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1.  Peptide HIV-1 Integrase Inhibitors from HIV-1 Gene Products 
Journal of medicinal chemistry  2010;53(14):5356-5360.
Anti-HIV peptides with inhibitory activity against HIV-1 integrase (IN) have been found in overlapping peptide libraries derived from HIV-1 gene products. In a strand transfer assay using IN, inhibitory active peptides with certain sequential motifs related to Vpr- and Env-derived peptides were found. The addition of an octa-arginyl group to the inhibitory peptides caused a remarkable inhibition of the strand transfer and 3′-end-processing reactions catalyzed by IN and significant inhibition against HIV replication.
PMCID: PMC4486249  PMID: 20586421
integrase inhibitor; octa-arginyl group; overlapping peptide; sequential motif; strand transfer assay
2.  Almiramides A–C: Discovery and Development of a New Class of Leishmaniasis Lead Compounds 
Journal of medicinal chemistry  2010;53(10):4187-4197.
Leishmaniasis is a debilitating disease caused by protozoan parasites of the genus Leishmania, which affects an estimated 12 million people worldwide. The discovery of new lead compounds for leishmaniasis is therefore a pressing concern for global health programs. The organic extract of a Panamanian collection of the marine cyanobacterium Lyngbya majuscula showed strong in vitro activity in two complementary screens against the tropical parasite Leishmania donovani, the causative agent of visceral leishmaniasis. Chromatographic separation of this complex mixture led to the isolation of the highly N-methylated linear lipopeptides, almiramides A–C (1–3). Comparison with the biological activities of a number of related metabolites and semisynthetic derivatives revealed key features required for activity and afforded one new compound (11) with superior in vitro activity. Subsequent synthesis of a library of simplified analogues led to the discovery of several compounds with improved therapeutic indices to the natural products.
PMCID: PMC4418807  PMID: 20441198
3.  A Novel Insulin Secretagogue Based on a Dinucleoside Polyphosphate Scaffold 
Journal of medicinal chemistry  2010;53(6):2472-2481.
Dinucleoside polyphosphates exert their physiological effects via P2 receptors (P2Rs). They are attractive drug candidates, as they offer better stability and specificity compared to nucleotides, the most common P2 receptor ligands. The activation of pancreatic P2Y receptors by nucleotides increases insulin secretion. Therefore, in the current study, dinucleoside polyphosphate analogues (di-(2-MeS)-adenosine-5′,5″-P1,P4,α,β-methylene-tetraphosphate), 8, (di-(2-MeS)-adenosine-5′,5″-P1,P4,β,γ-methylene-tetraphosphate), 9, and di-(2-MeS)-adenosine-5′,5″-P1,P3,α,β-methylene triphosphate, 10, were developed as potential insulin secretagogues. Analogues 8 and 9 were found to be agonists of the P2Y1R with EC50 values of 0.42 and 0.46 μM, respectively, whereas analogue 10 had no activity. Analogues 8–10 were found to be completely resistant to hydrolysis by alkaline phosphatase over 3 h at 37°C. Analogue 8 also was found to be 2.5-fold more stable in human blood serum than ATP, with a half-life of 12.1 h. Analogue 8 administration in rats caused a decrease in a blood glucose load from 155 mg/dL to ca. 100 mg/dL and increased blood insulin levels 4-fold as compared to basal levels. In addition, analogue 8 reduced a blood glucose load to normal values (80–110 mg/dL), unlike the commonly prescribed glibenclamide, which reduced glucose levels below normal values (60 mg/dL). These findings suggest that analogue 8 may prove to be an effective and safe treatment for type 2 diabetes.
PMCID: PMC4363086  PMID: 20175517
4.  2-MeS-β,γ-CCl2-ATP is a Potent Agent for Reducing Intraocular Pressure† 
Journal of medicinal chemistry  2010;53(8):3305-3319.
