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2.  Multicomponent Mannich Reactions Using Boron Enolates Derived from Diazo Esters and 9-BBN 
Organic letters  2011;13(9):2510-2513.
Diazo esters, arylboranes and carbamoyl imines undergo a 3-component Mannich condensation reaction. Catalyzed by Cu(II) salts, the reaction affords the corresponding isocyanate Mannich product; one that can be easily trapped in situ by other nucleophiles. The Mannich condensation corresponds to an α,α-disubstituted enolate addition to imines. The reaction was rendered asymmetric using the (-)-phenylmenthol ester in good yield and selectivities.
Graphical abstract
doi:10.1021/ol200766t
PMCID: PMC4671502  PMID: 21473584
3.  Enantioselective Addition of Boronates to Ortho-Quinone Methides Catalyzed by Chiral Biphenols 
Journal of the American Chemical Society  2012;134(49):19965-19968.
Chiral biphenols were found to catalyze the enantioselective asymmetric addition of aryl- or alkenyl-boronates to ortho-quinone methides. Substituted 2-styryl phenols were obtained in good yields (up to 95%) and high enantiomeric ratios (up to 98:2) in presence of 10 mol % of 3,3′-Br2-BINOL. A two step synthesis of (S)-4-Methoxy-dalbergione is achieved in good yield and selectivity.
doi:10.1021/ja309076g
PMCID: PMC4655814  PMID: 23206197
4.  Enantioselective Boronate Additions to N-Acyl Quinoliniums Catalyzed by Tartaric Acid 
Organic letters  2011;13(23):6316-6319.
Tartaric acid catalyzes the asymmetric addition of vinylboronates to N-acyl quinoliniums, affording highly enantioenriched dihydroquinolines. The catalyst serves to activate the boronate through a ligand-exchange reaction and generates the N-acyl quinolinium in situ from the stable quinoline-derived N,O-acetal.
doi:10.1021/ol2028702
PMCID: PMC4655815  PMID: 22067040
5.  Iron-catalyzed Rearrangements and Cycloaddition Reactions of 2H-Chromenes 
Organic letters  2011;13(24):6480-6483.
Iron(III) salts catalyse the tandem rearrangement/hetero-Diels—Alder reaction of 2H-chromenes to yield tetrahydrochromeno heterocycles. The process can occur as a homodimerization and cycloaddition process using electron rich dienophiles. Deuterium labeling and mechanistic studies revealed a hydride shift and ortho-quinone methide cycloaddition reaction pathway.
doi:10.1021/ol202772k
PMCID: PMC4655818  PMID: 22098535
6.  Brønsted Acid/Lewis Acid Cooperatively Catalyzed Addition of Diazoester to 2H-chromene Acetals 
European journal of organic chemistry  2014;2014(31):6868-6872.
A novel Brønsted acid/Lewis acid dual catalyst system has been developed to promote an efficient C–C bond formation between a range of oxocarbenium precursors derived from chromene acetals and ethyl diazoacetate. The reaction proceeds under mild conditions and is tolerant of common functionalized 2H-chromene and isochromene acetals. In addition, an asymmetric variant of diazoacetate addition towards 2H-chromene acetal is described. Continued investigations include the further optimization of asymmetric induction towards the formation of diazo ester substituted 2H-chromene.
doi:10.1002/ejoc.201403043
PMCID: PMC4233145  PMID: 25411552
Brønsted Acid; Lewis acid; Diazo compounds; Oxocarbenium; Enantioselectivity
7.  Small molecule inhibitors of Late SV40 Factor (LSF) abrogate hepatocellular carcinoma (HCC): Evaluation using an endogenous HCC model 
Oncotarget  2015;6(28):26266-26277.
Hepatocellular carcinoma (HCC) is a lethal malignancy with high mortality and poor prognosis. Oncogenic transcription factor Late SV40 Factor (LSF) plays an important role in promoting HCC. A small molecule inhibitor of LSF, Factor Quinolinone Inhibitor 1 (FQI1), significantly inhibited human HCC xenografts in nude mice without harming normal cells. Here we evaluated the efficacy of FQI1 and another inhibitor, FQI2, in inhibiting endogenous hepatocarcinogenesis. HCC was induced in a transgenic mouse with hepatocyte-specific overexpression of c-myc (Alb/c-myc) by injecting N-nitrosodiethylamine (DEN) followed by FQI1 or FQI2 treatment after tumor development. LSF inhibitors markedly decreased tumor burden in Alb/c-myc mice with a corresponding decrease in proliferation and angiogenesis. Interestingly, in vitro treatment of human HCC cells with LSF inhibitors resulted in mitotic arrest with an accompanying increase in CyclinB1. Inhibition of CyclinB1 induction by Cycloheximide or CDK1 activity by Roscovitine significantly prevented FQI-induced mitotic arrest. A significant induction of apoptosis was also observed upon treatment with FQI. These effects of LSF inhibition, mitotic arrest and induction of apoptosis by FQI1s provide multiple avenues by which these inhibitors eliminate HCC cells. LSF inhibitors might be highly potent and effective therapeutics for HCC either alone or in combination with currently existing therapies.
