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1.  Defunctionalized Lobeline Analogues: Structure–Activity of Novel Ligands for the Vesicular Monoamine Transporter 
Journal of medicinal chemistry  2005;48(17):5551-5560.
(−)-Lobeline (2R,6S,10S; 1a), an antagonist at nicotinic acetylcholine receptors (nAChRs), inhibits the neurochemical and behavioral effects of methamphetamine and inhibits dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) function. VMAT2 is a target for the development of treatments for methamphetamine abuse. Structural modification of lobeline affords the defunctionalized analogues meso-transdiene (MTD) and lobelane, which have high potency and selectivity for VMAT2. To establish the structure–activity relationships within this novel class of VMAT2 ligands, specific stereochemical forms of MTD, lobelane, and other structurally related analogues have been synthesized. These compounds have been evaluated for inhibition of [3H]nicotine ([3H]NIC) binding (α4β2* nAChR), [3H]methyllycaconitine ([3H]MLA) binding (α7* nAChR), and [3H]dihydrotetrabenazine ([3H]DTBZ) binding (VMAT2). Generally, all of these analogues had lower affinities at α4β2* and α7* nAChRs compared to lobeline, thereby increasing selectivity for VMAT2. The following structural modifications resulted in only modest changes in affinity for VMAT2, affording analogues that were less potent than the lead compound, lobelane: (1) altering the stereochemistry at the C-2 and C-6 positions of the piperidino ring, (2) varying unsaturation in the piperidino C-2 and C-6 substituents, (3) introducing unsaturation into the piperidine ring, (4) ring-opening or eliminating the piperidine ring, and (5) removing the piperidino N-methyl group. Furthermore, incorporating a quaternary ammonium group into defunctionalized lobeline molecules in the cis-series resulted in significant loss of affinity for VMAT2, whereas only a modest change in affinity was obtained in the trans-series. The most potent (Ki = 630 nM) and VMAT2-selective compound evaluated was the N-methyl-2,6-cis-bis(naphthaleneethyl)piperidine analogue 28b (1-NAP-lobelane), in which the phenyl groups of lobelane were replaced with 1-naphthyl moieties. Thus, initial structure–activity relationship studies reveal that the most promising structural changes to the lobeline molecule that lead to enhancement of VMAT2 affinity and selectivity are defunctionalization, affording lobelane and MTD, and replacement of the phenyl rings of lobelane with other aromatic moieties that have a π-extended structure.
doi:10.1021/jm0501228
PMCID: PMC3617589  PMID: 16107155
2.  Alkyl-Substituted Polyaminohydroxamic Acids: A Novel Class of Targeted Histone Deacetylase Inhibitors 
Journal of medicinal chemistry  2005;48(20):6350-6365.
The reversible acetylation of histones is critical for regulation of eukaryotic gene expression. The histone deacetylase inhibitors trichostatin (TSA, 1), MS-275 (2) and suberoylanilide hydroxamic acid (SAHA, 3) arrest growth in transformed cells and in human tumor xenografts. However, 1–3 suffer from lack of specificity among the various HDAC isoforms, prompting us to design and synthesize polyaminohydroxamic acid (PAHA) derivatives 6–21. We felt that PAHAs would be selectively directed to chromatin and associated histones by the positively charged polyamine side chain. At 1 μM, compounds 12, 15 and 20 inhibited HDAC by 74.86, 59.99 and 73.85%, respectively. Although 20 was a less potent HDAC inhibitor than 1, it was more potent than 2, more effective as an initiator of histone hyperacetylation, and significantly more effective than 2 at re-expressing p21Waf1 in ML-1 leukemia cells. On the basis of these results, PAHAs 6–21 represent an important new chemical class of HDAC inhibitors.
doi:10.1021/jm0505009
PMCID: PMC3554812  PMID: 16190761
3.  ‘Reversine’ and its 2-Substituted Adenine Derivatives as Potent and Selective A3 Adenosine Receptor Antagonists 
Journal of medicinal chemistry  2005;48(15):4910-4918.
