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1.  Toward Orthopoxvirus Countermeasures: A Novel Heteromorphic Nucleoside of Unusual Structure 
Journal of medicinal chemistry  2006;49(14):4052-4054.
Two privileged drug scaffolds have been hybridized to create the novel heteromorphic nucleoside 5-(2-amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromen-4-yl)-1-(2-deoxypentofuranosyl)pyrimidine-2,4-(1H,3H)-dione (2). Compound 2 inhibited the replication of two orthopoxviruses, vaccinia virus (VV) (EC50 = 4.6 ± 2.0 μM), and cowpox virus (CV) (EC50 = 2.0 ± 0.3 μM). Compound 2 exhibited reduced activity against a thymidine kinase (TK) negative strain of CV, implying a requirement for 5′-monophosphorylation for antiorthopoxvirus activity. Compound 2 was efficiently phosphorylated by VV TK, establishing that VV TK is more promiscuous than previously believed.
doi:10.1021/jm060404n
PMCID: PMC4298854  PMID: 16821766
2.  5-(Dimethoxymethyl)-2′-Deoxyuridine: A Novel Gem Diether Nucleoside with Anti-Orthopoxvirus Activity 
Journal of medicinal chemistry  2006;49(11):3377-3382.
To provide potential new leads for the treatment of orthopoxvirus infections, the 5-position of the pyrimidine nucleosides have been modified with a gem diether moiety to yield the following new nucleosides: 5-(dimethoxymethyl)-2′-deoxyuridine (2b), 5-(diethoxymethyl)-2′-deoxyuridine (3b), 5-formyl-2′-deoxyuridine ethylene acetal (4b), and 5-formyl-2′-deoxyuridine propylene acetal (5b). These were evaluated in human foreskin fibroblast cells challenged with the vaccinia virus or cowpox virus. Of the four gem diether nucleosides, only the dimethyl gem diether congener showed significant antiviral activity against both viruses. This antiviral activity did not appear to be related to the decomposition to the 5-formyl-2′-deoxyuridine, which was itself devoid of anti-orthopoxvirus activity in these assays. Moreover, at the pH of the in vitro assays, 2b was very stable with a decomposition (to aldehyde) half-life of >15 d. The anti-orthopoxvirus activity of pyrimidine may be favored by the introduction of hydrophilic moieties to the 5-position side chain.
doi:10.1021/jm0601710
PMCID: PMC4262926  PMID: 16722657
3.  TOPOMIMETICS OF AMPHIPATHIC β-SHEET AND HELIX-FORMING BACTERICIDAL PEPTIDES NEUTRALIZE LIPOPOLYSACCHARIDE ENDOTOXINS 
Journal of medicinal chemistry  2006;49(26):7754-7765.
Release of lipopolysaccharide (LPS) endotoxin from Gram negative bacterial membranes triggers macrophages to produce large quantities of cytokines that can lead to septic shock and eventual death. Agents that bind to and neutralize LPS may provide a means to clinically prevent septic shock upon bacterial infection. Previously, we reported the design of antibacterial helix peptide SC4 and β-sheet-forming βpep peptides that neutralize LPS in vitro. We hypothesized that the ability of these and other such peptides to neutralize LPS rested in the common denominator of positively charged amphipathic structure. Here, we describe the design and synthesis of non-peptide, calixarene-based helix/sheet topomimetics that mimic the folded conformations of these peptides in their molecular dimensions, amphipathic surface topology, and compositional properties. From a small library of topomimetics, we identified several compounds that neutralize LPS in the 10−8 M range, making them as effective as bactericidal/permeability increasing (BPI) protein and polymyxin B. In an endotoxemia mouse model, three of the most in vitro effective topomimetics are shown to be at least partially protective against challenges of LPS from different bacterial species. NMR studies provide mechanistic insight by suggesting the site of molecular interaction between topomimetics and the lipid A component of LPS, with binding being mediated by electrostatic and hydrophobic interactions. This research contributes to the development of pharmaceutical agents against endotoxemia and septic shock.
doi:10.1021/jm0610447
PMCID: PMC4242098  PMID: 17181157
4.  Simplified Cyclic Analogs of Bastadin-5. Structure Activity Relationships for Modulation of the RyR1/FKBP12 Ca2+ Channel Complex 
Journal of medicinal chemistry  2006;49(15):4497-4511.