PMCID: PMC4694900  PMID: 26313006
LSF; HCC; FQI; mitotic arrest; apoptosis
8.  Diastereoselective Three-Component Synthesis of β-Amino Carbonyl Compounds Using Diazo Compounds, Boranes, and Acyl Imines under Catalyst-Free Conditions 
The Journal of Organic Chemistry  2014;79(10):4694-4698.
Diazo compounds, boranes, and acyl imines undergo a three-component Mannich condensation reaction under catalyst-free conditions to give the anti β-amino carbonyl compounds in high diastereoselectivity. The reaction tolerates a variety of functional groups, and an asymmetric variant was achieved using the (−)-phenylmenthol as chiral auxiliary in good yield and selectivity. These β-amino carbonyl compounds are valuable intermediates, which can be transformed to many potential bioactive molecules.
doi:10.1021/jo5003505
PMCID: PMC4033649  PMID: 24787904
9.  Gold Catalyzed Cyclization of Alkyne-Tethered Dihydropyrimidones 
Organic letters  2011;13(16):4228-4231.
Dihydropyrimidones are an important class of biologically active heterocycles accessible from the multicomponent Biginelli condensation. Further manipulation of the dihydropyrimidone skeleton gives access to unique heterocycles. Presented herein is a Au-catalyzed cyclization of alkyne-tethered dihydropyrimidinones to yield pyridopyrimidones.
doi:10.1021/ol2015658
PMCID: PMC4251731  PMID: 21749159
10.  Metal-Catalyzed Cascade Rearrangements of 3-Alkynyl Flavone Ethers 
Organic letters  2013;15(8):1962-1965.
Metal-mediated rearrangements of 3-alkynyl flavone ethers are reported. The overall process involves 5-endo enynecyclization to a platinum-containing spiro-oxocarbenium intermediate which may be trapped with methanol to produce spirodihydrofurans or further rearranged to afford either allenyl chromanediones or benzofuranones.
doi:10.1021/ol400631b
PMCID: PMC3773515  PMID: 23574045
11.  Improvement of experimental testing and network training conditions with genome-wide microarrays for more accurate predictions of drug gene targets 
Background
Genome-wide microarrays have been useful for predicting chemical-genetic interactions at the gene level. However, interpreting genome-wide microarray results can be overwhelming due to the vast output of gene expression data combined with off-target transcriptional responses many times induced by a drug treatment. This study demonstrates how experimental and computational methods can interact with each other, to arrive at more accurate predictions of drug-induced perturbations. We present a two-stage strategy that links microarray experimental testing and network training conditions to predict gene perturbations for a drug with a known mechanism of action in a well-studied organism.
Results
S. cerevisiae cells were treated with the antifungal, fluconazole, and expression profiling was conducted under different biological conditions using Affymetrix genome-wide microarrays. Transcripts were filtered with a formal network-based method, sparse simultaneous equation models and Lasso regression (SSEM-Lasso), under different network training conditions. Gene expression results were evaluated using both gene set and single gene target analyses, and the drug’s transcriptional effects were narrowed first by pathway and then by individual genes. Variables included: (i) Testing conditions – exposure time and concentration and (ii) Network training conditions – training compendium modifications. Two analyses of SSEM-Lasso output – gene set and single gene – were conducted to gain a better understanding of how SSEM-Lasso predicts perturbation targets.
Conclusions
This study demonstrates that genome-wide microarrays can be optimized using a two-stage strategy for a more in-depth understanding of how a cell manifests biological reactions to a drug treatment at the transcription level. Additionally, a more detailed understanding of how the statistical model, SSEM-Lasso, propagates perturbations through a network of gene regulatory interactions is achieved.
doi:10.1186/1752-0509-8-7
PMCID: PMC3911882  PMID: 24444313
12.  A Cycloisomerization/Friedel-Crafts Alkylation Strategy for the Synthesis of Pyrano[3,4-b]indoles 
Organic letters  2011;13(15):4012-4015.