The dedifferentiation agent ‘reversine’ (2-(4-morpholinoanilino)-N6-cyclohexyladenine 2) was found to be a moderately potent antagonist for the human A3 adenosine receptor (AR) with a Ki value 0.66 μM. This result prompted an exploration of the structure-activity relationship of related derivatives, synthesized via sequential substitution of 6-chloro-2-fluoropurine with selected nucleophiles. Optimization of substituents at these two positions identified 2-phenylamino-N6-(cyclohexyl)adenine 12, 2-phenylamino-N6-(cycloheptyl)adenine 19, and 2-phenylamino-N6-(endo-norbornyl)adenine 21 as potent A3 AR ligands with Ki values of 51, 42 and 37 nM, respectively, with 30 – 200-fold selectivity in comparison to A1 and A2A ARs. The most selective A3 AR antagonist (>200-fold) was 2-phenyloxy-N6-(cyclohexyl)adenine 22. 9-Methylation of 12, but not 19, was well tolerated in A3 AR binding. Extension of the 2-phenylamino group to 2-benzyl- and 2-(2-phenylethylamino) reduced affinity. In the series of 2-phenylamino, 2-phenyloxy, and 2-phenylthio substitutions, the order of affinity at the A3 AR was oxy ≥ amino > thio. Selected derivatives, including reversine (KB value of 466 nM in Schild analysis), competitively antagonized the functional effects of a selective A3 AR agonist, i.e. inhibition of forskolin-stimulated cAMP production in stably transfected Chinese hamster ovary (CHO) cells. These results are in agreement with other studies suggesting the presence of a lipophilic pocket in the AR binding site that is filled by moderately sized cycloalkyl rings at the N6 position of both adenine and adenosine derivatives. Thus, the compound series reported herein comprise an important new series of selective A3 AR antagonists. We were unable to reproduce the dedifferentiation effect of reversine, previously reported, or to demonstrate any connection between A3 AR antagonist effects and dedifferentiation.
doi:10.1021/jm050221l
PMCID: PMC3474371  PMID: 16033270
4.  (N)-Methanocarba 2,N6-Disubstituted Adenine Nucleosides as Highly Potent and Selective A3 Adenosine Receptor Agonists 
Journal of medicinal chemistry  2005;48(6):1745-1758.
A series of ring-constrained (N)-methanocarba-5′-uronamide 2,N6-disubstituted adenine nucleosides have been synthesized via Mitsunobu condensation of the nucleobase precursor with a pseudosugar ring containing a 5′-ester functionality. Following appropriate functionalization of the adenine ring, the ester group was converted to the 5′-N-methylamide. The compounds, mainly 2-chloro substituted derivatives, were tested in both binding and functional assays at human adenosine receptors (ARs), and many were found to be highly potent and selective A3AR agonists. Selected compounds were compared in binding to the rat A3AR to assess their viability for testing in rat disease models. The N6-(3-chlorobenzyl) and N6-(3-bromobenzyl) analogues displayed Ki values at the human A3AR of 0.29 and 0.38 nM, respectively. Other subnanomolar affinities were observed for the following N6 derivatives: 2,5-dichlorobenzyl, 5-iodo-2-methoxybenzyl, trans-2-phenyl-1-cyclopropyl, and 2,2-diphenylethyl. Selectivity for the human A3AR in comparison to the A1AR was (fold): the N6-(2,2-diphenylethyl) analogue 34 (1900), the N6-(2,5-dimethoxybenzyl) analogue 26 (1200), the N6-(2,5-dichlorobenzyl) and N6-(2-phenyl-1-cyclopropyl) analogues 20 and 33 (1000), and the N6-(3-substituted benzyl) analogues 17, 18, 28, and 29 (700–900). Typically, even greater selectivity ratios were obtained in comparison with the A2A and A2BARs. The (N)-methanocarba-5′-uronamide analogues were full agonists at the A3AR, as indicated by the inhibition of forskolin-stimluated adenylate cyclase at a concentration of 10 µM. The N6-(2,2-diphenylethyl) derivative was an A3AR agonist in the (N)-methanocarba-5′-uronamide series, although it was an antagonist in the ribose series. Thus, many of the previously known groups that enhance A3AR affinity in the 9-riboside series, including those that reducing intrinsic efficacy, may be adapted to the (N)-methanocarba nucleoside series of full agonists.
doi:10.1021/jm049580r
PMCID: PMC3463111  PMID: 15771421
5.  The Protein Farnesyltransferase Inhibitor Tipifarnib as a new Lead for the Development of Drugs against Chagas Disease 
Journal of Medicinal Chemistry  2005;48(17):5415-5418.
