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1.  Bioconjugation by Native Chemical Tagging of C–H Bonds 
Journal of the American Chemical Society  2013;135(35):10.1021/ja407739y.
A general C–H functionalization method for the tagging of natural products and pharmaceuticals is described. An azide-containing sulfinate reagent allows the appendage of azidoalkyl chains onto heteroaromatics, the product of which can then be attached to a monoclonal antibody by a “click” reaction. This strategy expands the breadth of bioactive small molecules that can be linked to macromolecules in a manner that is beyond the scope of existing methods in bioconjugation to permit tagging of the “seemingly untaggable.”
doi:10.1021/ja407739y
PMCID: PMC3812917  PMID: 23957305
2.  Antiproliferative Acetogenins from a Uvaria sp. from the Madagascar Dry Forest1 
Journal of Natural Products  2011;75(3):479-483.
Investigation of the endemic Madagascan plant Uvaria sp. for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of two new acetogenins. The structures of these two compounds were elucidated based on analysis of their 1D and 2D NMR spectra, circular dichroism and mass spectrometric data, together with chemical modification. The two acetogenins display weak antiproliferative activity against the A2780 ovarian cancer, the A2058 melanoma, and the H522 lung cancer cell lines.
doi:10.1021/np200697j
PMCID: PMC3243105  PMID: 22136523
3.  Association of prostate cancer risk with SNPs in regions containing androgen receptor binding sites captured by ChIP-on-chip analyses 
The Prostate  2011;72(4):376-385.
Background
Genome-wide association studies (GWAS) have identified approximately three dozen single nucleotide polymorphisms (SNPs) consistently associated with prostate cancer (PCa) risk. Despite the reproducibility of these associations, the molecular mechanism for most of these SNPs has not been well elaborated as most lie within non-coding regions of the genome. Androgens play a key role in prostate carcinogenesis. Recently, using ChIP-on-chip technology, 22,447 androgen receptor (AR) binding sites have been mapped throughout the genome, greatly expanding the genomic regions potentially involved in androgen-mediated activity.
Methodology/Principal findings
To test the hypothesis that sequence variants in AR binding sites are associated with PCa risk, we performed a systematic evaluation among two existing PCa GWAS cohorts; the Johns Hopkins Hospital and the Cancer Genetic Markers of Susceptibility (CGEMS) study population. We demonstrate that regions containing AR binding sites are significantly enriched for PCa risk-associated SNPs, i.e. more than expected by chance alone. In addition, compared with the entire genome, these newly observed risk-associated SNPs in these regions are significantly more likely to overlap with established PCa risk-associated SNPs from previous GWAS. These results are consistent with our previous finding from a bioinformatics analysis that one-third of the 33 known PCa risk-associated SNPs discovered by GWAS are located in regions of the genome containing AR binding sites.
Conclusions/Significance
The results to date provide novel statistical evidence suggesting an androgen-mediated mechanism by which some PCa associated SNPs act to influence PCa risk. However, these results are hypothesis generating and ultimately warrant testing through in-depth molecular analyses.
doi:10.1002/pros.21439
PMCID: PMC3366362  PMID: 21671247
AR; prostate cancer; GWAS; pathway association study
4.  Isolation and Synthesis of Antiproliferative Eupolauridine Alkaloids of Ambavia gerrardii from the Madagascar Dry Forest1 
Journal of natural products  2011;74(5):1169-1174.
Investigation of the Madagascan endemic plant Ambavia gerrardii (Baill.) Le Thomas (Annonaceae) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the three new alkaloids 8-hydroxyeupolauridine (1), 9-methoxyeupolauridine 1-oxide (2) and 11-methoxysampangine (3), and the three known alkaloids 4–6. The structures of 1 and 2 were confirmed by synthesis. Compounds 3, 4, and 6 showed moderate to good antiproliferative activities, with IC50 values of 10.3, 3.5, and 0.60 µM, respectively, against the A2780 human ovarian cancer cell line, and with IC50 values of 0.57, 1.77, and 0.58 µM, respectively, against the H460 human lung cancer cell line.
doi:10.1021/np200093n
PMCID: PMC3103620  PMID: 21504145
5.  Cardenolides of Leptadenia madagascariensis from the Madagascar dry forest† 
Bioorganic & medicinal chemistry  2010;19(1):422-428.