The synthesis of pyrano[3,4-b]indoles is described. The reaction sequence involves Sonogashira coupling of dihydropyran propargyl ether scaffolds with iodoanilines to afford intermediate indoles. Lewis acid-catalyzed ionization of the dihydropyrans, followed by intramolecular C3 alkylation of the indole, provides the title compounds.
doi:10.1021/ol201532k
PMCID: PMC3146574  PMID: 21740020
13.  Asymmetric Propargylation of Ketones using Allenylboronates Catalyzed by Chiral Biphenols 
Organic letters  2011;13(15):4020-4023.
Chiral biphenols catalyze the enantioselective asymmetric propargylation of ketones using allenylboronates. The reaction uses 10 mol % of 3,3′-Br2-BINOL as the catalyst and allenyldioxoborolane as the nucleophile, in the absence of solvent, and under microwave irradiation to afford the homopropargylic alcohol. The reaction products are obtained in good yields (60 – 98%) and high enantiomeric ratios (3:1 – 99:1). Diastereoselective propargylations using chiral racemic allenylboronates result in good diastereoselectivities (dr > 86:14) and enantioselectivities (er > 92:8) under the catalytic conditions.
doi:10.1021/ol201535b
PMCID: PMC3155969  PMID: 21732609
14.  The transcription factor LSF: a novel oncogene for hepatocellular carcinoma 
The transcription factor LSF (Late SV40 Factor), also known as TFCP2, belongs to the LSF/CP2 family related to Grainyhead family of proteins and is involved in many biological events, including regulation of cellular and viral promoters, cell cycle, DNA synthesis, cell survival and Alzheimer’s disease. Our recent studies establish an oncogenic role of LSF in Hepatocellular carcinoma (HCC). LSF overexpression is detected in human HCC cell lines and in more than 90% cases of human HCC patients, compared to normal hepatocytes and liver, and its expression level showed significant correlation with the stages and grades of the disease. Forced overexpression of LSF in less aggressive HCC cells resulted in highly aggressive, angiogenic and multi-organ metastatic tumors in nude mice. Conversely, inhibition of LSF significantly abrogated growth and metastasis of highly aggressive HCC cells in nude mice. Microarray studies revealed that as a transcription factor LSF modulated specific genes regulating invasion, angiogenesis, chemoresistance and senescence. LSF transcriptionally regulates thymidylate synthase (TS) gene, thus contributing to cell cycle regulation and chemoresistance. Our studies identify a network of proteins, including osteopontin (OPN), Matrix metalloproteinase-9 (MMP-9), c-Met and complement factor H (CFH), that are directly regulated by LSF and play important role in LSF-induced hepatocarcinogenesis. A high throughput screening identified small molecule inhibitors of LSF DNA binding and the prototype of these molecules, Factor Quinolinone inhibitor 1 (FQI1), profoundly inhibited cell viability and induced apoptosis in human HCC cells without exerting harmful effects to normal immortal human hepatocytes and primary mouse hepatocytes. In nude mice xenograft studies, FQI1 markedly inhibited growth of human HCC xenografts as well as angiogenesis without exerting any toxicity. These studies establish a key role of LSF in hepatocarcinogenesis and usher in a novel therapeutic avenue for HCC, an invariably fatal disease.
PMCID: PMC3365805  PMID: 22679558
Late SV40 Factor (LSF); hepatocellular carcinoma (HCC); osteopontin (OPN); matrix metalloproteinase-9 (MMP-9); c-Met; thymidylate synthase (TS); angiogenesis; metastasis; cell cycle regulation; small molecule inhibitors; FQI1
15.  Enantioselective Additions of Boronates to Chromene Acetals Catalyzed by a Chiral Brønsted acid-Lewis acid System 
Chiral α,β-dihydroxy carboxylic acids catalyze the enantioselective addition of alkenyl- and aryl boronates to chromene acetals. The optimal carboxylic acid is a tartaric acid amide, easily synthesized via a 3-step procedure. The reaction is enhanced by the addition of Lanthanide triflate salts such as cerium(IV)-and ytterbium(III) triflate. The chiral Brønsted acid and metal Lewis acid may be used in as low as 5 mol % relative to acetal substrate. Optimization of the reaction conditions can lead to yields >70% and enantiomeric ratios as high as 99:1. Spectroscopic and kinetic mechanistic studies demonstrate an exchange process leading to a reactive dioxoborolane intermediate leading to enantioselective addition to the pyrylium generated from the chromene acetal.
doi:10.1002/anie.201003469
PMCID: PMC3035997  PMID: 20721997
16.  Skeletal Diversity via Cationic Rearrangements of Substituted Dihydropyrans 
Organic letters  2010;12(14):3222-3225.