Bastadin-5, a brominated macro-dilactam from the marine sponge Ianthella basta, enhances release of Ca2+ from stores within the sarcoplasmic reticulum (SR) of muscle and non-muscle cells by modulating RyR1/FKBP12 complex. Analogs of bastadin-5 present desirable targets for SAR studies to shed light on the gating mechanism and locus of bastadin-5 binding on these heteromeric channels that mediate essential steps in early coupling of membrane excitation to Ca2+ signaling cascades. Simple, ring-constrained analogs of bastadin-5 were synthesized from substituted benzaldehydes in a convergent manner, featuring an efficient SNAr macroetherification, and evaluated in an assay that measures [3H]-ryanodine that is known to correlate with the functional open state of the Ca2+ channel. The simplified 14-membered ring, atropisomeric analog (±)-7, like bastadin-5, enhanced ryanodine binding to the RyR1/FKBP12 complex (EC50 11 μM), however, unexpectedly, the corresponding achiral 18-membered ring analog 14 potently inhibited binding (IC50 6 μM) under the same conditions. Structure-activity relationships of both families of cyclic analogs showed activity in a ryanodine binding assay that varied with substitutions of the Br atom on the trisubstituted aryl ring by various functional groups. The most active analogs were those that conserved the dibromocatechol ether moiety that corresponds to the ‘western edge’ of the bastadin-5 structure. These data suggest that cyclic analogs of bastadin-5 interact with the channel complex in a complex manner that can either enhance or inhibit channel activity.
doi:10.1021/jm050708u
PMCID: PMC3987770  PMID: 16854055
5.  Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists 
Journal of medicinal chemistry  2006;49(9):2689-2702.
An alternative approach to overcome the inherent lack of specificity of conventional agonist therapy can be the reengineering of the GPCRs and their agonists. A reengineered receptor (neoceptor) could be selectively activated by a modified agonist, but not by the endogenous agonist. Assisted by rhodopsin-based molecular modeling, we pinpointed mutations of the A3 adenosine receptor (AR) for selective affinity enhancement following complementary modifications of adenosine. Ribose modifications examined included, at 3′: amino, aminomethyl, azido, guanidino, ureido; and at 5′: uronamido, azidodeoxy. N6-variations included: 3-iodobenzyl, 5-chloro-2-methyloxybenzyl, and methyl. An N6-3-iodobenzyl-3′-ureido adenosine derivative 10 activated phospholipase C in COS-7 cells (EC50=0.18 μM) or phospholipase D in chick primary cardiomyocytes mediated by a mutant (H272E), but not the wild-type, A3AR. The affinity enhancements for 10 and the corresponding 3′-acetamidomethyl analogue 6 were >100-fold and >20-fold, respectively. 10 concentration-dependently protected cardiomyocytes transfected with the neoceptor against hypoxia. Unlike 10, adenosine activated the wild-type A3AR (EC50 of 1.0 μM), but had no effect on the H272E mutant A3AR (100 μM). Compound 10 was inactive at human A1, A2A, and A2BARs. The orthogonal pair comprising an engineered receptor and a modified agonist should be useful for elucidating signaling pathways and could be therapeutically applied to diseases following organ-targeted delivery of the neoceptor gene.
doi:10.1021/jm050968b
PMCID: PMC3471142  PMID: 16640329
6.  Structure activity relationship of uridine 5′-diphosphate analogues at the human P2Y6 receptor 
Journal of medicinal chemistry  2006;49(18):5532-5543.
