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1.
Tetrahedron ; 70(27-28): 4094-4104, 2014 Jul 08.
Article in English | MEDLINE | ID: mdl-24882888

ABSTRACT

A concise total synthesis of the complex indole alkaloid (±)-actinophyllic acid was accomplished by a sequence of reactions requiring only 10 steps from readily-available, known starting materials. The approach featured a Lewis acid-catalyzed cascade of reactions involving stabilized carbocations that delivered the tetracyclic core of the natural product in a single chemical operation. Optimal conversion of this key intermediate into (±)-actinophyllic acid required judicious selection of a protecting group strategy.

2.
J Am Chem Soc ; 135(35): 12984-6, 2013 Sep 04.
Article in English | MEDLINE | ID: mdl-23972114

ABSTRACT

Actinophyllic acid is a biologically active indole alkaloid with a unique structural framework that incorporates five contiguous stereocenters. A total synthesis of (±)-actinophyllic acid has been completed that proceeds in only 10 steps from readily available, known compounds and with the isolation of nine intermediates. The synthesis features a novel cascade of reactions of N-stabilized carbocations with π-nucleophiles to create the tetracyclic core of actinophyllic acid in a single chemical operation. This pivotal cascade sequence generates substructures of the actinophyllic acid core that are not otherwise accessible, and one key intermediate was modified to furnish several novel compounds having potentially promising anticancer activity, one of which induces cell death in a wide range of cancer cell lines.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Indole Alkaloids/chemical synthesis , Indole Alkaloids/pharmacology , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Indole Alkaloids/chemistry , Molecular Structure , Stereoisomerism , Structure-Activity Relationship
3.
Hepatology ; 57(4): 1498-508, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23184636

ABSTRACT

UNLABELLED: Antimitochondrial antibodies (AMAs) directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2) are detected in 95% of patients with primary biliary cirrhosis (PBC) and are present before the onset of clinical disease. The recent demonstration that AMAs recognize xenobiotic modified PDC-E2 with higher titers than native PDC-E2 raises the possibility that the earliest events involved in loss of tolerance are related to xenobiotic modification. We hypothesized that reactivity to such xenobiotics would be predominantly immunoglobulin M (IgM) and using sera from a large cohort of PBC patients and controls (n = 516), we examined in detail sera reactivity against either 6,8-bis(acetylthio) octanoic acid (SAc)-conjugated bovine serum albumin (BSA), recombinant PDC-E2 (rPDC-E2) or BSA alone. Further, we also defined the relative specificity to the SAc moiety using inhibition enzyme-linked immunosorbent assay (ELISA); SAc conjugate and rPDC-E2-specific affinity-purified antibodies were also examined for antigen specificity, isotype, and crossreactivity. Reactivity to SAc conjugates is predominantly IgM; such reactivity reflects a footprint of previous xenobiotic exposure. Indeed, this observation is supported by both direct binding, crossreactivity, and inhibition studies. In both early and late-stage PBC, the predominant Ig isotype to SAc is IgM, with titers higher with advanced stage disease. We also note that there was a higher level of IgM reactivity to SAc than to rPDC-E2 in early-stage versus late-stage PBC. Interestingly, this finding is particularly significant in light of the structural similarity between SAc and the reduced form of lipoic acid, a step which is similar to the normal physiological oxidation of lipoic acid. CONCLUSION: Specific modifications of the disulfide bond within the lipoic-acid-conjugated PDC-E2 moiety, i.e., by an electrophilic agent renders PDC-E2 immunogenic in a genetically susceptible host.


Subject(s)
Antibodies, Anti-Idiotypic/immunology , Liver Cirrhosis, Biliary/etiology , Liver Cirrhosis, Biliary/immunology , Mitochondria/immunology , Xenobiotics/adverse effects , Antibody Specificity , Autoantigens/immunology , Case-Control Studies , Cholangitis, Sclerosing/blood , Cholangitis, Sclerosing/immunology , Dihydrolipoyllysine-Residue Acetyltransferase/immunology , Hepatitis, Autoimmune/blood , Hepatitis, Autoimmune/immunology , Humans , Immunoglobulin M/blood , Liver Cirrhosis, Biliary/blood , Mitochondrial Proteins/immunology , Recombinant Proteins/immunology , Serum Albumin, Bovine/immunology
4.
J Autoimmun ; 37(3): 209-16, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21763105

ABSTRACT

Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC.


Subject(s)
Autoantibodies/blood , Autoantigens/immunology , Autoimmunity , Cholangitis/immunology , Dihydrolipoyllysine-Residue Acetyltransferase/immunology , Liver Cirrhosis, Biliary/immunology , Mitochondria/immunology , Mitochondrial Proteins/immunology , Acetaminophen/administration & dosage , Acetaminophen/adverse effects , Acetaminophen/chemistry , Acetaminophen/immunology , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/immunology , Autoantibodies/immunology , Autoantigens/blood , Cattle , Cholangitis/blood , Cholangitis/etiology , Enzyme-Linked Immunosorbent Assay , Fatty Acids, Monounsaturated/chemistry , Fatty Acids, Monounsaturated/immunology , Humans , Hydrophobic and Hydrophilic Interactions , Liver Cirrhosis, Biliary/blood , Liver Cirrhosis, Biliary/etiology , Mice , Mitochondria/chemistry , Protein Structure, Tertiary , Quantitative Structure-Activity Relationship , Serum Albumin/chemistry , Serum Albumin/immunology , Thioctic Acid/immunology , Thioctic Acid/metabolism
5.
J Org Chem ; 76(14): 5803-12, 2011 Jul 15.
Article in English | MEDLINE | ID: mdl-21650164

ABSTRACT

Routes to structurally unique spiro-fused pyrazolidoylisoxazolines are reported. These methods start with monosubstituted hydrazines or hydrazides and utilize the nitrile oxide 1,3-dipolar cycloaddition reaction to generate the targeted spiro-fused bis-heterocycles. Molecular shape space diversity analyses were performed on these pyrazolidoylisoxazolines showing that manipulation of the appended R groups significantly changes the molecular shape.


