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

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

Biochemical Characterization of NotB as an FAD-Dependent Oxidase in the Biosynthesis of Notoamide Indole Alkaloids

Notoamides produced by <i>Aspergillus</i> spp. bearing the bicyclo[2.2.2]­diazaoctane core structure with unusual structural diversity represent a compelling system to understand the biosynthesis of fungal prenylated indole alkaloids. Herein, we report the <i>in vitro</i> characterization of NotB, which catalyzes the indole 2,3-oxidation of notoamide E (<b>13</b>), leading to notoamides C (<b>11</b>) and D (<b>12</b>) through an apparent pinacol-like rearrangement. This unique enzymatic reaction with high substrate specificity, together with the information derived from precursor incorporation experiments using [¹³C]₂–[¹⁵N]₂ quadruply labeled notoamide S (<b>10</b>), demonstrates <b>10</b> as a pivotal branching point in notoamide biosynthesis

Enantioselective inhibitory abilities of enantiomers of notoamides against RANKL-induced formation of multinuclear osteoclasts

The marine-derived Aspergillus protuberus MF297-2 and the terrestrial A. amoenus NRRL 35600 produce enantiomeric prenylated indole alkaloids. Investigation of biological activities of the natural and synthetic derivatives revealed that (−)-enantiomers of notoamides A and B, 6-epi-notoamide T, and stephacidin A inhibited receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)–induced osteoclastogenic differentiation of murine RAW264 cells more strongly than their respective (+)-enantiomers. Among them, (−)-6-epi-notoamide T was the most potent inhibitor with an IC50 value of 1.7 μM

Synthesis and Bioconversions of Notoamide T: A Biosynthetic Precursor to Stephacidin A and Notoamide B

In an effort to further elucidate the biogenesis of the stephacidin and notoamide families of natural products, notoamide T has been identified as the likely precursor to stephacidin A. The total synthesis of notoamide T is described along with it is C-6-epimer, 6-<i>epi</i>-notoamide T. The chemical conversion of stephacidin A to notoamide T by reductive ring opening is described as well as the oxidative conversion of notoamide T to stephacidin A. Furthermore, [¹³C]₂-notoamide T was synthesized and provided to <i>Aspergillus versicolor</i> and <i>Aspergillus</i> sp. MF297-2, in which significant incorporation was observed in the advanced metabolite, notoamide B

Bioconversion of 6-epi-Notoamide T produces metabolites of unprecedented structures in a marine-derived Aspergillus sp.

We previously described the bioconversion of Notoamide T into (+)-Stephacidin A and (−)-Notoamide B, which suggested that Versicolamide B (8) is biosynthesized from 6-epi-Notoamide T (10) via 6-epi-Stephacidin A. Here we report that [13C]2-10 was incorporated into isotopically enriched 8 and seven new metabolites, which were not produced under normal culture conditions. The results suggest that the addition of excess precursor activated the expression of dormant tailoring genes giving rise to these structurally unprecedented metabolites