The structure activity relationships and molecular modeling of the uracil nucleotide-activated P2Y6 receptor have been studied. A series of UDP analogues bearing substitutions of the ribose moiety, the uracil ring, and the diphosphate group was synthesized and assayed for activity at the human P2Y6 receptor. The uracil ring was modified at the 4-position, with the synthesis of 4-substituted-thiouridine-5′-diphosphate analogues, as well as at positions 3 and 5. The effect of modifications at the level of the phosphate chain was studied by preparing a cyclic 3′,5′-diphosphate analogue, a 3′-diphosphate analogue and several dinucleotide diphosphates. 5-Iodo-UDP 32 (EC50 0.15 μM) was equipotent to UDP, while substitutions of the 2′-hydroxyl (amino, azido) greatly reduce potency. 2- and 4-Thio analogues, 20 and 21, respectively, were also relatively potent in comparison to UDP. However, most other modifications greatly reduced potency. Molecular modeling indicates that the β-phosphate of 5′-UDP and analogs is essential for the establishment of electrostatic interactions with two of the three conserved cationic residues of the receptor. Among 4-thioether derivatives, a 4-ethylthio analogue 23 displayed an EC50 of 0.28 μM, indicative of favorable interactions predicted for a small 4-alkylthio moiety with the aromatic ring of Y33 in TM1. The activity of analogue 19 in which the ribose was substituted with a 2-oxabicyclohexane ring in a rigid (S) conformation (P= 126°, 1′-exo) was consistent with molecular modeling. These results provide a better understanding of molecular recognition at the P2Y6 receptor and will be helpful in designing selective and potent P2Y6 receptor ligands
doi:10.1021/jm060485n
PMCID: PMC3405152  PMID: 16942026
G protein-coupled receptor; nucleotides; thionucleotides; phospholipase C; pyrimidines; homology modeling
7.  Benchmarking Sets for Molecular Docking 
Journal of Medicinal Chemistry  2006;49(23):6789-6801.
Ligand enrichment among top-ranking hits is a key metric of molecular docking. To avoid bias, decoys should resemble ligands physically, so that enrichment is not simply a separation of gross features, yet be chemically distinct from them, so that they are unlikely to be binders. We have assembled a directory of useful decoys (DUD), with 2950 ligands for 40 different targets. Every ligand has 36 decoy molecules that are physically similar but topologically distinct, leading to a database of 98,266 compounds. For most targets, enrichment was at least half a log better with uncorrected databases such as the MDDR than with DUD, evidence of bias in the former. These calculations also allowed forty-by-forty cross docking, where the enrichments of each ligand set could be compared for all 40 targets, enabling a specificity metric for the docking screens. DUD is freely available online as a benchmarking set for docking at http://blaster.docking.org/dud/.
doi:10.1021/jm0608356
PMCID: PMC3383317  PMID: 17154509
virtual screening; molecular docking; docking decoy; automation; enrichment; binding pose
8.  Facile Purification of Honokiol and its Antiviral and Cytotoxic Properties 
Journal of medicinal chemistry  2006;49(11):3426-3427.
A separation of honokiol 1 from the closely structurally related magnolol 2 was developed. Honokiol demonstrated weak activity against HIV-1 in human lymphocytes.
doi:10.1021/jm060268m
PMCID: PMC3195338  PMID: 16722664
9.  Anthrax Lethal Factor Protease Inhibitors: Synthesis, SAR and Structure-Based 3D QSAR Studies 
Journal of medicinal chemistry  2006;49(1):27-30.
We have recently identified a series of compounds which efficiently inhibit Anthrax lethal factor (LF) metallo-protease. Here we present further structure activity relationship and CoMFA (Comparative Molecular Field Analysis) studies on newly derived inhibitors. The obtained 3D QSAR model was subsequently compared with the X-ray structure of the complex between LF and a representative compound. Our studies form the basis for the rational design of additional compounds with improved activity and selectivity.
doi:10.1021/jm050892j
PMCID: PMC3164827  PMID: 16392787
10.  Synthesis and Properties of Benzo[a]phenoxazinium Chalcogen Analogues as Novel Broad-Spectrum Antimicrobial Photosensitizers 
Journal of medicinal chemistry  2006;49(17):5291-5299.