Extracellular nucleotides can modify the production or drainage of the aqueous humor via activation of P2 receptors and therefore affect the intraocular pressure (IOP). We have synthesized slowly hydrolyzable nucleoside di- and triphosphate analogues, 1, and 8–14. Analogues 8–14 were completely resistant to hydrolysis by alkaline phosphatase over 30 min at 37 °C. In human blood serum, analogues 8–14 exhibited high stability, e.g., analogues 9 and 10–14 were only 15% and 0% degraded after 24 h, respectively. Moreover, analogues 8–14 were highly stable at pH 1.4 (t1/21 h–30 days). Analogues 8–14 were agonists of the P2Y1 receptor (EC50 0.57–9.54μM). Ocular administration of most analogues into rabbits reduced IOP, e.g., analogue 9 reduced IOP by 32% (EC50 95.5 nM). Analogue 9 was more effective at reducing IOP than several common glaucoma drugs and represents a promising alternative to timolol maleate, which cannot be used for the treatment of patients suffering from asthma or cardiac problems.
PMCID: PMC4358770  PMID: 20337495
5.  A Type-II Kinase Inhibitor Capable of Inhibiting the T315I “Gatekeeper” mutant of Bcr-Abl 
Journal of medicinal chemistry  2010;53(15):5439-5448.
The second generation of Bcr-Abl inhibitors nilotinib, dasatinib, and bosutinib developed to override imatinib resistance are not active against the T315I ‘gatekeeper’ mutation. Here we describe a Type-II T315I inhibitor GNF-7, based upon a 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one scaffold which is capable of potently inhibiting wild-type and T315I Bcr-Abl as well as other clinically relevant Bcr-Abl mutants such as G250E, E255V, F317L and M351T in biochemical and cellular assays. In addition, GNF-7 displayed significant in vivo efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. GNF-7 is amongst the first type II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design next generation Bcr-Abl kinase inhibitors.
PMCID: PMC4134510  PMID: 20604564
Bcr-Abl kinase; Chronic Myelogenous Leukemia (CML); T315I gatekeeper mutation; Type-II T315I-Bcr-Abl inhibitor
6.  Synthesis and Identification of New 4-Arylidene Curcumin Analogs as Potential Anticancer Agents Targeting Nuclear Factor-κB Signaling Pathway 
Journal of medicinal chemistry  2010;53(23):8260-8273.
A series of curcumin analogues including new 4-arylidene curcumin analogs (4-arylidene-1,7-bisaryl-hepta-1,6-diene-3,5-diones) were synthesized. Cell growth inhibition assays revealed that most 4-arylidene curcumin analogs can effectively decrease the growth of a panel of lung cancer cells in sub- and low micromolar concentration ranges. High content analysis technology coupled with biochemical studies showed that this new class of 4-arylidene curcumin analogs exhibits significantly improved NF-κB inhibition activity over the parent compound curcumin, at least in part by inhibiting IκB phosphorylation and degradation via IKK blockage; selected 4-arylidene curcumin analogs also reduced the tumorigenic potential of cancer cells in a clonogenic assay.
PMCID: PMC3990230  PMID: 21070043
4-arylidene curcumin analogs; NF-κB; inhibition; anticancer
7.  Crystal Structure-Based Selective Targeting of the Pyridoxal 5′-Phosphate Dependent Enzyme Kynurenine Aminotransferase II for Cognitive Enhancement† 
Journal of medicinal chemistry  2010;53(15):5684-5689.
Fluctuations in the brain levels of the neuromodulator kynurenic acid may control cognitive processes and play a causative role in several catastrophic brain diseases. Elimination of the pyridoxal 5′-phosphate dependent enzyme kynurenine aminotransferase II reduces cerebral kynurenic acid synthesis and has procognitive effects. The present description of the crystal structure of human kynurenine aminotransferase II in complex with its potent and specific primary amine-bearing fluoroquinolone inhibitor (S)-(−)-9-(4-aminopiperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azaphenalene-5-carboxylic acid (BFF-122) should facilitate the structure-based development of cognition-enhancing drugs. From a medicinal chemistry perspective our results demonstrate that the issue of inhibitor specificity for highly conserved PLP-dependent enzymes could be successfully addressed.