Tipifarnib (R115777), an inhibitor of human protein farnesyltransferase (PFT), is shown to be a highly potent inhibitor of Trypanosoma cruzi growth (ED50 = 4 nM). Surprisingly, this is due to the inhibition of cytochrome P450 sterol 14-demethylase (CYP51, EC 1.14.13.70). Homology models of the T. cruzi CYP51 were used for the prediction of the binding modes of the substrate lanosterol and of Tipifarnib, providing a basis for the design of derivatives with selectivity for TcCYP51 over human PFT.
doi:10.1021/jm050441z
PMCID: PMC3265986  PMID: 16107140
6.  Synthesis and Immunological Properties of N-Modified GM3 Antigens as Therapeutic Cancer Vaccines 
Journal of medicinal chemistry  2005;48(3):875-883.
The problem of immunotolerance to GM3, an important tumor-associated trisaccharide antigen, seriously hinders its usage in cancer vaccine development. To solve this problem, the keyhole limpet hemocyanin (KLH) conjugates of a series of GM3 derivatives were synthesized and screened as therapeutic cancer vaccines. First, the β-linked anomeric azides of differently N-acylated GM3 analogs were prepared by a highly convergent procedure. Next, a pentenoyl group was linked to the reducing end of the carbohydrate antigens following selective reduction of the azido group. The linker was thereafter ozonolyzed to give an aldehyde functionality permitting the conjugation of the antigens to KLH via reductive amination. Finally, the immunological properties of the resultant glycoconjugates were studied in C57BL/6 mice by assessing the titers of specific antibodies induced by the GM3 analogs. While KLH-GM3 elicited low levels of immune response, the KLH conjugates of N-propionyl, N-butanoyl, N-iso-butanoyl and N-phenylacetyl GM3’s induced robust immune reactions with antibodies of multiple isotypes, indicating significantly improved and T-cell dependent immune responses that lead to isotype switching, affinity maturation and the induction of immunological ‘memory’. It was suggested that GM3PhAc-KLH is a promising vaccine candidate for glycoengineered immunotherapy of cancer with GM3 as the primary target.
doi:10.1021/jm0494422
PMCID: PMC3180873  PMID: 15689172
carbohydrate; sialic acid; GM3; glycoconjugate; cancer vaccine
7.  A Combination of Docking, QM/MM Methods, and MD Simulation for Binding Affinity Estimation of Metalloprotein Ligands 
Journal of medicinal chemistry  2005;48(17):5437-5447.
To alleviate the problems in the receptor-based design of metalloprotein ligands due to inadequacies in the force-field description of coordination bonds, a four-tier approach was devised. Representative ligand-metalloprotein interaction energies are obtained by subsequent application of (1) docking with metal-binding-guided selection of modes; (2) optimization of the ligand-metalloprotein complex geometry by combined quantum mechanics and molecular mechanics (QM/MM) methods; (3) conformational sampling of the complex with constrained metal bonds by force-field based molecular dynamics (MD); and (4) a single point QM/MM energy calculation for the time-averaged structures. The QM/MM interaction energies are, in a linear combination with the desolvation-characterizing changes in the solvent-accessible surface areas, correlated with experimental data. The approach was applied to structural correlation of published binding free energies of a diverse set of 28 hydroxamate inhibitors to zinc-dependent matrix metalloproteinase 9 (MMP-9). Inclusion of step 3 and step 4 significantly improved both correlation and prediction. The two descriptors explained 90% of variance in inhibition constants of all 28 inhibitors, ranging from 0.08 to 349 nM, with the average unassigned error of 0.318 log units. The structural and energetic information obtained from the time-averaged MD simulation results helped understand the differences in binding modes of related compounds.
doi:10.1021/jm049050v
PMCID: PMC2896055  PMID: 16107143
molecular dynamics - MD; QM/MM; docking; linear response approximation; binding affinity; free energy of binding; matrix metalloproteinases; metalloproteins
8.  A Comparison of the Binding Sites of Matrix Metalloproteinases and Tumor Necrosis Factor-α Converting Enzyme: Implications for Selectivity 
Journal of medicinal chemistry  2005;48(7):2361-2370.