Substituted dihydropyrans, easily accessed from a commercially available glycal, undergo acid-catalyzed rearrangement to provide highly functionalized isochroman and dioxabicyclooctane scaffolds.
doi:10.1021/ol101144k
PMCID: PMC2937281  PMID: 20550144
17.  Enantioselective Synthesis of 3,4-Chromanediones via Asymmetric Rearrangement of 3-Allyloxyflavones 
The Journal of organic chemistry  2010;75(13):4584-4590.
Asymmetric scandium (III)-catalyzed rearrangement of 3-allyloxyflavones was utilized to prepare chiral, non-racemic 3,4-chromanediones in high yields and enantioselectivities. These synthetic intermediates have been further elaborated to novel heterocyclic frameworks including angular pyrazines and dihydropyrazines. The absolute configuration of rearrangement products was initially determined by a nonempirical analysis of circular dichroism (CD) using time-dependent density functional theory (TDDFT) calculations and verified by x-ray crystallography of a hydrazone derivative. Initial studies of the mechanism support an intramolecular rearrangement pathway that may proceed through a benzopyrylium intermediate.
doi:10.1021/jo100889c
PMCID: PMC2896495  PMID: 20527786
18.  Mechanism and an Improved Asymmetric Allylboration of Ketones Catalyzed by Chiral Biphenols** 
A mechanistic study of the enantioselective asymmetric allylboration of ketones with allyldiisopropoxyborane catalyzed by chiral biphenols resulted in the development of improved reaction process. In a ligand exchange process involving the chiral biphenol and the boronate to liberate isopropanol as the key step, addition of isopropanol to the reaction was found to increase the overall rate and enantioselectivity. In the design of an improved reaction, a boronate possessing a tethered alcohol would more readily liberate catalyst at the end of a reaction. The use of allyldioxaborinane with 2 mol% (S)-3,3′-Br2-BINOL and 2 equivalents t-BuOH relative to ketone at room temperature results in high yields and enantioselectivities. Insight gathered from the mechanistic investigation resulted in the development of a reaction process that uses less catalyst (from 15 mol% to 2 mol%) at warmer temperatures (from -35 °C to room temperature).
doi:10.1002/anie.200904715
PMCID: PMC2819187  PMID: 19816902
20.  Enantioselective Synthesis of SNAP-7941 
The Journal of organic chemistry  2008;73(19):7651-7656.
An enantioselective synthesis of SNAP-7941, a potent melanin concentrating hormone receptor antagonist, was achieved using two organocatalytic methods. The first method utilized to synthesize the enantioenriched dihydropyrimidone core was the Cinchona alkaloid-catalyzed Mannich reaction of β-keto esters to acyl imines and the second was chiral phosphoric acid-catalyzed Biginelli reaction. Completion of the synthesis was accomplished via selective urea formation at the N3 position of the dihydropyrimidone with the 3-(4-phenylpiperidin-1-yl)propyl amine side chain fragment. The synthesis of SNAP-7921 highlights the utility of asymmetric organocatalytic methods in the construction of an important class of chiral heterocycles.
doi:10.1021/jo801463j
PMCID: PMC2666257  PMID: 18767801
Mannich; Cinchona alkaloids; Biginelli; phosphoric acid; dihydropyrimidone; SNAP-7941; MCH1-R
21.  Asymmetric Petasis Reactions Catalyzed by Chiral Biphenols 
doi:10.1021/ja8018934
PMCID: PMC2440570  PMID: 18459782
22.  Asymmetric Allylboration of Acyl Imines Catalyzed by Chiral Diols 
Journal of the American Chemical Society  2007;129(49):15398-15404.
Chiral BINOL-derived diols catalyze the enantioselective asymmetric allylboration of acyl imines. The reaction requires 15 mol% of (S)-3,3′-Ph2-BINOL as the catalyst and allyldiisopropoxyborane as the nucleophile. The reaction products are obtained in good yields (75 – 94%) and high enantiomeric ratios (95:5 – 99.5:0.5) for aromatic and aliphatic imines. High diastereoselectivities (dr > 98:2) and enantioselectivities (er > 98:2) are obtained in the reactions of acyl imines with crotyldiisopropoxyboranes. This asymmetric transformation is directly applied to the synthesis of maraviroc, the selective CCR5 antagonist with potent activity against HIV-1 infection. Mechanistic investigations of the allylboration reaction including IR, NMR, and mass spectrometry study indicate that acyclic boronates are activated by chiral diols via exchange of one of the boronate alkoxy groups with activation of the acyl imine via hydrogen bonding.
doi:10.1021/ja075204v
PMCID: PMC2638762  PMID: 18020334

Results 1-22 (22)