PMCID: PMC3929320  PMID: 20684605
8.  A Series of α-Amino Acid Ester Prodrugs of Camptothecin: In vitro Hydrolysis and A549 Human Lung Carcinoma Cell Cytotoxicity 
Journal of medicinal chemistry  2010;53(3):1038-1047.
The objective of the present study was to identify a camptothecin (CPT) prodrug with optimal release and cytotoxicity properties for immobilization on a passively targeted microparticle delivery system. A series of α-amino acid ester prodrugs of CPT were synthesized, characterized and evaluated. Four CPT prodrugs were synthesized with increasing aliphatic chain length (glycine (Gly) (2a), alanine (Ala) (2b), aminobutyric acid (Abu) (2c) and norvaline (Nva) (2d)). Prodrug reconversion was studied at pH 6.6, 7.0 and 7.4 corresponding to tumor, lung and extracellular/physiological pH, respectively. Cytotoxicity was evaluated in A549 human lung carcinoma cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The hydrolytic reconversion rate to parent CPT increased with decreasing side chain length as well as increasing pH. The Hill slope of 2d was significantly less than CPT and the other prodrugs tested, indicating a higher cell death rate at lower concentrations. These results suggest that 2d is the best candidate for a passively targeted sustained release lung delivery system.
PMCID: PMC3901077  PMID: 20063889
Amino acid prodrug; camptothecin; bioconjugate; lung cancer
9.  Discovery of 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one as a highly potent, selective Mammalian Target of Rapamycin (mTOR) inhibitor for the treatment of cancer 
Journal of medicinal chemistry  2010;53(19):7146-7155.
The mTOR protein is a master regulator of cell growth and proliferation, and inhibitors of its kinase activity have the potential to become new class of anti-cancer drugs. Starting from quinoline 1, which was identified in a biochemical mTOR assay, we developed a tricyclic benzonaphthyridinone inhibitor Torin1(26), which inhibited phosphorylation of mTORC1 and mTORC2 substrates in cells at concentrations of 2 nM and 10 nM, respectively. Moreover, Torin1 exhibits 1000-fold selectivity for mTOR over PI3K (EC50 = 1800 nM) and exhibits 100-fold binding selectivity relative to 450 other protein kinases. Torin1 was efficacious at a dose of 20 mg/kg in a U87MG xenograft model, and demonstrated good pharmacodynamic inhibition of downstream effectors of mTOR in tumor and peripheral tissues. These results demonstrate that Torin1 is a useful probe of mTOR-dependent phenomena and that benzonaphthridinones represent a promising scaffold for the further development of mTOR-specific inhibitors with the potential for clinical utility.
PMCID: PMC3893826  PMID: 20860370
10.  Synthesis, Fluorine-18 Radiolabeling, and Biological Evaluation of N-((E)-4-Fluorobut-2-en-1-yl)-2β-carbomethoxy-3β-(4′-halophenyl)nortropanes: Candidate Radioligands for In Vivo Imaging of the Brain Dopamine Transporter with Positron Emission Tomography 
Journal of medicinal chemistry  2010;53(15):5549-5557.
The N-(E)-fluorobutenyl-3β-(para-halo-phenyl)nortropanes 9-12 were synthesized as ligands of the dopamine transporter (DAT) for use as 18F-labeled positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that compounds 9-12 have a high affinity for the DAT and are selective for the DAT compared to the serotonin and norepinephrine transporters. MicroPET imaging with [18F]9-[18F]11 in anesthetized cynomolgus monkeys showed high uptake in the putamen with lesser uptake in the caudate, but significant washout of the radiotracer was only observed for [18F]9. PET imaging with [18F]9 in an awake rhesus monkey showed high and nearly equal uptake in both the putamen and caudate with peak uptake achieved after 20 min followed by a leveling-off for about 10 min and then a steady washout and attainment of a quasi-equilibrium. During the time period 40-80 min post-injection of [18F]9 the ratio of uptake in the putamen and caudate vs. cerebellum uptake was ≥ 4.