MMPs and TACE (ADAM-17) assume independent, parallel or opposite pathological roles in cancer, arthritis, and several other diseases. For therapeutic purposes, selective inhibition of individual MMPs and TACE is required in most cases due to distinct roles in diseases and the need to preserve activities in normal states. Toward this goal, we compared force-field interaction energies of five ubiquitous inhibitor atoms with flexible binding sites of 24 known human MMPs and TACE. The results indicate that MMPs 1−3, 10, 11, 13, 16, and 17 have at least one subsite very similar to TACE. S3 subsite is the best target for development of specific TACE inhibitors. Specific binding to TACE compared to most MMPs is promoted by placing a negatively charged ligand part at the bottom of S2 subsite, at the entrance of S1’ subsite, or the part of S3’ subsite that is close to catalytic zinc. Numerous other clues, consistent with available experimental data, are provided for design of selective inhibitors.
doi:10.1021/jm0491703
PMCID: PMC2896057  PMID: 15801829
matrix metalloproteinase - MMP; tumor necrosis factor-α converting enzyme – TACE; ADAM-17; binding site; similarity; selectivity; ligand design; drug design
9.  Studies Toward the Pharmacophore of Salvinorin A, a Potent Kappa Opioid Receptor Agonist 
Journal of medicinal chemistry  2005;48(2):345-348.
Salvinorin A (1), from the sage Salvia divinorum, is a potent and selective kappa opioid receptor (KOR) agonist. We screened other salvinorins and derivatives for binding affinity and functional activity at opioid receptors. Our results suggest that the methyl ester and furan ring are required for activity, but that the lactone and ketone functionalities are not. Other salvinorins showed negligible binding affinity at the KOR. None of the compounds bound to mu or delta opioid receptors.
doi:10.1021/jm049438q
PMCID: PMC2777653  PMID: 15658846
10.  Semi-Rational Design of (N)-Methanocarba Nucleosides as Dual Acting A1 and A3Adenosine Receptor Agonists: Novel Prototypes for Cardioprotection 
Journal of medicinal chemistry  2005;48(26):8103-8107.
Ring-constrained adenosine analogues have been designed to act as dualagonists at tissue-protective A1 and A3 adenosine receptors (ARs). 9-Ribosides transformed into the ring-constrained (N)-methanocarba-2-chloro-5′-uronamides consistently lost affinity at A1/A2AARs and gained at A3AR. Among 9-riboside derivatives, only N6-cyclopentyl and 7-norbornyl moieties were extrapolated for mixed A1/A3 selectivity and rat/human A3AR equipotency. Consequently, 2 was balanced in affinity and potency at A1/A3ARs as envisioned and dramatically protected in an intact heart model of global ischemia and reperfusion.
doi:10.1021/jm050726b
PMCID: PMC2597460  PMID: 16366590
11.  Conversion of the Potent δ-Opioid Agonist H-Dmt-Tic-NH-CH2-Bid into δ-Opioid Antagonists by N1-Benzimidazole Alkylation1 
Journal of medicinal chemistry  2005;48(26):8112-8114.
N1-Alkylation of 1H-benzimidizole of the δ agonist H-Dmt-Tic-NH-CH2-Bid with hydrophobic, aromatic, olefinic, acid, ethyl ester or amide (1–6) became δ antagonists (pA2 = 8.52–10.14). δ- and μ-Opioid receptor affinities were high (Kiδ = 0.12–0.36 nM and Kiμ = 0.44–1.42 nM). Only δ antagonism (pA2 = 8.52–10.14) was observed; μ agonism (IC50 = 30–450 nM) was not correlated with changes in alkylating agent or δ antagonism and some compounds yielded mixed δ antagonism/μ agonism.
doi:10.1021/jm058259l
PMCID: PMC2597450  PMID: 16366592
12.  N-Picolyl Derivatives of Kemp’s Triamine as Potential Antitumor Agents: A Preliminary Investigation 
Journal of medicinal chemistry  2005;48(25):7993-7999.
Pre-organized tripodal ligands such as the N-picolyl derivatives of cis,cis-1,3,5-triamino-cis,cis-1,3,5-trimethylcyclohexane (Kemp’s triamine) were prepared as analogs to N,N’,N”- tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane (tachpyr) in hopes of enhancing the rate of formation and stability of the metal complexes. A tricyclic bisaminal was formed via the reduction of the Schiff base while the tri(picolyl) derivative was synthesized via reductive amination of pyridine carboxaldehyde. Their cytotoxicities to the HeLa cell line were evaluated and directly compared to tachpyr and N,N’,N”- tris(2-pyridylmethyl)-tris(2-aminoethyl)amine (trenpyr). Results indicate that N,N’,N”-tris(2-pyridylmethyl)-cis,cis-1,3,5-triamino-cis,cis-1,3,5-trimethylcyclohexane (Kemp’s pyr) exhibits cytotoxic activity against the HeLa cancer cell line comparable to tachpyr (IC50 ~ 8.0 µM). Both Kemp’s pyr and tachpyr show higher cytotoxic activity over the aliphatic analogue of trenpyr (IC50 ~ 14 µM) suggesting that the major contributor to the activity is the ligand’s ability to form a stable and tight complex and that the equatorial/axial equilibrium impacting the complex formation for the cyclohexane-based ligands is not significant.