Subject(s)
Isoxazoles/chemical synthesis , Spiro Compounds/chemistry , Cyclization , Isoxazoles/chemistry , Molecular Structure , Stereoisomerism
7.
Org Lett ; 12(15): 3410-3, 2010 Aug 06.
Article in English | MEDLINE | ID: mdl-20617821

ABSTRACT

A diastereoselective organocatalytic aldol/oxa-Michael reaction has been developed to efficiently deliver medicinally relevant 2,3-ring-substituted chromanones. Development of this synthetic strategy revealed an unexpected kinetic anti-Saytzeff elimination; an origin for the observed selectivity is suggested on the basis of the results of quantum chemical calculations. This unusual kinetic selectivity necessitated an isomerization protocol that in turn led to the discovery of an intriguing Pd-mediated isomerization/intramolecular Friedel-Crafts-type alkylation.


Subject(s)
Chromones/chemical synthesis , Alkylation , Catalysis , Chromones/chemistry , Cyclization , Molecular Structure , Palladium/chemistry , Stereoisomerism
8.
Org Lett ; 12(11): 2524-7, 2010 Jun 04.
Article in English | MEDLINE | ID: mdl-20438102

ABSTRACT

A variety of nucleophiles, thiolates, alkoxides, amines, iodide, and cyanide, react with oxazino-, oxazolino-, and benzoxazin[3,2-b]indazoles under microwave conditions to yield a diverse set of 2-substituted 1H-indazolones. The synthetic utility of these indazoles is further demonstrated by ANRORC (addition of the nucleophile, ring-opening, and ring closure) reactions to yield isomeric pyrazoloindazolones by a process wherein iodide acts first as a nucleophile and subsequently as a leaving group.


Subject(s)
Indazoles/chemistry , Indazoles/chemical synthesis , Catalysis , Cyclization , Microwaves , Molecular Structure , Stereoisomerism
9.
Bioorg Med Chem Lett ; 20(1): 87-91, 2010 Jan 01.
Article in English | MEDLINE | ID: mdl-19954980

ABSTRACT

A developing therapy of cystic fibrosis caused by the DeltaF508 mutation in CFTR employs correction of defective CFTR chloride channel gating by a 'potentiator' and of defective CFTR protein folding by a 'corrector'. Based on SAR data for phenylglycine-type potentiators and bithiazole correctors, we designed a hybrid molecule incorporating an enzymatic hydrolysable linker to deliver the potentiator (PG01) fragment 2 and the corrector (Corr-4a) fragment 13. The hybrid molecule 14 contained PG01-OH and Corr-4a-linker-CO(2)H moieties, linked with an ethylene glycol spacer through an ester bond. The potentiator 2 and corrector 13 fragments (after cleavage) had low micromolar potency for restoration of DeltaF508-CFTR channel gating and cellular processing, respectively. Cleavage of hybrid molecule 14 by intestinal enzymes under physiological conditions produced the active potentiator 2 and corrector fragments 13, providing proof-of-concept for small-molecule potentiator-corrector hybrids as a single drug therapy for CF caused by the DeltaF508 mutation.


Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/agonists , Glycine/analogs & derivatives , Thiazoles/chemistry , Cystic Fibrosis/drug therapy , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Drug Design , Glycine/chemistry , Humans , Ion Channel Gating , Mutation , Protein Folding , Small Molecule Libraries , Structure-Activity Relationship
10.
Cell ; 137(1): 110-22, 2009 Apr 03.
Article in English | MEDLINE | ID: mdl-19303136

ABSTRACT

The transcriptional status of a gene can be maintained through multiple rounds of cell division during development. This epigenetic effect is believed to reflect heritable changes in chromatin folding and histone modifications or variants at target genes, but little is known about how these chromatin features are inherited through cell division. A particular challenge for maintaining transcription states is DNA replication, which disrupts or dilutes chromatin-associated proteins and histone modifications. PRC1-class Polycomb group protein complexes are essential for development and are thought to heritably silence transcription by altering chromatin folding and histone modifications. It is not known whether these complexes and their effects are maintained during DNA replication or subsequently re-established. We find that when PRC1-class Polycomb complex-bound chromatin or DNA is replicated in vitro, Polycomb complexes remain bound to replicated templates. Retention of Polycomb proteins through DNA replication may contribute to maintenance of transcriptional silencing through cell division.


Subject(s)
Chromatin/metabolism , DNA Replication , DNA/metabolism , Repressor Proteins/metabolism , Animals , Drosophila , Histones/metabolism , Polycomb-Group Proteins , S Phase , Xenopus laevis
11.
J Org Chem ; 73(1): 234-40, 2008 Jan 04.
Article in English | MEDLINE | ID: mdl-18052193

ABSTRACT

The parent 5H-indazolo[3,2-b]benzo[d]-1,3-oxazine heterocycle as well as a series of novel analogues have been synthesized utilizing two subsequent intramolecular heterocyclizations in one pot. A variety of diversity groups were added to explore the scope of this reaction and to provide a number of new compounds for biological screening.


Subject(s)
Indazoles/chemical synthesis , Oxazines/chemical synthesis , Cyclization , Indazoles/chemistry , Molecular Structure , Oxazines/chemistry , Stereoisomerism
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