A5033303405- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Synthetic Organic Chemistry Methods
- Chemical Synthesis and Analysis
- Lung Cancer Treatments and Mutations
- Asymmetric Synthesis and Catalysis
- Cyclopropane Reaction Mechanisms
- Microbial Natural Products and Biosynthesis
- Click Chemistry and Applications
- Computational Drug Discovery Methods
- Marine Sponges and Natural Products
- Cell death mechanisms and regulation
- RNA modifications and cancer
- Oxidative Organic Chemistry Reactions
- Cancer Treatment and Pharmacology
- Catalytic C–H Functionalization Methods
- Radical Photochemical Reactions
- Fluorine in Organic Chemistry
- Microtubule and mitosis dynamics
- Chemical synthesis and alkaloids
- Synthesis and Biological Evaluation
- MicroRNA in disease regulation
- Cancer therapeutics and mechanisms
- Asymmetric Hydrogenation and Catalysis
- Synthesis and Catalytic Reactions
University of California, Los Angeles
2015-2024
LAC+USC Medical Center
2021
Los Angeles City College
2015-2016
The University of Texas Southwestern Medical Center
1998-2011
Arog Pharmaceuticals (United States)
2011
Howard Hughes Medical Institute
2004-2007
Yale University
1993-2001
Southwestern Medical Center
2000
Stanford University
1998-1999
Cancer Research Institute
1998
We describe the synthesis and properties of a small molecule mimic Smac, pro-apoptotic protein that functions by relieving inhibitor-of-apoptosis (IAP)-mediated suppression caspase activity. The compound binds to X chromosome- encoded IAP (XIAP), cellular 1 (cIAP-1), 2 (cIAP-2) synergizes with both tumor necrosis factor alpha (TNFalpha) TNF-related apoptosis-inducing ligand (TRAIL) potently induce activation apoptosis in human cancer cells. has allowed temporal, unbiased evaluation roles...
The remarkable action of an IIII species on a tripeptide containing acyclic tyrosine/tryptophan is the key step in total synthesis (−)-diazonamide A. completed preparation this new antimitotic concise, multiply convergent, and amenable to diversification intermediates.
Abstract An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring‐forming dehydrogenation initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring substrate and occurs ambient temperature in aqueous DMF an undivided cell open air. This unique chemistry has enabled concise, scalable preparation DZ‐2384; refined analog diazonamide A slated for clinical development as cancer therapeutic.
Unable to bear the weight of scrutiny, original structure proposed for (−)-diazonamide A (1) must be revised. convergent, stereocontrolled total synthesis provided 1, which shows altered physical and spectroscopic characteristics relative those a sample natural product. Reinterpretation reported data new insight indicate that actual diazonamide is aminal-containing (S)-α-hydroxy isovaleric acid conjugate 2. Gratifyingly, synthetic C11 acetal congener 2 is, by all biological measures...
Unable to bear the weight of scrutiny, original structure proposed for (−)-diazonamide A (1) must be revised. convergent, stereocontrolled total synthesis provided 1, which shows altered physical and spectroscopic characteristics relative those a sample natural product. Reinterpretation reported data new insight indicate that actual diazonamide is aminal-containing (S)-α-hydroxy isovaleric acid conjugate 2. Gratifyingly, synthetic C11 acetal congener 2 is, by all biological measures...
We have studied a naturally occurring small-molecule antimitotic called diazonamide A. Diazonamide A is highly effective at blocking spindle assembly in mammalian cell culture and does so through unique mechanism. biotinylated form of affinity purifies ornithine delta-amino transferase (OAT), mitochondrial enzyme, from HeLa Xenopus egg extracts. In the latter system, interaction between OAT regulated by RanGTP. find that specific knockdown human cervical carcinoma osteosarcoma cells RNA...
The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities protein kinase C (PKC) isozymes, compete phorbol ester binding site on PKC, and stimulate in vitro vivo . Unlike esters, they first-stage tumor promoters. design, computer modeling, NMR solution structure, PKC binding, functional assays class synthetic bryostatin...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTSynthesis of the First Members a New Class Biologically Active Bryostatin AnaloguesPaul A. Wender, Jef De Brabander, Patrick G. Harran, Juan-Miguel Jimenez, Michael F. T. Koehler, Blaise Lippa, Cheol-Min Park, and Makoto ShiozakiView Author Information Department Chemistry, Stanford University Stanford, California 94305-5080 Cite this: J. Am. Chem. Soc. 1998, 120, 18, 4534–4535Publication Date (Web):April 23, 1998Publication History Received7...
