmacologic Properties of 18F-labeled Rhodamine B, a Potential Myocardial Perfusion Agent for PET 
Journal of medicinal chemistry  2012;55(24):11004-11012.
We recently reported the development of the 2-[18F]fluoroethyl ester of rhodamine B as a potential positron emission tomography (PET) tracer for myocardial perfusion imaging. This compound, which was prepared using a [18F]fluoroethyl prosthetic group, has significant uptake in the myocardium in rats, but also demonstrates relatively high liver uptake and is rapidly hydrolyzed in vivo in mice. We have now prepared 18F-labeled rhodamine B using three additional prosthetic groups (propyl, diethylene glycol, and triethylene glycol) and found that the prosthetic group has a significant effect on the in vitro and in vivo properties of these compounds. Of the esters prepared to date, the diethylene glycol ester is superior in terms of in vitro stability and pharmacokinetics. These observations suggest that the prosthetic group plays a significant role in determining the pharmacological properties of 18F-labeled compounds. They also support the value of continued investigation of 18F-labeled rhodamines as PET radiopharmaceuticals for myocardial perfusion imaging.
doi:10.1021/jm301453p
PMCID: PMC3544362  PMID: 23210516
22.  Design and Synthesis of Inhibitors of Plasmodium falciparum N-Myristoyltransferase, a Promising Target for Anti-Malarial Drug Discovery 
Journal of medicinal chemistry  2012;55(20):10.1021/jm301160h.
Design of inhibitors for N-myristoyltransferase (NMT), an enzyme responsible for protein trafficking in P. falciparum, the most lethal species of parasites that cause malaria, is described. Chemistry-driven optimization of compound 1 from a focused NMT inhibitor library led to the identification of two early lead compounds 4 and 25, which showed good enzyme and cellular potency and excellent selectivity over human NMT. These molecules provide a valuable starting point for further development.
doi:10.1021/jm301160h
PMCID: PMC3863768  PMID: 23035716
Anti-Malarial Target; Inhibitor Design; Crystal Structure; Selectivity; Mutagenesis
23.  Discovery of Plasmodium vivax N–Myristoyltransferase Inhibitors: Screening, Synthesis, and Structural Characterization of their Binding Mode 
Journal of medicinal chemistry  2012;55(7):10.1021/jm300040p.
N-myristoyltransferase (NMT) is a prospective drug target against parasitic protozoa. Herein we report the successful discovery of a series of Plasmodium vivax NMT inhibitors by high throughput screening. A high-resolution crystal structure of the hit compound in complex with NMT was obtained, allowing understanding of its novel binding mode. A set of analogues was designed and tested to define the chemical groups relevant for activity and selectivity.
doi:10.1021/jm300040p
PMCID: PMC3863987  PMID: 22439843
24.  The molecular mechanisms of acquired proteasome inhibitor resistance 
Journal of medicinal chemistry  2012;55(23):10317-10327.
The development of proteasome inhibitors (PIs) has transformed the treatment of multiple myeloma and mantle cell lymphoma. To date, two PIs have been FDA approved, the boronate peptide bortezomib and, most recently, the epoxyketone peptide carfilzomib. However, intrinsic and acquired resistance to PIs, for which the underlying mechanisms are poorly understood, may limit their efficacy. In this perspective, we discuss recent advances in the molecular understanding of PI resistance through acquired bortezomib resistance in human cell lines to evolved saliniosporamide A (marizomib) resistance in nature. Resistance mechanisms discussed include the upregulation of proteasome subunits and mutations of the catalytic β-subunits. Additionally, we explore potential strategies to overcome PI resistance.
doi:10.1021/jm300434z
PMCID: PMC3521846  PMID: 22978849
25.  Design of a novel cyclotide-based CXCR4 antagonist with anti-human immunodeficiency virus (HIV)-1 activity 
Journal of medicinal chemistry  2012;55(23):10729-10734.
Herein, we report for the first time the design and synthesis of a novel cyclotide able to efficiently inhibit HIV-1 viral replication by selectively targeting cytokine receptor CXCR4. This was accomplished by grafting a series of topologically modified CVX15 based peptides onto the loop 6 of cyclotide MCoTI-I. The most active compound produced in this study was a potent CXCR4 antagonist (EC50 ≈ 20 nM) and an efficient HIV-1 cell-entry blocker (EC50 ≈ 2 nM). This cyclotide also showed high stability in human serum thereby providing a promising lead compound for the design of a novel type of peptide-based anti-cancer and anti-HIV-1 therapeutics.
doi:10.1021/jm301468k
PMCID: PMC3521869  PMID: 23151033

Results 1-25 (224)