The goal of this investigation was to develop improved photosensitizers for use as antimicrobial drugs in photodynamic therapy of localized infections. Replacement of the oxygen atom in 5-(ethylamino)-9-diethylaminobenzo[a]phenoxazinium chloride (1) with sulfur and selenium afforded thiazinium and selenazinium analogues 2 and 3, respectively. All three dyes are water soluble, lipophilic, and red light absorbers. The relative photodynamic activities of the chalcogen series were evaluated against a panel of prototypical pathogenic microorganisms: the Gram-positive Enterococcus faecalis, the Gram-negative Escherichia coli, and the fungus Candida albicans. Selenium dye 3 was highly effective as a broad-spectrum antimicrobial photosensitizer with fluences of 4–32 J/cm2 killing 2–5 more logs of all cell types than sulfur dye 2, which was slightly more effective than oxygen analogue 1. These data, taken with the findings of uptake and retention studies, suggest that the superior activity of selenium derivative 3 can be attributed to its much higher triplet quantum yield.
doi:10.1021/jm060153i
PMCID: PMC3071243  PMID: 16913718
11.  Susceptibility of Potent Antiviral Inhibitor to Highly Drug Resistant Mutations D30N, I50V and L90M of HIV-1 Protease 
Journal of medicinal chemistry  2006;49(4):1379-1387.
The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V and L90M that provide resistance to the major clinical inhibitors. The inhibition constants (Ki) of TMC-114 for mutants PRD30N, PRI50V, and PRL90M were 30-, 9- and 0.14-fold, respectively, relative to wild type PR. The molecular basis for the inhibition was analyzed using high resolution (1.22–1.45 Å) crystal structures of PR mutant complexes with TMC-114. In PRD30N the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PRI50V the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PRL90M structure compared to the PR structure leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.
doi:10.1021/jm050943c
PMCID: PMC3015180  PMID: 16480273
HIV-1; protease inhibitor; crystal structure; enzyme kinetics; hydrogen bonds
12.  Prototypic Opioid Peptidomimetics Based on the Dmt-Aba-Gly Scaffold 
Journal of medicinal chemistry  2006;49(13):3990-3993.
Peptidomometic analogues, H-Dmt-Tic-NH2-CH2-Ph or -Bid exhibit δ-opioid receptor activities. Substitution of Tic by the Aba-Gly scaffold coupled to the C-termini -CH2-Ph (1), -NH-Ph (2) and Gly*-Bid (3) shifted receptor affinity and selectivity to μ-opioid receptors (Kiμ = 0.46, 1.48 and 19.9 nM, respectively) with μ agonism. These represent templates for a new class of μ-opioid agonists. Further modification with negative or positive charges could yield altered properties suitable for therapeutic application for pain relief.
doi:10.1021/jm0603264
PMCID: PMC2983084  PMID: 16789756
13.  The First Potent Inhibitor of Mammalian Group X Secreted Phospholipase A2: Elucidation of Sites for Enhanced Binding 
Journal of medicinal chemistry  2006;49(10):2858-2860.
Using the X-ray structure of human group X secreted phospholipase A2 (hGX), we carried out structure-based design of indole-based inhibitors and prepared the compounds using a new synthetic route. The most potent compound inhibited hGX and the mouse orthologue with an IC50 of 75 nM. This compound is the most potent hGX inhibitor reported to date and was also found to inhibit a subset of the other mouse and human sPLA2s.
doi:10.1021/jm060136t
PMCID: PMC2963729  PMID: 16686528
14.  Line-Walking Method for Predicting Inhibition of P450 Drug Metabolism 
Journal of medicinal chemistry  2006;49(14):4367-4373.