doi:10.1021/jm050724r
PMCID: PMC2597376  PMID: 16335923
13.  F-18 Stilbenes As PET Imaging Agents For Detecting β-Amyloid Plaques In The Brain 
Journal of medicinal chemistry  2005;48(19):5980-5988.
Imaging agents targeting β,-amyloid (Aβ) may be useful for diagnosis and treatment of patients with Alzheimer’s disease (AD). Compounds 3e and 4e are fluorinated stilbene derivatives displaying high binding affinities for Aβ plaques in AD brain homogenates (Ki = 15 ± 6 and 5.0 ± 1.2 nM, respectively). In vivo biodistributions of [18F]3e and [18F]4e in normal mice exhibited excellent brain penetrations (5.55 and 9.75 % dose/g at 2 min) and rapid brain washouts were observed, especially for [18F]4e (0.72% dose/g at 60 min). They also showed in vivo plaque labeling in APP/PS1 or Tg2576 transgenic mice, animal models for AD. Autoradiography of postmortem AD brain sections and AD homogenate binding studies confirmed the selective and specific binding properties to Aβ plaques. In conclusion, the preliminary results strongly suggest that these fluorinated stilbene derivatives, [18F]3e and [18F]4e, are suitable candidates as Aβ plaque imaging agents for studying patients with AD.
doi:10.1021/jm050166g
PMCID: PMC2593886  PMID: 16162001
14.  Iterative Approach to the Discovery of Novel Degarelix Analogues: Substitutions at Positions 3, 7 and 8. Part II 
Journal of medicinal chemistry  2005;48(15):4851-4860.
Degarelix, (FE200486, Ac-d-2Nal1-d-4Cpa2-d-3Pal3-Ser4-4Aph(l-Hor)5-d-4Aph(Cbm)6-Leu7-Ilys8-Pro9-d-Ala10-NH2) is a potent and very long acting antagonist of gonadotropin-releasing hormone (GnRH) after subcutaneous administration in mammals including humans. Analogues of degarelix were synthesized, characterized and screened for the antagonism of GnRH-induced response in a reporter gene assay in HEK-293 cells expressing the human GnRH receptor. The duration of action was also determined in the castrated male rat assay in order to measure the extent (efficacy and duration of action) of inhibition of luteinizing hormone (LH) release. Structurally, this series of analogues has novel substitutions at positions 3, 7, 8 and Nα-methylation at positions 6, 7 and 8 in the structure of degarelix. These substitutions were designed to probe the spatial limitations of the receptors cavity and to map the steric and ionic boundaries. Some functional groups were introduced that were hypothesized to influence the phamacokinetic properties of the analogues like bioavailability, solubility, intra- or inter-molecular hydrogen bond forming capacity and ability to bind carrier proteins. Substitutions at positions 3 ([Nβ-(2-pyridyl-methyl)d-Dap3]degarelix, IC50 = 2.71 nM) (5), 7 ([Pra7]degarelix, IC50 = 2.11 nM) (16), 8 ([Nδ-(IGly)Orn8]degarelix, IC50 = 1.38 nM) (20), and N-methylation ([Nα-methyl-Leu7]degarelix, IC50 = 1.47 nM) (32) yielded analogues that were equipotent to degarelix (2) in vitro (IC50 = 1.64 nM) but shorter acting in vivo. Out of the 33 novel analogues tested for the duration of action in this series, two analogues ([Nε-cyclohexyl-Lys8]degarelix, IC50 = 1.50 nM) (23) and ([Nβ-(IβAla)Dap8]degarelix, IC50 = 1.98 nM) (26) had antagonist potencies and duration of action similar to that of azaline B {inhibited LH (>80%) release for >72 h after sc injection to castrated male rats at a standard dose of 50 µg/rat in 5% mannitol}. Under similar conditions analogues ([Nγ-(IGly)Dab8]degarelix, IC50 = 1.56 nM) (21) and ([IOrn8]degarelix, IC50 = 1.72 nM) (18) had a longer duration of action {inhibited LH (>96 h) release} than azaline B, however they were shorter acting than degarelix. Hydrophilicity of these analogues, a potential measure of their ability to be formulated for sustained release, was determined using RP-HPLC at neutral pH yielding analogues with shorter as well as longer retention times. No correlation was found between retention times, antagonist potency or duration of action.