PMCID: PMC3756492  PMID: 20597489
11.  Design and Synthesis of Potent “Sulfur-free” Transition State Analogue Inhibitors of 5′-Methylthioadenosine Nucleosidase and 5′-Methylthioadenosine Phosphorylase 
Journal of medicinal chemistry  2010;53(18):6730-6746.
5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a dual substrate bacterial enzyme involved in S-adenosylmethionine (SAM)-related quorum sensing pathways that regulates virulence in many bacterial species. MTANs from many bacteria are directly involved in the quorum sensing mechanism by regulating the synthesis of autoinducer molecules that are used by bacterial communities to communicate. In humans, 5′-methylthioadenosine phosphorylase (MTAP) is involved in polyamine biosynthesis as well as in purine and SAM salvage pathways and thus has been identified as an anticancer target. Previously we have described the synthesis and biological activity of several aza-C-nucleoside mimics with a sulfur atom at the 5′ position that are potent E. coli MTAN and human MTAP inhibitors. Because of the possibility that the sulfur may affect bioavailability we were interested in synthesizing “sulfur-free” analogues. Herein we describe the preparation of a series of “sulfur-free” transition state analogues inhibitors, of E. coli MTAN and human MTAP that have low nano- to pico-molar dissociation constants and are potentially novel bacterial anti-infective and anti-cancer drug candidates.
PMCID: PMC3742014  PMID: 20718423
12.  Heteroadamantyl Cannabinoids 
Journal of medicinal chemistry  2010;53(15):5656-5666.
The aliphatic side chain plays a pivotal role in determining the cannabinergic potency of tricyclic classical cannabinoids. We have synthesized a series of analogues in which the C3 position is substituted either directly or through a one-carbon atom linker with an adamantylamine or with an oxa- or an oxazaadamantane. The oxaadamantane pharmacophore in analogue 16 showed the best binding profile for both receptors.
PMCID: PMC3699191  PMID: 20593789
13.  Novel 1′,1′-Chain Substituted Hexahydrocannabinols: 9β-Hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol (AM2389) a Highly Potent Cannabinoid Receptor 1 (CB1) Agonist 
Journal of medicinal chemistry  2010;53(19):6996-7010.
In pursuit of a more detailed understanding of the structural requirements for the key side chain cannabinoid pharmacophore we have extended our SAR to cover a variety of conformationally modified side chains within the 9-keto and 9-hydroxyl tricyclic structures. Of the compounds described here, those with a seven-atom long side chain substituted with a cyclopentyl ring at C1′ position have very high affinities for both CB1 and CB2 (0.97 nM
PMCID: PMC3650853  PMID: 20925434
Journal of medicinal chemistry  2010;53(20):7327-7336.
Several antifolates, including trimethoprim (TMP) and a series of propargyl-linked analogs, bind dihydrofolate reductase from Bacillus anthracis (BaDHFR) with lower affinity than is typical in other bacterial species. To guide lead optimization for BaDHFR, we explored a new approach to determine structure-activity relationships whereby the enzyme is altered and the analogs remain constant, essentially reversing the standard experimental design. Active site mutants of the enzyme, Ba(F96I)DHFR and Ba(Y102F)DHFR, were created and evaluated with enzyme inhibition assays and crystal structures. The affinities of the antifolates increase up to 60-fold with the Y102F mutant, suggesting that interactions with Tyr 102 are critical for affinity. Crystal structures of the enzymes bound to TMP and propargyl-linked inhibitors reveal the basis of TMP resistance and illuminate the influence of Tyr 102 on the lipophilic linker between the pyrimidine and aryl rings. Two new inhibitors test and validate these conclusions and show the value of the technique for providing new directions during lead optimization.
PMCID: PMC3618964  PMID: 20882962
Bacillus anthracis; dihydrofolate reductase; trimethoprim; antifolates; SAR
Journal of medicinal chemistry  2010;53(7):2836-2842.
