PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-8 (8)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Modulation of Esterified Drug Metabolism by Tanshinones from Salvia miltiorrhiza (“Danshen”) 
Journal of natural products  2013;76(1):36-44.
The roots of Salvia miltiorrhiza (“Danshen”) are used in traditional Chinese medicine for the treatment of numerous ailments including cardiovascular disease, hypertension, and ischemic stroke. Extracts of S. miltiorrhiza roots in formulation “Compound Danshen Dripping Pill” is undergoing clinical trials in the U.S. To date, the active components of this material have not been conclusively identified. We have determined that S. miltiorrhiza roots contain potent human carboxylesterase (CE) inhibitors, due to the presence of tanshinones. Ki values in the nM range were determined for inhibition of both the liver and intestinal CEs. As CEs hydrolyze clinically used drugs, the ability of tanshinones and S. miltiorrhiza root extracts to modulate the metabolism of the anticancer prodrug irinotecan (CPT-11) was assessed. Our results indicate that marked inhibition of human CEs occurs following incubation with both pure compounds and crude material, and that drug hydrolysis is significantly reduced. Consequently, a reduction in the cytotoxicity of irinotecan is observed following dosing with either purified tanshinones or S. miltiorrhiza root extracts. It is concluded that remedies containing tanshinones should be avoided when individuals are taking esterified agents, and that patients should be warned of the potential drug-drug interaction that may occur with this material.
doi:10.1021/np300628a
PMCID: PMC3556224  PMID: 23286284
2.  IDH1 and IDH2 mutations in pediatric acute leukemia 
Leukemia  2011;25(10):10.1038/leu.2011.133.
To investigate the frequency of isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in pediatric acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), we sequenced these genes in diagnostic samples from 515 patients (227 AMLs and 288 ALLs). Somatic IDH1/IDH2 mutations were rare in ALL (N=1), but were more common in AML, occurring in 3.5% (IDH1 N=3 and IDH2 N=5), with the frequency higher in AMLs with a normal karyotype (9.8%). The identified IDH1 mutations occurred in codon 132 resulting in replacement of arginine with either cysteine (N=3) or histidine (N=1). By contrast, mutations in IDH2 did not affect the homologous residue but instead altered codon 140, resulting in replacement of arginine with either glutamine (N=4) or tryptophan (N=1). Structural modeling of IDH2 suggested that codon 140 mutations disrupt the enzyme's ability to bind its substrate isocitrate. Accordingly, recombinant IDH2 R140Q/W were unable to carry out the decarboxylation of isocitrate to α-ketoglutarate (α-KG), but instead gained the neomorphic activity to reduce α-KG to R(−)-2-hydroxyglutarete (2-HG). Analysis of primary leukemic blasts confirmed high levels of 2-HG in AMLs with IDH1/IDH2 mutations. Interestingly, 3/5 AMLs with IDH2 mutations had FLT3 activating mutations, raising the possibility that these mutations cooperate in leukemogenesis.
doi:10.1038/leu.2011.133
PMCID: PMC3883450  PMID: 21647154
acute myeloid leukemia; pediatric AML; isocitrate dehydrogenase; IDH1; IDH2; acute lymphoblastic leukemia
3.  Synthesis and evaluation of sulfonylnitrophenylthiazoles (SNPT's) as thyroid hormone receptor-coactivator interaction inhibitors 
Journal of Medicinal Chemistry  2012;55(5):2301-2310.
We previously identified a series of methylsulfonylnitrobenzoates (MSNB's) that block the interaction of the thyroid hormone receptor with its coactivators. MSNB's inhibits coactivator binding through irreversibly modifying cysteine 298 of thyroid hormone receptor (TR). Although MSNB's have better pharmacological features than our first generation inhibitors (β-aminoketones) they contain a potentially unstable ester linkage. Here we report the bioisosteric replacement of the ester linkage with a thiazole moiety, yielding sulfonylnitrophenylthiazoles (SNPT's). An array of SNPT's representing optimal side chains from the MSNB series was constructed using parallel chemistry and evaluated to test their antagonism of the TR-coactivator interaction. Selected active compounds were evaluated in secondary confirmatory assays including regulation of thyroid response element driven transcription in reporter constructs and native genes. In addition the selected SNPT's shown to be selective for TR relative to other nuclear hormone receptor (NR).
doi:10.1021/jm201546m
PMCID: PMC3308170  PMID: 22324546
4.  Optimization of Propafenone Analogues as Anti-Malarial Leads 
Journal of medicinal chemistry  2011;54(21):7477-7485.