doi:10.1021/jm050134t
PMCID: PMC2593149  PMID: 16033265
antagonist; azaline B; degarelix; endometriosis; GnRH receptor; gonadotropin-releasing hormone; luteinizing hormone; prostate cancer
15.  N-Substituted cis-4a-(3-Hydroxyphenyl)-8a-methyloctahydroisoquinolines Are Opioid Receptor Pure Antagonists 
Journal of medicinal chemistry  2005;48(26):8182-8193.
N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a–g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a–g can exist in conformations where the 3-hydroxyphenyl substituent is either axial or equatorial similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl equatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single crystal X-ray analysis of 6a shows that the 3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling studies also suggest that the equatorial conformation has the lower potential energy relative to the axial conformation. Evaluation of compounds 6a–g in the [35S]GTP-γ-S in vitro functional assay showed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a Ke of 0.27 nM at the κ opioid receptor with 154- and 46-fold selectively relative to the μ and δ receptors, respectively, possessed the best combination of κ potency and selectivity.
doi:10.1021/jm058261c
PMCID: PMC2585695  PMID: 16366600
16.  Human P2Y6 Receptor: Molecular Modeling Leads to the Rational Design of a Novel Agonist Based on a Unique Conformational Preference 
Journal of medicinal chemistry  2005;48(26):8108-8111.
Combining molecular dynamics (MD) in a hydrated phospholipids (DOPC) bilayer, Monte Carlo search, and synthesis of locked nucleotide analogues we discovered that the Southern conformation of the ribose is preferred for ligand recognition by the P2Y6 receptor. 2′-Deoxy-(S)-methanocarbaUDP was found to be a full agonist of the receptor and displayed a 10-fold higher potency than the corresponding flexible 2′-deoxyUDP. MD results also suggested a conformational change of the second extracellular loop consequent to agonist binding.
doi:10.1021/jm050911p
PMCID: PMC2583457  PMID: 16366591
17.  QSAR Studies of Copper Azamacrocycles and Thiosemicarbazones 
Journal of medicinal chemistry  2005;48(17):5561-5569.
Genetic algorithms (GA) were used to develop specific copper metal-ligand force field parameters for the MM3 force field, from a combination of crystallographic structures and ab initio calculations. These new parameters produced results in good agreement with experiment and previously reported copper metal-ligand parameters for the AMBER force field. The MM3 parameters were then used to develop several Quantitative Structure Activity Relationship (QSAR) models. A successful QSAR for predicting the lipophilicity (logPow) of several classes of Cu(II) chelating ligands, was built using a training set of thirty-two Cu(II) radiometal complexes and six simple molecular descriptors. The QSAR exhibited a correlation between the predicted and experimental logPow with a r2 = 0.95, q2 = 0.92. When applied to an external test set of eleven Cu(II) complexes the QSAR preformed with great accuracy; r2 = 0.93 and a q2 = 0.91 utilizing a leave-one-out cross-validation analysis. Additional QSAR models were developed to predict the biodistribution of a smaller set of Cu(II) bis(thiosemicarbazone) complexes.
doi:10.1021/jm0501376
PMCID: PMC2566539  PMID: 16107156
18.  Conformationally Constrained Analogues of Diacylglycerol (DAG). 25. Exploration of the sn-1 and sn-2 carbonyl functionality reveals the essential role of the sn-1 carbonyl at the lipid interface in the binding of DAG-lactones to protein kinase C 
Journal of medicinal chemistry  2005;48(18):5738-5748.