A new method, called line-walking recursive partitioning (LWRP), for partitioning diverse structures based on chemical properties that uses only nine descriptors of the shape, polarizability, and charge of the molecule is described. We use a training set of over 600 compounds, and a validation set of 100 compounds for the cytochrome P450 enzymes 2C9, 2D6 and 3A4. The LWRP algorithm itself incorporates elements from support vector machines (SVM) and recursive partitioning, while circumventing the need for linear or quadratic programming methods required in SVM. We compare LWRP with a many-descriptor SVM model, using the same dataset as described in the literature1. The line-walking method, using nine descriptors, predicted the validation set with about 84-90 % accuracy, a success rate comparable to the SVM method. Furthermore, line-walking was able to find errors in the assignment of inhibitor values within the validation set for the 2C9 inhibitors. When these errors are corrected, the model predicts with an even higher level of accuracy. While this method has been applied to P450 enzymes it should be of general use in partitioning molecules based on function.
doi:10.1021/jm0601553
PMCID: PMC2871544  PMID: 16821796
QSAR; P450; Drug metabolism; Drug Design; recursive partitioning; support vector machines
15.  The Development of Quantitative Structure-Binding Affinity Relationship (QSBR) Models Based on Novel Geometrical Chemical Descriptors of the Protein-Ligand Interfaces 
Journal of medicinal chemistry  2006;49(9):2713-2724.
Novel geometrical chemical descriptors have been derived based on the computational geometry of protein-ligand interfaces and Pauling atomic electronegativities (EN). Delaunay tessellation has been applied to a diverse set of 517 X-ray characterized protein-ligand complexes yielding a unique collection of interfacial nearest neighbor atomic quadruplets for each complex. Each quadruplet composition was characterized by a single descriptor calculated as the sum of the EN values for the four participating atom types. We termed these simple descriptors generated from atomic EN values and derived with the Delaunay Tessellation the ENTess descriptors and used them in the variable selection k-Nearest Neighbor quantitative structure-binding affinity relationship (QSBR) studies of 264 diverse protein-ligand complexes with known binding constants. 24 complexes with chemically dissimilar ligands were set aside as an independent validation set, and the remaining dataset of 240 complexes was divided into multiple training and test sets. The best models were characterized by the leave-one-out cross-validated correlation coefficient q2 as high as 0.66 for the training set and the correlation coefficient R2 as high as 0.83 for the test set. High predictive power of these models was confirmed independently by applying them to the validation set of 24 complexes yielding R2 as high as 0.85. We conclude that QSBR models built with the ENTess descriptors can be instrumental for predicting the binding affinity of receptor-ligand complexes.
doi:10.1021/jm050260x
PMCID: PMC2773514  PMID: 16640331
Receptor-Ligand Interactions; Delaunay Tessellation; k-Nearest Neighbors; Quantitative Structure-Activity Relationships; QSAR; Binding Affinity; Geometrical Chemical Descriptors; Model Validation; Consensus Prediction
16.  Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination 
Journal of medicinal chemistry  2006;49(10):2939-2952.