Investigation of the endemic Madagascar plant Leptadenia madagascariensis Decne. (Apocynaceae) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the four new cardenolides 1–4. The structure elucidations of these compounds were based on analyses of their 1D and 2D NMR spectra and mass spectrometric data. The cardenolides were strongly antiproliferative to the A2780 ovarian cancer cell line, with IC50 values of 0.18, 0.21, 0.17 and 0.29 μM line, and to the H460 human lung cancer cell line, with IC50 values of 0.16, 0.68, 0.37 and 0.48 μM respectively.
doi:10.1016/j.bmc.2010.11.021
PMCID: PMC3023904  PMID: 21159516
Antiproliferative activity; cardenolide; biodiversity; NMR
6.  Antiproliferative Compounds from Pongamiopsis pervilleana from the Madagascar Dry Forest 
Journal of natural products  2010;73(9):1559-1562.
Bioassay-guided fractionation of an ethanol extract of the roots of the endemic Malagasy plant Pongamiopsis pervilleana (Baill.) R. Vig. led to the isolation of the three new compounds 2′R,4′-hydroxyemoroidocarpan (1), pongavilleanine (3), and epipervilline (4) together with two known compounds identified as emoroidocarpan (2) and rotenolone (5). The structures of all compounds were determined by physical, chemical and spectroscopic evidence. The stereochemistry at C-2′ of the previously reported compound emoroidocarpan was determined to be R by the observation of a negative Cotton effect at 474 nm in the CD spectrum of its osmate ester derivative. Compounds 2–5 displayed moderate antiproliferative activity against the A2780 human ovarian cancer cell line, and rotenolone also showed micromolar antiproliferative activity towards the breast cancer BT-549, prostate cancer DU 145, NSCLC NCI-H460, and colon cancer HCC-2998 cell lines.
doi:10.1021/np100430r
PMCID: PMC2945424  PMID: 20804165
7.  Euphane triterpenoids of Cassipourea lanceolata from the Madagascar rainforest* 
Phytochemistry  2010;71(5-6):669-674.
Fractionation of an ethanol extract of a Madagascar collection of the leaves and fruit of Cassipourea lanceolata Tul. led to the isolation of three euphane triterpenoids 1–3. The 1H and 13C NMR spectra of all compounds were fully assigned using a combination of 2D NMR experiments, including COSY, TOCSY, HSQC (HMQC), HMBC and ROESY sequences. The three compounds showed weak antiproliferative activities against the A2780 human ovarian cancer cell line, with IC50 values of 25, 25 and 32 μM, respectively.
doi:10.1016/j.phytochem.2009.12.009
PMCID: PMC2847016  PMID: 20074760
Cassipourea lanceolata; Rhizophoraceae; Euphanes; Triterpenoids; NMR; Antiproliferative activity
8.  A motif-based analysis of glycan array data to determine the specificities of glycan-binding proteins 
Glycobiology  2009;20(3):369-380.
Glycan arrays have enabled detailed studies of the specificities of glycan-binding proteins. A challenge in the interpretation of glycan array data is to determine the specific features of glycan structures that are critical for binding. To address this challenge, we have developed a systematic method to interpret glycan array data using a motif-based analysis. Each glycan on a glycan array is classified according to its component sub-structures, or motifs. We analyze the binding of a given lectin to each glycan in terms of the motifs in order to identify the motifs that are selectively present in the glycans that are bound by the lectin. We compared two different methods to calculate the identification, termed intensity segregation and motif segregation, for the analysis of three well-characterized lectins with highly divergent behaviors. Both methods accurately identified the primary specificities as well as the weaker, secondary specificities of all three lectins. The complex binding behavior of wheat germ agglutinin was reduced to its simplified, independent specificities. We compiled the motif specificities of a wide variety of plant lectins, human lectins, and glycan-binding antibodies to uncover the relationships among the glycan-binding proteins and to provide a means to search for lectins with particular binding specificities. This approach should be valuable for rapidly analyzing and using glycan array data, for better describing and understanding glycan-binding specificities, and as a means to systematize and compare data from glycan arrays.
doi:10.1093/glycob/cwp187
PMCID: PMC2815654  PMID: 19946132
glycan arrays; glycan microarrays; glycan-binding protein; lectin; motif analysis
9.  Antiproliferative Triterpenoid Saponins of Dodonaea viscosa from the Madagascar Dry Forest1 
Journal of natural products  2009;72(9):1705-1707.
