Novel approach to tumor specific drug delivery: use of a naphthyridine drug linker with a DNA hairpin, A

2011 Summer.Includes bibliographical references.Herein are documented our efforts in two projects, beginning with studies toward elucidating the biosynthesis of prenylated indole alkaloids from two different Aspergillus species. Marine-derived Aspergillus sp. and terrestrial-derived Aspergillus versicolor were found to produce antipodal metabolites, in which we have developed several putative biosynthetic pathways to determine the enantio-diverging point of these fungal cultures. Through the synthesis of several potential intermediates, both with and without isotopic labeling, as well as through bioinformatics analysis of both the (-)- and (+)-notoamide biosynthetic gene clusters, significant progress has been made toward identifying a single biosynthetic precursor that serves as an intermediate to the postulated enantio-diverging event, the intramolecular hetero Diels-Alder cycloaddition. In the second project discussed, through collaboration with Dr. James Berenson at the University of California, Los Angeles, we have developed a novel tumor specific drug delivery system. Two naphthyridine-drug derivatives were synthesized and conjugated to a modified DNA oligonucleotide specifically targeted for multiple myeloma cells. The oligonucleotide-drug conjugate was successfully delivered and activated specifically within RMI8226 multiple myeloma cells

What is a plant gall and how do insects make them?

Abstract only availableGalls are novel plant organs, produced under the insect's direction. These ecotopic organs provide food and shelter for the developing larvae. The cell of many galls are richer in starch and sugars than normal tissues and the insect uses this rich food to grow in a protected place. In a previous study of galls on grape leaves, the lab found that plant genes specifying the vegetative-to-reproductive transition and fruit and seed identity were expressed in developing galls. To fully test the hypothesis that insects make plant galls by upregulating fruit genes, one needs to block expression of the genes and show that a gall can't be made. This is difficult to do in grape but can be done in poplar, so we are working with galls on poplar leaves. In poplar leaves with or without galls, sectioned and stained using Toluene Blue O dye and examined under polarized light at 20 magnification, we identified changes that galls make in leaf development. We detected a number of histological changes in galled leaves, including patterning of xylem & phloem, palisade and spongy parenchyma. We prepared RNA from fruit, ungalled leaf and galled leaf to study diffences in their expression of meristem identity and carpel genes. Although we didn't have time to do the gene expression work, we predict that the expression of fruit genes will be elevated in the gall tissue compared to surrounding normal leaf tissue.Gyeongsang National Universit

Fungal Origins of the Bicyclo[2.2.2]diazaoctane Ring System of Prenylated Indole Alkaloids

Over eight different families of natural products, consisting of nearly seventy secondary metabolites, which contain the bicyclo[2.2.2]diazaoctane ring system, have been isolated from various Aspergillus, Penicillium, and Malbranchea species. Since 1968, these secondary metabolites have been the focus of numerous biogenetic, synthetic, taxonomic, and biological studies, and, as such, have made a lasting impact across multiple scientific disciplines. This review covers the isolation, biosynthesis, and biological activity of these unique secondary metabolites containing the bridging bicyclo[2.2.2]diazaoctane ring system. Furthermore, the diverse fungal origin of these natural products is closely examined and, in many cases, updated to reflect the currently accepted fungal taxonomy