3-Methyl-1,2,3,4-tetrahydroisoquinolines (3-methyl-THIQs) are potent inhibitors of phenylethanolamine N-methyltransferase (PNMT), but are not selective due to significant affinity for the α2-adrenoceptor. Fluorination of the methyl group lowers the pKa of the THIQ amine from 9.53 (CH3) to 7.88 (CH2F), 6.42 (CHF2), and 4.88 (CF3). This decrease in pKa results in a reduction in affinity for the α2-adrenoceptor. However, increased fluorination also results in a reduction in PNMT inhibitory potency, apparently due to steric and electrostatic factors. Biochemical evaluation of a series of 3-fluoromethyl-THIQs and 3-trifluoromethyl-THIQs showed that the former were highly potent inhibitors of PNMT, but were often non-selective due to significant affinity for the α2-adrenoceptor, while the latter were devoid of α2-adrenoceptor affinity, but also lost potency at PNMT. 3-Difluoromethyl-7-substituted-THIQs have the proper balance of both steric and pKa properties and thus have enhanced selectivity versus the corresponding 3-fluoromethyl-7-substituted-THIQs and enhanced PNMT inhibitory potency versus the corresponding 3-trifluoromethyl-7-substituted-THIQs. Using the “Goldilocks Effect” analogy, the 3-fluoromethyl-THIQs are too potent (too hot) at the α2-adrenoceptor and the 3-trifluoromethyl-THIQs are not potent enough (too cold) at PNMT, but the 3-difluoromethyl-THIQs are just right. They are both potent inhibitors of PNMT and highly selective due to low affinity for the α2-adrenoceptor. This seems to be the first successful use of the β-fluorination of aliphatic amines to impart selectivity to a pharmacological agent while maintaining potency at the site of interest.
doi:10.1021/jm051262k
PMCID: PMC2770873  PMID: 16686536
17.  Structurally Simple, Potent, Plasmodium Selective Farnesyltransferase Inhibitors That Arrest the Growth of Malaria Parasites 
Journal of medicinal chemistry  2006;49(19):5710-5727.
Third world nations require immediate access to inexpensive therapeutics to counter the high mortality inflicted by malaria. Here, we report a new class of antimalarial protein farnesyltransferase (PFT) inhibitors, designed with specific emphasis on simple molecular architecture, to facilitate easy access to therapies based on this recently validated antimalarial target. This novel series of compounds represents the first Plasmodium falciparum selective PFT inhibitors reported (up to 145-fold selectivity), with lead inhibitors displaying excellent in vitro activity (IC50 < 1 nM) and toxicity to cultured parasites at low concentrations (ED50 < 100 nM). Initial studies of absorption, metabolism, and oral bioavailability are reported.
doi:10.1021/jm060081v
PMCID: PMC2728208  PMID: 16970397
18.  Discovery of Novel Triazole-Based Opioid Receptor Antagonists 
Journal of medicinal chemistry  2006;49(14):4044-4047.
We report the computer-aided design, chemical synthesis, and biological evaluation of a novel family of δ opioid receptor (DOR) antagonists containing a 1,2,4-triazole core structure that are structurally distinct from other known opioid receptor active ligands. Among those δ antagonists sharing this core structure, 8 exhibited strong binding affinity (Ki = 50 nM) for the DOR and appreciable selectivity for δ over μ and opioid receptors (δ/μ = 80; δ/κ > 200).
doi:10.1021/jm0601250
PMCID: PMC2693423  PMID: 16821764
19.  S-ALKYLATED HOMOCYSTEINE DERIVATIVES: NEW INHIBITORS OF HUMAN BETAINE-HOMOCYSTEINE S-METHYLTRANSFERASE 
Journal of medicinal chemistry  2006;49(13):3982-3989.
A series of S-alkylated derivatives of homocysteine were synthesized and characterized as inhibitors of human recombinant betaine-homocysteine S-methyltransferase (BHMT). Some of these compounds inhibit BHMT with IC50 values in the nanomolar range. BHMT is very sensitive to the structure of substituents on the sulfur atom of homocysteine. The S-Carboxybutyl and S-carboxypentyl derivatives make the most potent inhibitors, and an additional sulfur atom in the alkyl chain is well tolerated. The respective (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic, (R,S)-6-(3-amino-3-carboxy-propylsulfanyl)-hexanoic and (R,S)-2-amino-4-(2-carboxymethylsulfanyl-ethylsulfanyl)-butyric acids are very potent inhibitors and are the strongest ever reported. We determined that (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid displays competitive inhibition with respect to betaine binding with a Kiapp of 12 nM. Some of these compounds are currently being tested in mice to study the influence of BHMT on the metabolism of sulfur amino acids in vivo.
doi:10.1021/jm050885v
PMCID: PMC2622432  PMID: 16789755
Inhibitor; BHMT; zinc; transition-state; homocysteine derivatives
20.  INHIBITION OF HUMAN ACETYL- AND BUTYRYLCHOLINESTERASE BY NOVEL CARBAMATES OF (−)- AND (+)-TETRAHYDROFUROBENZOFURAN AND METHANOBENZODIOXEPINE 
Journal of medicinal chemistry  2006;49(7):2174-2185.