Bioassay-guided fractionation of an EtOH extract obtained from the roots of the Madagascan plant Dodonaea viscosa led to the isolation of two new antiproliferative oleanane-type triterpenoid saponins, dodoneasides A and B (1 and 2). The structures of these two new compounds were elucidated using 1D and 2D NMR experiments and mass spectrometry. Compounds 1 and 2 showed antiproliferative activity against the A2780 human ovarian cancer cell line with IC50 values of 0.79 and 0.70 μM, respectively.
doi:10.1021/np900293x
PMCID: PMC2930020  PMID: 19719093
10.  Antiproliferative Limonoids of a Malleastrum sp. from the Madagascar Rainforest1,† 
Journal of natural products  2008;71(3):325-329.
Bioassay-guided fractionation of an ethanol extract of a Malleastrum sp. afforded three new limonoids (1-3), malleastrones A-C, respectively. Each limonoid contained the rare tetranortriterpenoid skeleton. Structure elucidation of the isolates was carried out by analysis of one and two-dimensional NMR and X-ray diffraction data. The novel isolates 1 and 2 were tested for antiproliferative activity against a panel of cancer cell lines, and exhibited IC50 values ranging from 0.19 – 0.63 μM.
doi:10.1021/np070487q
PMCID: PMC2908263  PMID: 18177014
11.  Antiproliferative Cardenolide Glycosides of Elaeodendron alluaudianum from the Madagascar Rainforest1 
Bioorganic & medicinal chemistry  2008;17(6):2215-2218.
Bioassay-guided fractionation of an ethanol extract of a Madagascar collection of Elaeodendron alluaudianum led to the isolation of two new cardenolide glycosides (1 and 2). The 1H and 13C NMR spectra of both compounds were fully assigned using a combination of 2D NMR experiments, including 1H-1H COSY, HSQC, HMBC, and ROESY sequences. Both compounds 1 and 2 were tested against the A2780 human ovarian cancer cell line and the U937 human histiocytic lymphoma cell line assays, and showed significant antiproliferative activity with IC50 values of 0.12 and 0.07 μM against the A2780 human ovarian cancer cell line, and 0.15 and 0.08 μM against the U937 human histiocytic lymphoma cell line, respectively.
doi:10.1016/j.bmc.2008.10.092
PMCID: PMC2860880  PMID: 19058971
12.  Statistical Comparison Framework and Visualization Scheme for Ranking-Based Algorithms in High-Throughput Genome-Wide Studies 
Journal of Computational Biology  2009;16(4):565-577.
Abstract
As a first step in analyzing high-throughput data in genome-wide studies, several algorithms are available to identify and prioritize candidates lists for downstream fine-mapping. The prioritized candidates could be differentially expressed genes, aberrations in comparative genomics hybridization studies, or single nucleotide polymorphisms (SNPs) in association studies. Different analysis algorithms are subject to various experimental artifacts and analytical features that lead to different candidate lists. However, little research has been carried out to theoretically quantify the consensus between different candidate lists and to compare the study specific accuracy of the analytical methods based on a known reference candidate list. Within the context of genome-wide studies, we propose a generic mathematical framework to statistically compare ranked lists of candidates from different algorithms with each other or, if available, with a reference candidate list. To cope with the growing need for intuitive visualization of high-throughput data in genome-wide studies, we describe a complementary customizable visualization tool. As a case study, we demonstrate application of our framework to the comparison and visualization of candidate lists generated in a DNA-pooling based genome-wide association study of CEPH data in the HapMap project, where prior knowledge from individual genotyping can be used to generate a true reference candidate list. The results provide a theoretical basis to compare the accuracy of various methods and to identify redundant methods, thus providing guidance for selecting the most suitable analysis method in genome-wide studies.
doi:10.1089/cmb.2008.0151
PMCID: PMC3148127  PMID: 19361328
genome-wide association studies; candidate lists
13.  Antiproliferative compounds of Artabotrys madagascariensis from the Madagascar rainforest† 
Natural product research  2008;22(13):1169-1175.