Six-membered ring systems: with O and/or S atoms

A large variety of publications have emerged in 2012 involving O- and S-6- membered ring systems. The increasing number of reviews and other communica- tions dedicated to natural and synthetic derivatives and their biological significance highlights the importance of these heterocycles. Reviews on natural products involve biosynthesis and isolation of enantiomeric derivatives h12AGE4802i, biosynthesis, isolation, synthesis, and biological studies on the pederin family h12NPR980i and xanthones obtained from fungi, lichens, and bacteria h12CR3717i and on the potential chemotherapeutic value of phyto- chemical products and plant extracts as antidiabetic h12NPR580i, antimicrobial, and resistance-modifying agents h12NPR1007i. A more specific review covers a structure–activity relationship of endoperoxides from marine origin and their antitry- panosomal activity h12OBC7197i. New synthetic routes to naturally occurring, biologically active pyran derivatives have been the object of several papers. Different approaches have been discussed for the total synthesis of tetrahydropyran-containing natural products (")-zampanolide h12CEJ16868, 12EJO4130, 12OL3408i, (")-aspergillides A and B h12H(85)587, 12H(85)1255, 12TA252i, (þ)-neopeltolide h12JOC2225, 12JOC9840, 12H(85) 1255i, or their macrolactone core h12OBC3689, 12OL2346i. The total synthesis of bistramide A h12CEJ7452i and (þ)-kalihinol A h12CC901i and the stereoselec- tive synthesis of a fragment of bryostatin h12S3077, 12TL6163i have also been sur- veyed. Other papers relate the total synthesis of naturally occurring carbocyclic and heterocyclic-fused pyran compounds, such as (")-dysiherbaine h12CC6295i, penos- tatin B h12OL244i, Greek tobacco lactonic products, and analogues h12TL4293i and on the structurally intriguing limonoids andhraxylocarpins A–E h12CEJ14342i. The stereocontrolled synthesis of fused tetrahydropyrans was used in the preparation of blepharocalyxin D h12AGE3901i. Polyphenolic heterocyclic compounds have also received great attention in 2012. The biological activities and the chemistry of prenylated caged xanthones h12PCB78i, the occurrence of sesquiterpene coumarins h12PR77i, and the medicinal properties of the xanthone mangiferin h12MRME412i have been reviewed. An overview on the asymmetric syntheses of flavanones and chromanones h12EJO449i, on the synthesis and reactivity of flavones h12T8523i and xanthones h12COC2818i, on the synthesis and biosynthesis of biocoumarins h12T2553i, and on the synthesis and applications of flavylium compounds h12CSR869i has been discussed. The most recent developments in the synthesis and applications of sultones, a very important class of sulfur compounds, were reported h12CR5339i. A review on xanthene-based fluorescent probes for sensing cations, anions, bio- logical species, and enzyme activity has described the spiro-ring-opening approach with a focus on the major mechanisms controlling their luminescence behavior h12CR1910i. The design and synthesis of other derivatives to be used as sensors of gold species h12CC11229i and other specific metal cations h12PC823i have also been described. Recent advances related to coumarin-derived fluorescent chemosen- sors for metal ions h12COC2690i and to monitoring in vitro analysis and cellular imaging of monoamine oxidase activity h12CC6833i have been discussed. The study of various organic chromophores allowed the synthesis of novel dica- tionic phloroglucinol-type bisflavylium pigments h12SL2053i, and the optical and spectroscopic properties of several synthetic 6-aryldibenzo[b,d]pyrylium salts were explored h12TL6433i. Discussion of specific reactions leading to O- and S-membered heterocyclic compounds covers intramolecular radical cyclization h12S2475i and asymmetric enamine and dienamine catalysis h12EJO865i, oxa-Michael h12CSR988i and dom- ino Knoevenagel–hetero-Diels–Alder (hDA) reactions h12T5693i, and the versatility in cycloadditions as well as nucleophilic reactions using o-quinones h12CSR1050i. The use of specific reagents relevant to this chapter includes molecular iodine h12CEJ5460, 12COS561i, samarium diiodide–water for selective reductive transfor- mations h12CC330i, o-quinone methides as versatile intermediates h12CEJ9160i, InCl3 as catalyst h12T8683i, and gold and platinum p-acid mediated insertion of alkynes into carbon–heteroatom s-bonds h12S3401i. The remainder of this chapter discusses the most studied transformations on O- and S-6-membered heterocycles

Enantiomeric Natural Products: Occurrence and Biogenesis

In nature, chiral natural products are usually produced in optically pure form—however, occasionally both enantiomers are formed. These enantiomeric natural products can arise from a single species or from different genera and/or species. Extensive research has been carried out over the years in an attempt to understand the biogenesis of naturally occurring enantiomers; however, many fascinating puzzles and stereochemical anomalies still remain. Two sides to the story : The formation of enantiomerically opposite natural products by nature is known, although rare (see examples). To date, many puzzles and stereochemical anomalies remain regarding the biogenesis of these unique natural products, despite the substantial body of research that has been carried out over the years in an attempt to understand the biogenesis of enantiomeric metabolites.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92098/1/4802_ftp.pd

Enantiomere Naturstoffe: Vorkommen und Biogenese

In der Natur werden chirale Substanzen meist in enantiomerenreiner Form synthetisiert – manchmal entstehen aber auch beide Enantiomere. Solche enantiomeren Naturstoffe können von einer Art oder von verschiedenen Gattungen und/oder Arten gebildet werden. Intensive Forschungen wurden über viele Jahre durchgeführt, um die Biogenese natürlich vorkommender Enantiomere zu verstehen, doch viele faszinierende Rätsel und stereochemische Anomalien sind nach wie vor ungelöst. Bild und Spiegelbild in der Natur: Die Bildung von natürlich vorkommenden Enantiomerenpaaren ist bekannt, wenn auch selten (siehe Beispiel). Bis heute sind noch viele Rätsel und stereochemische Anomalien bei der Biogenese dieser einmaligen Naturstoffe ungelöst, auch wenn im Laufe der Jahre viel Arbeit investiert worden ist, um die Entstehung enantiomerer Metaboliten zu verstehen.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91315/1/4886_ftp.pd