Significance Cyclic peptides and peptidomimetics are valuable tools in biomedical research. This paper describes chemistry to convert linear, unmodified directly into stable, templated macrocycles. The ring-closing reaction is an allylic substitution catalyzed by palladium(0). It requires no tailored amino acid residues or protecting groups. proceeds rapidly at room temperature largely independent of product-ring size composition. catalysis shows broad scope predictable chemoselectivity...
The facile spirocyclization of tethered bisalkylidene 1 suggests a general synthetic strategy for preparing alkaloids the palau'amine family. development and characteristics this core model system are discussed.
Blocking cell division through the inhibition of mitosis is one most successful clinical strategies for treatment cancer. Taxanes and vinca alkaloids are in widespread use have demonstrated substantive therapeutic efficacy. Both classes compounds bind directly to tubulin, a structural component mitotic spindle. The ubiquitous utilization tubulin both cancerous normal cells, however, tempers broad spectrum activity currently used antimitotics by significant toxicities dividing tissue....
Abstract Inhibitors of apoptosis proteins (IAP) are key regulators and inhibited by the second mitocondrial activator caspases (SMAC). Previously, a small subset TNF-α–expressing non–small cell lung cancers (NSCLC) was found to be sensitive SMAC mimetics alone. In this study, we determined if mimetic (JP1201) could sensitize nonresponsive NSCLC lines standard chemotherapy. We that JP1201 sensitized NSCLCs doxorubicin, erlotinib, gemcitabine, paclitaxel, vinorelbine, combination carboplatin...
A compound that binds to tubulin in an unusual way has superior antitumor efficacy and safety a distinctive impact on microtubule curvature dynamics.
Der durch eine IIII-Spezies vermittelte Ringschluss eines acyclischen Tripeptids ist der Schlüsselschritt hier vorgestellten Totalsynthese von (−)-Diazonamid A. Dieser Zugang nicht nur schnell, sondern bietet auch etliche Möglichkeiten zur Diversifizierung.
Ansa-bridged prodiginines are bioactive pigments produced by bacteria. Certain of these structures reported to be antagonists protein–protein interactions involved in apoptosis. We describe a new entry alkaloids this type, demonstrated with concise asymmetric synthesis (+)-roseophilin (3). Our route constructs the pyrrolophane motif via phosphoryl transfer-terminated macroaldolization and passes through previously unexplored prototropic form natural product.
An asymmetric synthesis of (−)-callyspongiolide is described. The route builds the macrolide domain atypically from a disaccharide and monoterpene without passing through seco-acid. Chiral iridium catalysis selectively joins fragments. Subsequent degradation an imbedded butyrolactone via perhemiketal fragmentation affords stereo- regio-defined homoallylic alcohol that engaged directly in carbonylative macrolactonization. Further elaboration polyunsaturated appendage provides natural product...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTMacrocyclic Triarylethylenes via Heck Endocyclization: A System Relevant to Diazonamide SynthesisSusan Jeong, Xin Chen, and Patrick G. HarranView Author Information Department of Biochemistry, The University Texas Southwestern Medical Center at Dallas, 75235-9038 Cite this: J. Org. Chem. 1998, 63, 24, 8640–8641Publication Date (Web):November 5, 1998Publication History Received3 September 1998Published online5 November inissue 1...
A synthetic approach to palau'amine is described that exploits veiled symmetry in the structure. Bis-alkylidenes i have been prepared and found susceptible halogenative desymmetrization using t-BuOCl. This oxidation forms imbedded spirocyclopentane motif observed natural product. host of atypical reactions processes developed during these studies are discussed, as plans for completing total syntheses this compound class.
Hiding in plain sight: Tailored synthetic dimers of the natural product dispacamide exist as a dynamic set structural isomers. These materials isomerize readily to unveil spirocyclic glycocyamidine from which ring systems common complex pyrrole/imidazole alkaloids can be derived. Fully axinellamine congeners have been prepared this way (see scheme), wherein host unusual and unanticipated reactions are employed. Detailed facts importance specialist readers published "Supporting Information"....
Diazonamide A is a bioactive secondary metabolite whose synthesis and mode of action remain elusive decade after its discovery. In this the A/E/F-ring fragment diazonamides, 1 was converted into single isomer 2 by ring-contraction rearrangement. The stereochemistry at C10 in can be reliably predicted from configuration glycol 1.
The antimitotic depsipeptide dolastatin 15 was radiolabeled with tritium in its amino‐terminal dolavaline residue. Dolastatin 15, although potently cytotoxic, is a relatively weak inhibitor of tubulin assembly and does not inhibit the binding any other ligand to tubulin. only methodology found demonstrate an interaction between Hummel–Dreyer equilibrium chromatography on Sephadex G‐50 superfine. average apparent K d value obtained these studies about 30 µ m , no difference observed when...