CCK2 receptor antagonists potentiate pain relief by MOP receptor agonists. In an attempt to enhance this effect, we prepared bivalent ligands incorporating CCK2 receptor antagonist and MOP receptor agonist pharmacophores.9 Ligands with 16- to 22-atom spacers could simultaneously bind both receptors but provided no advantage in activity over individual ligands. We now examine the effect of these ligands on receptor internalization as a mechanism of receptor regulation. We prepared CHO cell lines expressing nonfluorescent halves (YN and YC) of yellow fluorescent protein attached to each receptor. Spatial approximation of constructs was needed to yield fluorescence. Monovalent MOP agonist 1 signaled normally and internalized the MOP receptor. Monovalent CCK2 antagonist 2 did not stimulate receptor internalization. In the dual receptor-bearing cells, bivalent ligands 3a–c capable of simultaneously binding both receptors resulted in cell surface fluorescence and internalization of the fluorescent complex in a time- and temperature-dependent manner. Bivalent ligand 4 with spacer too short to occupy both receptors simultaneously yielded no signal. Receptor tethering with appropriate bivalent ligands can down-regulate signaling by moving a nonactivated receptor into the endocytic pathway.
PMCID: PMC3593351  PMID: 20235611
Journal of medicinal chemistry  2010;53(21):7573-7586.
Some antipsychotic drugs are known to cause valvular heart disease by activating serotonin 5-HT2B receptors. We have developed and validated binary classification QSAR models capable of predicting potential 5-HT2B binders. The classification accuracies of the models to discriminate 5-HT2B actives from the inactives were as high as 80% for the external test set. These models were used to screen in silico 59,000 compounds included in the World Drug Index and 122 compounds were predicted as actives with high confidence. Ten of them were tested in radioligand binding assays and nine were found active suggesting a success rate of 90%. All validated binders were then tested in functional assays and one compound was identified as a true 5-HT2B agonist. We suggest that the QSAR models developed in this study could be used as reliable predictors to flag drug candidates that are likely to cause valvulopathy.
PMCID: PMC3438292  PMID: 20958049
Journal of medicinal chemistry  2010;54(3):909-912.
The binding of zonisamide to purified, recombinant monoamine oxidases (MAOs) has been investigated. It is a competitive inhibitor of human MAO B (Ki = 3.1 ± 0.3 μM), of rat MAO B (Ki = 2.9 ± 0.5 μM), and of zebrafish MAO (Ki = 30.8 ± 5.3 μM). No inhibition is observed with purified human or rat MAO A. The 1.8 Å structure of the MAO B complex demonstrates that it binds within the substrate cavity.
PMCID: PMC3071873  PMID: 21175212
Zonisamide; human monoamine oxidase B; crystal structure; competitive inhibition
Journal of medicinal chemistry  2010;53(20):7356-7364.
Novel derivatives of the clinically established anticancer drug oxaliplatin were synthesized. Cytotoxicity of the compounds was studied in six human cancer cell lines by means of the MTT assay. Additionally, most promising complexes were also investigated in cisplatin- and oxaliplatin-resistant human cancer cell models. The therapeutic efficacy in vivo was studied in the murine L1210 leukemia model. Most remarkably, {(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine}oxalatoplatinum(II), comprising an equatorial methyl substituent at position 4 of the cyclohexane ring, was as potent as oxaliplatin in vitro but distinctly more effective in the L1210 model in vivo at the optimal dose. The advantage observed in the in vivo situation was mainly based on a more favorable therapeutic index. The maximum tolerated dose of the novel analogue was higher than that of oxaliplatin and caused a greater increase in life span (>200% versus 152%), with more animals experiencing long-term survival (5/6 versus 2/6). These data support further (pre)clinical development of the methyl-substituted oxaliplatin analogue with improved anticancer activity.
PMCID: PMC3374999  PMID: 20886814
Journal of medicinal chemistry  2010;53(23):8274-8286.