A new enantiomeric synthesis utilizing classical resolution provided two novel series of optically active inhibitors of cholinesterase: (−)- and (+)- O-carbamoyl phenols of tetrahydrofurobenzofuran and methanobenzodioxepine. An additional two series of (−)- and (+)-O-carbamoyl phenols of pyrroloindole and furoindole were obtained by known procedures, and their anticholinesterase actions were similarly quantified against freshly prepared human acetyl- (AChE) and butyrylcholinesterase (BChE). Both enantiomeric forms of each series demonstrated potent cholinesterase inhibitory activity (with IC50 values as low as 10 nM for AChE and 3 nM for BChE), with the exception of the (+)-O-carbamoyl phenols of pyrroloindole that lacked activity (IC50 values > 1 µM). Based on the biological data of these four series, a SAR analysis was provided by molecular volume calculations. In addition, a probable transition state model was established according to the known X-ray structure of a transition state complex of Torpedo californica AChE-m-(N,N,N,trimethylammonio)-2,2,2-trifluoroacetophenone (TcAChE-TMTFA). This model proved valuable in explaining the enantio-selectivity and enzyme subtype selectivity of each series. These carbamates are more or similarly potent to anticholinesterases in current clinical use; providing not only inhibitors of potential clinical relevance but also pharmacological tools to define drug-enzyme binding interactions within an enzyme crucial in the maintenance of cognition and numerous systemic physiological functions in health, aging and disease.
doi:10.1021/jm050578p
PMCID: PMC2610450  PMID: 16570913
21.  1-(4-Methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (Pyrovalerone) analogs. A promising class of monoamine uptake inhibitors 
Journal of medicinal chemistry  2006;49(4):1420-1432.
Dopamine, serotonin and norepinephrine are essential for neurotransmission in the mammalian system. These three neurotransmitters have been the focus of considerable research since modulation of their production and their interaction at monoamine receptors has profound effects upon a multitude of pharmacological outcomes. Our interest has focused on neurotransmitter reuptake mechanisms in a search for medications for cocaine abuse. Herein we describe the synthesis and biological evaluation of an array of 2-aminopentanophenones. This array has yielded selective inhibitors of the dopamine and norepinephrine transporters with little effect upon serotonin trafficking. A subset of compounds had no significant affinity at 5HT1A, 5HT1B, 5HT1C, D1, D2, or D3 receptors. The lead compound, racemic 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one 4a, was resolved into its enantiomers and the S isomer was found to be the most biologically active enantiomer. Among the most potent of these DAT/NET selective compounds are the 1-(3,4-dichlorophenyl)- (4u) and the 1-naphthyl- (4t) 2-pyrrolidin-1-yl-pentan-1-one analogs.
doi:10.1021/jm050797a
PMCID: PMC2602954  PMID: 16480278
22.  Novel Bifunctional Quinolonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors: Design, Synthesis, Biological Activities and Mechanism of Action 
Journal of medicinal chemistry  2006;49(6):1939-1945.
The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the β-diketo acids (DKAs) represent a major lead for anti-HIV-1drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3′-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-crosslinking experiments.
doi:10.1021/jm0511583
PMCID: PMC2602756  PMID: 16539381
23.  Synthesis and Characterization of Novel lacZ Gene Reporter Molecules: Detection of β-Galactosidase Activity Using 19F NMR of Polyglycosylated Fluorinated Vitamin B6 
Journal of medicinal chemistry  2006;49(6):1991-1999.