Bioassay-guided fractionation of an ethanol extract of Artabotrys madagascariensis led to the isolation of the new compound artabotrol A (1), two butenolides (2 and 3), and the tetracyclic triterpene polycarpol (4). Structure elucidation was determined on the basis of one and two-dimensional NMR, and absolute configuration of compounds 2–4 was verified by analysis of CD and optical rotation spectra. Two of the isolates, melodorinol (2) and acetylmelodorinol (3), were found to display antiproliferative activity against five different tumor cell lines with IC50 values ranging from 2.4 to 12 µM.
doi:10.1080/14786410701726525
PMCID: PMC2786269  PMID: 18855218
butenolides; Artabotrys; Annonaceae; antiproliferative activity; NMR; HPLC
14.  Antiproliferative Cardenolides of an Elaeodendron sp. from the Madagascar Rain Forest 
Journal of natural products  2007;70(6):1064-1067.
Bioassay-guided fractionation of an ethanol extract obtained from the Madagascar plant Elaeodendron sp. led to the isolation of two new cardenolides, elaeodendrosides T and U (1 and 2). The structures of the new compounds were elucidated using 1D and 2D NMR experiments, and mass spectrometry. Compounds 1, 3, 4, and 5 showed significant antiproliferative activity against A2780 human ovarian cancer cells with IC50 values of 0.085, 0.019, 0.19, and 0.10 µM, respectively, while compounds 2 and 6 were less active.
doi:10.1021/np0701428
PMCID: PMC2464365  PMID: 17547460
15.  Normalization Benefits Microarray-Based Classification 
When using cDNA microarrays, normalization to correct labeling bias is a common preliminary step before further data analysis is applied, its objective being to reduce the variation between arrays. To date, assessment of the effectiveness of normalization has mainly been confined to the ability to detect differentially expressed genes. Since a major use of microarrays is the expression-based phenotype classification, it is important to evaluate microarray normalization procedures relative to classification. Using a model-based approach, we model the systemic-error process to generate synthetic gene-expression values with known ground truth. These synthetic expression values are subjected to typical normalization methods and passed through a set of classification rules, the objective being to carry out a systematic study of the effect of normalization on classification. Three normalization methods are considered: offset, linear regression, and Lowess regression. Seven classification rules are considered: 3-nearest neighbor, linear support vector machine, linear discriminant analysis, regular histogram, Gaussian kernel, perceptron, and multiple perceptron with majority voting. The results of the first three are presented in the paper, with the full results being given on a complementary website. The conclusion from the different experiment models considered in the study is that normalization can have a significant benefit for classification under difficult experimental conditions, with linear and Lowess regression slightly outperforming the offset method.
doi:10.1155/BSB/2006/43056
PMCID: PMC3171318  PMID: 18427588
16.  Attachment Ligands of Viable Toxoplasma gondii Induce Soluble Immunosuppressive Factors in Human Monocytes 
Infection and Immunity  1999;67(5):2547-2551.
Previous studies have demonstrated that surface antigen proteins, in particular SAG-1, of Toxoplasma gondii are important to this parasite as attachment ligands for the host cell. An in vitro assay was developed to test whether these ligands and other secretory proteins are involved in the immune response of human cells to toxoplasma. Human monocytes were infected with tachyzoites in the presence of antiparasite antibodies, and their effect on mitogen-induced lymphoproliferation was examined. The presence of antibody to either parasite-excreted proteins (MIC-1 and MIC-2) or surface proteins (SAG-1 and SAG-2) during infection neutralized the marked decrease seen in mitogen-induced lymphoproliferation in the presence of infected monocytes. Conversely, antibodies to other secreted proteins (ROP-1) and cytoplasmic molecules had no effect on parasite-induced, monocyte-mediated downregulation. Fluorescence microscope analysis detected microneme and surface antigen proteins on the monocyte cell surface during infection. These results suggest that microneme and surface antigen proteins trigger monocytes to downregulate mitogen-induced lymphoproliferation.
PMCID: PMC116002  PMID: 10225919

Results 1-16 (16)