7,8-Dihydroxyflavone is a recently identified small molecular tropomyosin-receptor-kinase B (TrkB) agonist. Our preliminary structural activity relationship (SAR) study showed that the 7,8-dihydroxy groups are essential for the agonistic effect. To improve the lead compound's agonistic activity, we have conducted an extensive SAR study and synthesized numerous derivatives. We have successfully identified 4'-dimethylamino-7,8-dihydroxyflavone that displays higher TrkB agonistic activity than the lead. This novel compound also exhibits a more robust and longer TrkB activation effect in animals. Consequently, this new compound reveals more potent anti-apoptotic activity. Interestingly, chronic oral administration of 4'-dimethylamino-7,8-dihydroxyflavone and its lead strongly promotes neurogenesis in dentate gyrus and demonstrates marked antidepressant effects. Hence, our data support that the synthetic 4'-dimethylamino-7,8-dihydroxyflavone and its lead both are orally bioavailable TrkB agonists and possess potent antidepressant effects.
PMCID: PMC3150605  PMID: 21073191
TrkB agonist; BDNF; synthetic derivatives; antidepressant; neurogenesis
Journal of medicinal chemistry  2010;53(23):8376-8386.
The inhibition of the mammalian soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of hypertension, inflammation and other disorders. However, the problems of limited water solubility, high melting point and low metabolic stability complicated the development of 1,3-disubstituted urea-based sEH inhibitors. The current study explored the introduction of the substituted piperazino group as the tertiary pharmacophore, which resulted in substantial improvements in pharmacokinetic parameters over previously reported 1-adamantyl-urea based inhibitors while retaining high potency. The SAR studies revealed that the meta- or para-substituted phenyl spacer, and N4-acetyl or sulfonyl substituted piperazine were optimal structures for achieving high potency and good physical properties. The 1-(4-(4-(4-acetylpiperazin-1-yl)butoxy)phenyl)-3-adamantan-1-yl urea (29c) demonstrated excellent in vivo pharmacokinetic properties in mice: T1/2 =14 h, Cmax = 84 nM and AUC = 40200 nM • min with an IC50 value of 7.0 nM against human sEH enzyme.
PMCID: PMC3070159  PMID: 21070033
Journal of medicinal chemistry  2010;53(23):8368-8375.
A new series of 3-ethynyl-1H–indazoles has been synthesized and evaluated in both biochemical and cell-based assays as potential kinase inhibitors. Interestingly, a selected group of compounds identified from this series exhibited low micromolar inhibition against critical components of the PI3K pathway, targeting PI3K, PDK1 and mTOR kinases. Combination of computational modeling and structure-activity relationships studies reveal a possible novel mode for PI3K inhibition, resulting in a PI3Kα isoform specific compound. Hence, by targeting the most oncogenic mutant isoform of PI3K, the compound displays anti-proliferative activity both in monolayer human cancer cell cultures and in three-dimensional tumor models. Because of its favorable physicochemical, in vitro ADME and drug-like properties, we propose that this novel ATP mimetic scaffold could result useful in deriving novel selecting and multi-kinase inhibitors for clinical use.
PMCID: PMC3131451  PMID: 21062009
Journal of medicinal chemistry  2010;53(23):8345-8353.
There is a need for different and better aids to tobacco product use cessation. Useful smoking cessation aids, bupropion (2) and varenicline (3), share some chemical features with 3-phenyltropanes (4), which have promise in cocaine dependence therapy. Here we report studies to generate and characterize pharmacodynamic features of 3-phenyltropane analogues. These studies extend our work on the multiple molecular target model for aids to smoking cessation. We identified several new 3-phenyltropane analogues that are superior to 2 in inhibition of dopamine, norepinephrine, and sometimes serotonin reuptake. All of these ligands also act as inhibitors of nicotinic acetylcholine receptor (nAChR) function with a selectivity profile that favors, like 2, inhibition of α3β4*-nAChR. Many of these ligands also block acute effects of nicotine-induced antinociception, locomotor activity, and hypothermia. Importantly, all except one of the analogues tested have better potencies in inhibition of nicotine conditioned place preference than 2. We have identified new compounds that have utility as research tools and possible promise for treatment of nicotine dependence.