Gene therapy has emerged as a promising strategy for treatment of various diseases. However, widespread implementation is hampered by difficulties in assessing the success of transfection, in particular, the spatial extent of expression in the target tissue and the longevity of expression. Thus, the development of non-invasive reporter techniques based on appropriate molecules and imaging modalities may help to assay gene expression. We have previously demonstrated the ability to detect β-gal activity based on 19F NMR chemical shift associated with release of fluorophenyl aglycones from galactopyranoside conjugates. Use of fluoropyridoxol as the aglycone provides a potential less toxic alternative and we now report the design, synthesis and structural analysis of a series of novel polyglycosylated fluorinated vitamin B6 derivatives as 19F NMR sensitive aglycones for detection of lacZ gene expression. In particular, we report the activity of 3, α4, α5-tri-O-(β-D-galactopyranosyl)-6-fluoropyridoxol 4, 3-O-(β-D-galactopyranosyl)-α4, α5-di-O-(β-D-glucopyranosyl)-6-fluoropyridoxol 12 and 3-O-(β-D-galactopyranosyl)-α4, α5-di-O-(α-D-mannopyranosyl)-6-fluoropyridoxol 13. 4, 12, and 13 all show promising characteristics including highly sensitive 19F NMR response to β-gal activity (Δδ = 9.0 ~ 9.4 ppm), minimal toxicity for substrate or aglycone, and good water solubility. However, the differential glycosylation of 12 and 13 appears more advantageous for assessing lacZ gene expression in vivo.
doi:10.1021/jm051049o
PMCID: PMC2597532  PMID: 16539386
β-galactosidase; 19F NMR; lacZ gene reporter; 6-fluoropyridoxol; pH
24.  SYNTHESIS OF BIPHENYLTRIENES AS PROBES FOR β-AMYLOID PLAQUES 
Journal of medicinal chemistry  2006;49(9):2841-2844.
We report a series of p-hydroxy, p-amino, p-monomethylamino and p-monofluoroethylamino substituted biphenyltrienes (14c, 14e, 14f and 14h), which displayed high binding affinities to β-amyloid (Aβ) plaques. In an in vitro binding assay using postmortem brain homogenates of Alzheimer’s patients and [125I]9, the novel triene compounds showed excellent binding affinities (Ki = 9.0 ± 2.1, 9.0 ± 3.2, 7.5 ± 2.5 and 12 ± 3 nM for 14c, 14e, 14f and 14h, respectively). When labeled with suitable radionuclides they are potentially useful as in vivo imaging agents for detecting Aβ plaques in the brain of patients with Alzheimer’s disease.
doi:10.1021/jm051020k
PMCID: PMC2597440  PMID: 16640346
binding affinity; Alzheimer’s disease; imaging; Aβ peptides
25.  Antitumor Agents 250.† Design and Synthesis of New Curcumin Analogs as Potential Anti-Prostate Cancer Agents 
Journal of medicinal chemistry  2006;49(13):3963-3972.
In a continuing study of curcumin analogs as potential drug candidates to treat prostate cancer at both androgen-dependent and androgen-refractory stages, we designed and synthesized over 40 new analogs classified into four series: monophenyl analogs (series A), heterocycle-containing analogs (series B), analogs bearing various substituents on the phenyl rings (series C) and analogs with various linkers (series D). These new compounds were tested for cytotoxicity against two human prostate cancer cell lines, androgen-dependent LNCaP and androgen-independent PC-3. Antiandrogenic activity was also evaluated in LNCaP cells and PC-3 cells transfected with wild-type androgen receptor. Ten compounds possessed potent cytotoxicity against both LNCaP and PC-3 cells; seven only against LNCaP; and one solely against PC-3. This study established an advanced structure-activity relationship (SAR), and these correlations will guide the further design of new curcumin analogs with better anti-prostate cancer activity.
doi:10.1021/jm051043z
PMCID: PMC2597393  PMID: 16789753

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