A group of DAG-lactones with altered functionality (C=O → CH2 or C=O → C=S) at the sn-1 and sn-2 carbonyl pharmacophores was synthesized and used as probes to dissect the individual role of each carbonyl in binding to protein kinase C (PKC). The results suggest that the hydrated sn-1 carbonyl is engaged in very strong hydrogen bonding interactions with the charged lipid headgroups and organized water molecules at the lipid interface. Conversely, the sn-2 carbonyl has a more modest contribution to the binding process as a result of its involvement with the receptor (C1 domain) via conventional hydrogen bonding to the protein. The parent DAG-lactones, E-6 and Z-7, were designed to bind exclusively in the sn-2 binding mode to insure the correct orientation and disposition of pharmacophores at the binding site.
doi:10.1021/jm050352m
PMCID: PMC2563800  PMID: 16134942
19.  Synthesis of classical, four-carbon bridged 5-substituted furo[2,3-d]pyrimidine and 6-substituted pyrrolo[2,3-d]pyrimidine analogues as antifolates1 
Journal of medicinal chemistry  2005;48(16):5329-5336.
We report, for the first time, the biological activities of four carbon atom bridged classical antifolates on dihydrofolate reductase (DHFR), thymidylate synthase (TS) and folylpolyglutamate synthetase (FPGS) as well as on antitumor activity. Extension of the bridge homologation studies of classical two-carbon bridged antifolates, a 5-substituted 2,4-diaminofuro[2,3-d]pyrimidine (1) and a 6-subsituted 2-amino-4-oxopyrrolo[2,3-d]pyrimidine (2) afforded two, four-carbon bridged antifolates, analogues 5 and 6, with enhanced FPGS substrate activity and inhibitory activity against tumor cells in culture (EC50 values of ≤ 10−7 M) compared with the two-carbon bridged analogues. These results support our original hypothesis that the distance and orientation of the side chain para-aminobenzoyl-L-glutamate moiety with respect to the pyrimidine ring is a crucial determinant of biological activity. In addition, this study demonstrates that, for classical antifolates that are substrates for FPGS, poor inhibitory activity against isolated target enzymes is not necessarily a predictor of a lack of antitumor activity.
doi:10.1021/jm058213s
PMCID: PMC2538949  PMID: 16078850
20.  Synthesis, Anti-HIV Activity, and Metabolic Stability of New Alkenyldiarylmethane (ADAM) HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) 
Journal of medicinal chemistry  2005;48(19):6140-6155.
Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are part of the combination therapy currently used to treat HIV infection. Based on analogy with known HIV-1 NNRT inhibitors, eighteen novel alkenyldiarylmethanes (ADAMs) containing 5-chloro-2-methoxyphenyl, 3-cyanophenyl or 3-fluoro-5-trifluoromethylphenyl groups were synthesized and evaluated as HIV inhibitors. Their stabilities in rat plasma have also been investigated. Although introducing 5-chloro-2-methoxyphenyl, or 3-fluoro-5-trifluoromethylphenyl groups into alkenyldiarylmethanes does not maintain the antiviral potency, the structural modification of alkenyldiarylmethanes with a 3-cyanophenyl substituent can be made without a large decrease in activity. The oxazolidinonyl group was introduced into the alkenyldiarylmethane framework and found to confer enhanced metabolic stability in rat plasma.
doi:10.1021/jm050452s
PMCID: PMC2528834  PMID: 16162014
21.  Synthesis and evaluation of cyclic secondary amine substituted phenyl and benzyl nitrofuranyl amides as novel antituberculosis agents 
Journal of medicinal chemistry  2005;48(26):8261-8269.
In an ongoing effort to develop new and potent antituberculosis agents, a second generation series of nitrofuranyl amides was synthesized based on the lead compound 5-nitro-furan-2-carboxylic acid 3,4-dimethoxy-benzylamide. The primary design consideration was to improve the solubility and consequently bioavailability of the series by the addition hydrophilic rings to the benzyl and phenyl B ring core. The synthesis of 27 cyclic, secondary amine substituted phenyl and benzyl nitrofuranyl amides is described and their activity against M. tuberculosis reported. The series showed a strong structure-activity relationship as the benzyl nitrofuranyl amides were significantly more active than similarly substituted phenyl nitrofuranyl amides. Para-substituted benzyl piperazines showed the most antituberculosis activity. Compounds in the series were subsequently selected for bioavailability and in vivo testing. This study lead to the successful discovery of novel compounds with increased antituberculosis activity in vitro and a better understanding of the requisite pharmacological properties to advance this class.
doi:10.1021/jm050765n
PMCID: PMC2527484  PMID: 16366608
22.  A New Bisintercalating Anthracycline with Picomolar DNA Binding Affinity 
Journal of medicinal chemistry  2005;48(26):8209-8219.