PMCID: PMC3130825  PMID: 21058665
Nicotine; 3-phenyltropanes; structure activity relationship; dopamine uptake norepinephrine uptake; nAChR antagonism; antinociception; locomotor activity; hypothermia multiple target; conditioned place preference
Journal of medicinal chemistry  2010;53(23):8287-8297.
Based on the structures and activities of our previously identified non-nucleoside reverse transcriptase inhibitors (NNRTIs), we designed and synthesized two sets of derivatives, diarylpyridines (A) and diarylanilines (B), and tested their anti-HIV-1 activity against infection by HIV-1 NL4-3 and IIIB in TZM-bl and MT-2 cells, respectively. The results showed that most compounds exhibited potent anti-HIV-1 activity with low nanomolar EC50 values, and some of them, such as 13m, 14c, and 14e, displayed high potency with subnanomolar EC50 values, which were more potent than etravirine (TMC125, 1) in the same assays. Notably, these compounds were also highly effective against infection by multi-RTI-resistant strains, suggesting a high potential to further develop these compounds as a novel class of NNRTIs with improved antiviral efficacy and resistance profile.
PMCID: PMC3050082  PMID: 21049929
Journal of Medicinal Chemistry  2010;53(14):5333-5341.
Gallium-68 is a generator-produced radionuclide for positron emission tomography (PET) that is being increasingly used for radiolabeling of tumor-targeting peptides. Compounds [68Ga]3 and [68Ga]6 are high-affinity, urea-based inhibitors of the prostate-specific membrane antigen (PSMA) that were synthesized in decay-uncorrected yields ranging from 60 – 70% and radiochemical purities of more than 99%. Compound [68Ga]3 demonstrated 3.78 ± 0.90 percent injected dose per gram of tissue (%ID/g) within PSMA+ PIP tumor at 30 min post-injection, while [68Ga]6 showed a two hour PSMA+ PIP tumor uptake value of 3.29 ± 0.77%ID/g. Target (PSMA+ PIP) to non-target (PSMA− flu) ratios were 4.6 and 18.3, respectively, at those time points. Both compounds delineated tumor clearly by small animal PET. The urea series of imaging agents for PSMA can be radiolabeled with 68Ga, a cyclotron-free isotope useful for clinical PET studies, with maintenance of target specificity.
PMCID: PMC3341619  PMID: 20568777
gallium; molecular imaging; positron emission tomography; prostate-specific membrane antigen; radiopharmaceutical
Journal of Medicinal Chemistry  2010;53(2):624-632.
A prodrug strategy was applied to guanidino-containing analogs to increase oral absorption via hPEPT1 and hVACVase. L-Valine, L-isoleucine and L-phenylalanine esters of [3-(hydroxymethyl)phenyl]guanidine (3-HPG) were synthesized and evaluated for transport and activation. In HeLa/hPEPT1 cells, Val-3-HPG and Ile-3-HPG exhibited high affinity to hPEPT1 (IC50: 0.65 and 0.63 mM, respectively), and all three L-amino acid esters showed higher uptake (2.6- to 9-fold) than the parent compound 3-HPG. Val-3-HPG and Ile-3-HPG demonstrated remarkable Caco-2 permeability enhancement, and Val-3-HPG exhibited comparable permeability to valacyclovir. In rat perfusion studies, Val-3-HPG and Ile-3-HPG permeabilities were significantly higher than 3-HPG, and exceeded/matched the high-permeability standard metoprolol, respectively. All the L-amino acid 3-HPG esters were effectively activated in HeLa and Caco-2 cell homogenates, and were found to be good substrates of hVACVase (kcat/Km in mM−1·s−1: Val-3-HPG, 3370; Ile-3-HPG, 1580; Phe-3-HPG, 1660). In conclusion, a prodrug strategy is effective at increasing the intestinal permeability of polar guanidino analogs via targeting hPEPT1 for transport and hVACVase for activation.
PMCID: PMC3304101  PMID: 19957998
prodrug approach; guanidino functionality; hPEPT1; hVACVase; intestinal absorption

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