Propafenone, a class Ic antiarrythmic drug, inhibits growth of cultured Plasmodium falciparum. While the drug’s potency is significant, further development of propafenone as an antimalarial would require divorcing the antimalarial and cardiac activities as well as improving the pharmacokinetic profile of the drug. A small array of propafenone analogs was designed and synthesized to address the cardiac ion channel and PK liabilities. Testing of this array revealed potent inhibitors of the 3D7 (drug sensitive) and K1 (drug resistant) strains of P. falciparum that possessed significantly reduced ion channel effects and improved metabolic stability. Propafenone analogues are unusual among antimalarial leads in that they are more potent against the multi-drug resistant K1 strain of P. falciparum compared to the 3D7 strain.
doi:10.1021/jm2005546
PMCID: PMC3208124  PMID: 21955244
propafenone; malaria; microwave epoxide ring opening; hERG
5.  Functional regulation of CFTR-containing macromolecular complexes: a small-molecule inhibitor approach 
The Biochemical journal  2011;435(2):451-462.
SYNOPSIS
CFTR has been shown to form multiple-protein macromolecular complexes with its interacting partners at discrete subcellular microdomains to modulate trafficking, transport and signaling in cells. Targeting protein-protein interactions within these macromolecular complexes would affect the expression or function of the CFTR channel. We specifically targeted PDZ-based LPA2-NHERF2 interaction within the CFTR-NHERF2-LPA2-containing macromolecular complexes at airway epithelia and tested its regulatory role on CFTR channel function. We identified a cell-permeable small-molecule compound that preferentially inhibits LPA2-NHERF2 interaction. We show that this compound can disrupt LPA2-NHERF2 interaction in cells and thus compromises the integrity of macromolecular complexes. Functionally, it elevates cAMP levels in proximity to CFTR and upregulates its channel activity. Our results demonstrate that CFTR Cl− channel function can be finely tuned by modulating PDZ-based protein-protein interactions within the CFTR-containing macromolecular complexes. Our study might help to identify novel therapeutic targets to treat diseases associated with dysfunctional CFTR Cl− channel.
doi:10.1042/BJ20101725
PMCID: PMC3177239  PMID: 21299497
CFTR; LPA2 receptor; NHEFR2; PDZ; protein-protein interactions; small-molecule inhibitors
6.  Evaluation of Diarylureas for Activity Against Plasmodium falciparum 
ACS medicinal chemistry letters  2010;1(9):460-465.
A library of diarylurea IGFR inhibitors was screened for activity against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. The 4-aminoquinaldine-derived diarylureas displayed promising antimalarial potency. Further exploration of the B ring of 4-aminoquinaldinyl ureas allowed identification of several quinaldin-4-yl ureas 4{13, 39} and 4{13, 58} sufficiently potent against both 3D7 and K1 strains to qualify as bone fide leads.
doi:10.1021/ml100083c
PMCID: PMC3019604  PMID: 21243104
Malaria; diarylurea
7.  Evaluation of Diarylureas for Activity Against Plasmodium falciparum 
ACS Medicinal Chemistry Letters  2010;1(9):460-465.
A library of diarylurea insulin-like growth factor 1 receptor inhibitors was screened for activity against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. The 4-aminoquinaldine-derived diarylureas displayed promising antimalarial potency. Further exploration of the B ring of 4-aminoquinaldinyl ureas allowed identification of several quinaldin-4-yl ureas 4{13, 39} and 4{13, 58} sufficiently potent against both 3D7 and K1 strains to qualify as bone fide leads.
doi:10.1021/ml100083c
PMCID: PMC3019604  PMID: 21243104
Malaria; diarylurea
8.  Structure of Cationized Glycine, Gly·M2+ (M = Be, Mg, Ca, Sr, Ba), in the Gas Phase: Intrinsic Effect of Cation Size on Zwitterion Stability 
The journal of physical chemistry. A  2000;104(43):9793-9796.
Interactions between divalent metal ions and biomolecules are common both in solution and in the gas phase. Here, the intrinsic effect of divalent alkaline earth metal ions (Be, Mg, Ca, Sr, Ba) on the structure of glycine in the absence of solvent is examined. Results from both density functional and Moller–Plesset theories indicate that for all metal ions except beryllium, the salt-bridge form of the ion, in which glycine is a zwitterion, is between 5 and 12 kcal/mol more stable than the charge-solvated structure in which glycine is in its neutral form. For beryllium, the charge-solvated structure is 5–8 kcal/mol more stable than the salt-bridge structure. Thus, there is a dramatic change in the structure of glycine with increased metal cation size. Using a Hartree–Fock-based partitioning method, the interaction between the metal ion and glycine is separated into electrostatic, charge transfer and deformation components. The charge transfer interactions are more important for stabilizing the charge-solvated structure of glycine with beryllium relative to magnesium. In contrast, the difference in stability between the charge-solvated and salt-bridge structure for magnesium is mostly due to electrostatic interactions that favor formation of the salt-bridge structure. These results indicate that divalent metal ions dramatically influence the structure of this simplest amino acid in the gas phase.
doi:10.1021/jp002970e
PMCID: PMC1343513  PMID: 16467899

Results 1-8 (8)