A novel route towards cycle-tail peptides using oxime resin : teaching an old dog a new trick

Two anabaenopeptins, Schizopeptin 791 and anabaenopeptin NZ825, have similar structural features and have been synthesized via a novel acid-catalyzed head-to-side-chain concomitant cyclization/cleavage reaction on oxime resin. The methodology gave rapid access to the anabaenopeptin scaffold by taking advantage of a combined solid-phase/solution-phase synthetic strategy. Also, as side-products of the synthesis, large C2-symmetric 38-member cyclic peptides ring bearing two endocyclic lysine side-chains were isolated, constituting a novel cyclic peptide scaffold

Total synthesis of pseudacyclins A-E by an on-resin head-to-side chain concomitant cyclization-cleavage reaction

Taking advantage of the nucleophile-sensitive ester link of oxime resin, a novel synthetic strategy was applied to the first synthesis of a type of cyclic peptides known as pseudacyclins A–E. The endocyclic ornithine side-chain part was incorporated by an on-resin acid-catalyzed concomitant cyclization-cleavage reaction after a selective deprotection of orthogonally protected ornithine. The synthetic methodology gives high macrocyclization yields and low oligomerization side-products. The combination used of solid-phase/solution-phase strategy was efficient to prepare pseudacyclins and could prove useful to prepare other natural cycle-tail peptides

Total synthesis of chrysamide B

We report an efficient synthesis of the dimeric trans-epoxyamide chrysamide B, recently isolated from the deep-sea-derived fungus Penicillium chrysogenum SCSIO41001. Our synthetic strategy exploits a convergent approach using solid-phase peptide synthesis for the piperazine core and a Sharpless-Katsuki epoxidation to prepare the chiral epoxyacid. The double amidation final step provides chrysamide B that was thoroughly characterized with all spectra identical to those of the natural sample. The approach was devised to facilitate the preparation of a library of analogs of chrysamide B

Revisiting the Juliá–Colonna enantioselective epoxidation : supramolecular catalysis in water

We describe an efficient epoxidation process leading to chiral epoxyketones using the reusable homo-oligopeptide poly-L-leucine (PLL) in pure water, without any organic co-solvent. A range of substituted epoxyketones can be accessed with good conversions and high enantioselectivities. Based on the experimental results and computational studies, we propose a mechanism that demonstrates the importance of both the α-helical structure and the presence of a hydrophobic groove of the homo-oligopeptide catalyst for reactivity and selectivit

Total synthesis of Crotogossamide using an on-resin concomitant cyclization/cleavage reaction

Crotogossamide, a cyclic peptide isolated from the latex of Croton gossypifolius, has been synthesized by a rapid and efficient Boc solid-phase peptide synthesis. The strategy takes advantage of the oxime resin nucleophile susceptibility and comprises the synthesis of a linear precursor followed by on-resin head-to-tail concomitant cyclization/cleavage. In addition, we report the first antimicrobial and antibiofilm investigations on Crotogossamide

Multiple Promoters and Alternative Splicing: Hoxa5 Transcriptional Complexity in the Mouse Embryo

The genomic organization of Hox clusters is fundamental for the precise spatio-temporal regulation and the function of each Hox gene, and hence for correct embryo patterning. Multiple overlapping transcriptional units exist at the Hoxa5 locus reflecting the complexity of Hox clustering: a major form of 1.8 kb corresponding to the two characterized exons of the gene and polyadenylated RNA species of 5.0, 9.5 and 11.0 kb. This transcriptional intricacy raises the question of the involvement of the larger transcripts in Hox function and regulation.We have undertaken the molecular characterization of the Hoxa5 larger transcripts. They initiate from two highly conserved distal promoters, one corresponding to the putative Hoxa6 promoter, and a second located nearby Hoxa7. Alternative splicing is also involved in the generation of the different transcripts. No functional polyadenylation sequence was found at the Hoxa6 locus and all larger transcripts use the polyadenylation site of the Hoxa5 gene. Some larger transcripts are potential Hoxa6/Hoxa5 bicistronic units. However, even though all transcripts could produce the genuine 270 a.a. HOXA5 protein, only the 1.8 kb form is translated into the protein, indicative of its essential role in Hoxa5 gene function. The Hoxa6 mutation disrupts the larger transcripts without major phenotypic impact on axial specification in their expression domain. However, Hoxa5-like skeletal anomalies are observed in Hoxa6 mutants and these defects can be explained by the loss of expression of the 1.8 kb transcript. Our data raise the possibility that the larger transcripts may be involved in Hoxa5 gene regulation.Our observation that the Hoxa5 larger transcripts possess a developmentally-regulated expression combined to the increasing sum of data on the role of long noncoding RNAs in transcriptional regulation suggest that the Hoxa5 larger transcripts may participate in the control of Hox gene expression

Adventures in the Enormous: A 1.8 Million Clone BAC Library for the 21.7 Gb Genome of Loblolly Pine