A new bisintercalating anthracycline (WP762) has been designed, in which monomeric units of daunorubicin have been linked through their amino groups on the daunosamine moieties using an m-xylenyl linker. Differential scanning calorimetry and UV melting experiments were used to measure the ultratight binding of WP762 to DNA. The binding constant for the interaction of WP762 with herring sperm DNA was determined to be 7.3 (±0.2) × 1012 M−1 at 20°C. The large favorable binding free energy of −17.3 kcal mol−1 was found to result from a large negative enthalpic contribution of −33.8 kcal mol−1 and an opposing entropic term (−TΔS = +16.5 kcal mol−1). A comparative molecular modeling study rationalized the increased binding by the m-xylenyl linker of WP762 positioning in the DNA minor groove compared to the p-xylenyl linker found in WP631, the first bis-anthracycline of this type. The cytotoxicity of WP762 was compared to that of other anthracyclines in Jurkat T lymphocytes. These studies, together with an analysis of the cell-cycle traverse in the presence of WP762, suggest that in these cells the new drug is more cytotoxic than the structurally related WP631.
doi:10.1021/jm050902g
PMCID: PMC2522373  PMID: 16366602
23.  Binding of Rasagiline-related Inhibitors to Human Monoamine Oxidases 
Journal of medicinal chemistry  2005;48(26):8148-8154.
Monoamine oxidases A and B (MAO A and B) catalyze neurotransmitters degradation and represent drug targets for the treatment of neurodegenerative disorders. Rasagiline is an irreversible, MAO B-selective inhibitor that has been approved as a novel anti-Parkinson’s drug. In this study we investigate the inhibition of recombinant human MAO A and MAO B by several rasagiline analogues. Different substituents added onto the rasagiline scaffold alter the binding affinity depending on the position on the aminoindan ring and on the size of the substituent. Compounds with a hydroxyl group on either the C4 or the C6 atom inhibit both isozymes, whereas a bulkier substituent such as a carbamate is tolerated only at the C4 position. The 1.7 Å crystal structure of MAO B in complex with 4-(N-methyl-N-ethyl-carbamoyloxy)-N-methyl-N-propargyl-1(R)-aminoindan shows that the binding mode is similar to that of rasagiline with the carbamate moiety occupying the entrance cavity space. 1(R)-aminoindan, the major metabolic product of rasagiline, and its analogues reversibly inhibit both MAO A and MAO B. The crystal structure of N-methyl-1(R)-aminoindan bound to MAO B shows that its aminoindan ring adopts a different orientation compared to that of rasagiline.
doi:10.1021/jm0506266
PMCID: PMC2519603  PMID: 16366596
human MAO B structure; inhibitor binding; rasagiline; flavin
24.  Discovery of a Potent, Selective, and Efficacious Class of Reversible α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase Effective as Analgesicsa 
Journal of medicinal chemistry  2005;48(6):1849-1856.
Fatty acid amide hydrolase (FAAH) degrades neuromodulating fatty acid amides including anandamide (endogenous cannabinoid agonist) and oleamide (sleep-inducing lipid) at their sites of action and is intimately involved in their regulation. Herein we report the discovery of a potent, selective, and efficacious class of reversible FAAH inhibitors that produce analgesia in animal models validating a new therapeutic target for pain intervention. Key to the useful inhibitor discovery was the routine implementation of a proteomics-wide selectivity screen against all serine hydrolases ensuring selectivity for FAAH coupled with systematic in vivo examinations of candidate inhibitors.
doi:10.1021/jm049614v
PMCID: PMC2492884  PMID: 15771430
25.  Modifications to the Tetracaine Scaffold Produce Cyclic Nucleotide-Gated Channel Blockers with Widely Varying Efficacies 
Journal of medicinal chemistry  2005;48(18):5805-5812.
Five new tetracaine analogues were synthesized and evaluated for potency of blockade of cyclic nucleotide-gated channels relative to a multiply charged tetracaine analogue described previously (4). Increased positive charge at the tertiary amine end of tetracaine results in higher potency and voltage dependence of block. Modifications that reduce the hydrophobic character at the butyl tail are deleterious to block. The tetracaine analogues described here have apparent affinities for CNGA1 channels that vary over nearly 8 orders of magnitude.
doi:10.1021/jm0502485
PMCID: PMC2467444  PMID: 16134947

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