Loblolly pine (LP; Pinus taeda L.) is the most economically important tree in the U.S. and a cornerstone species in southeastern forests. However, genomics research on LP and other conifers has lagged behind studies on flowering plants due, in part, to the large size of conifer genomes. As a means to accelerate conifer genome research, we constructed a BAC library for the LP genotype 7-56. The LP BAC library consists of 1,824,768 individually-archived clones making it the largest single BAC library constructed to date, has a mean insert size of 96 kb, and affords 7.6X coverage of the 21.7 Gb LP genome. To demonstrate the efficacy of the library in gene isolation, we screened macroarrays with overgos designed from a pine EST anchored on LP chromosome 10. A positive BAC was sequenced and found to contain the expected full-length target gene, several gene-like regions, and both known and novel repeats. Macroarray analysis using the retrotransposon IFG-7 (the most abundant repeat in the sequenced BAC) as a probe indicates that IFG-7 is found in roughly 210,557 copies and constitutes about 5.8% or 1.26 Gb of LP nuclear DNA; this DNA quantity is eight times the Arabidopsis genome. In addition to its use in genome characterization and gene isolation as demonstrated herein, the BAC library should hasten whole genome sequencing of LP via next-generation sequencing strategies/technologies and facilitate improvement of trees through molecular breeding and genetic engineering. The library and associated products are distributed by the Clemson University Genomics Institute (www.genome.clemson.edu)

The sexuality of Malcolm X

This article engages the controversy over whether Malcolm Little, who would become Malcolm X, had same-sexual encounters. A minute sifting of all evidence and claims, augmented by new findings, yields strong indication that Malcolm Little did take part in sex acts with male counterparts. If set in the context of the 1930s and 1940s, these acts position him not as a “homosexual lover,” as has been asserted, but in the pattern of “straight trade”—heterosexual men open to sex with homosexuals—an understanding that in turn affords insights into the black revolutionary's mature masculinity

Rock alteration in alkaline cement waters over 15 years and its relevance to the geological disposal of nuclear waste

The interaction of groundwater with cement in a geological disposal facility (GDF) for intermediate level radioactive waste will produce a high pH leachate plume. Such a plume may alter the physical and chemical properties of the GDF host rock. However, the geochemical and mineralogical processes which may occur in such systems over timescales relevant for geological disposal remain unclear. This study has extended the timescale for laboratory experiments and shown that, after 15 years two distinct phases of reaction may occur during alteration of a dolomite-rich rock at high pH. In these experiments the dissolution of primary silicate minerals and the formation of secondary calcium silicate hydrate (C-S-H) phases containing varying amounts of aluminium and potassium (C-(A)-(K)-S-H) during the early stages of reaction (up to 15 months) have been superseded as the systems have evolved. After 15 years significant dedolomitisation (MgCa(CO3)2+2OH-→Mg(OH)2+CaCO3+CO3 2- (aq)) has led to the formation of magnesium silicates, such as saponite and talc, containing variable amounts of aluminium and potassium (Mg-(Al)-(K)-silicates), and calcite at the expense of the early-formed C-(A)-(K)-S-H phases. This occured in high pH solutions representative of two different periods of cement leachate evolution with little difference in the alteration processes in either a KOH and NaOH or a Ca(OH)2 dominated solution but a greater extent of alteration in the higher pH KOH/NaOH leachate. The high pH alteration of the rock over 15 years also increased the rock's sorption capacity for U(VI). The results of this study provide a detailed insight into the longer term reactions occurring during the interaction of cement leachate and dolomite-rich rock in the geosphere. These processes have the potential to impact on radionuclide transport from a geodisposal facility and are therefore important in underpinning any safety case for geological disposal

Synthèse et caractérisation de molécules peptidiques bioactives et catalytiques

Les peptides sont des molécules uniques et ubiquitaires puisqu’ils modulent presque tous les processus physiologiques et biochimiques des êtres vivants. En ce sens, l’essence de ma thèse de doctorat s’inscrit principalement dans le développement de nouvelles méthodologies de synthèse de peptides cycliques pour des fins catalytiques et pharmaceutiques. L’ensemble des molécules peptidiques cycliques ont été préparées via les propriétés uniques de la résine oxime, qui permet une étape simultanée de cyclisation/clivage, ce qui en fait une méthode efficace et rapide pour la synthèse de peptides sur support solide, particulièrement de peptides cycliques difficiles à préparer par les méthodes conventionnelles. D’abord, dans le bloc A, une chimiothèque (95) de nouveaux peptides bio-inspirés a été préparée. Ceux-ci ont été utilisés pour le développement de nouveaux procédés chimiques écoresponsables, soit l’époxydation énantiosélective en milieu aqueux. Le recours aux peptides comme biocatalyseurs opérant dans l'eau est très avantageux tant sur le plan environnemental que de l’économie puisque ces catalyseurs sont peu coûteux, ne génèrent que peu de déchets toxiques et sont réutilisables. La présente étude, séparée en quatre grands chapitres où la catalyse est une thématique centrale, nous fait comprendre les conditions expérimentales optimales selon l’utilisation de peptides cycliques ou d’oligopeptides linéaires pour l’époxydation énantiosélective de cétones insaturées. Parallèlement, certains dipeptides cycliques ont été employés comme précurseurs clés pour la synthèse de nouveaux ligands diaminés de type pipérazines ainsi que pour la première synthèse totale de la chrysamide B, partie intégrante du bloc B. Finalement, les deux derniers blocs (C et D) consistent à pallier aux problèmes de cyclisation de peptides en solution pour la synthèse de peptides cycliques. Celle-ci est fastidieuse et mène à de faibles rendements et puretés. Notre groupe s’intéresse à développer une nouvelle méthodologie de cyclisation/clivage à l’aide de la résine oxime afin d’offrir une alternative rapide, générale et efficace à la cyclisation de peptides en solution. L’efficacité de la stratégie a permis la synthèse totale et la caractérisation de plus de 18 peptides cycliques naturels, dont certains possèdent des activités antimalariales très intéressantes. Par ailleurs, l’étude de la méthodologie a permis le développement d’une nouvelle stratégie de cyclisation tête-chaîne latérale permettant la préparation de sept peptides cycliques naturels de type anabaénopeptines et pseudacyclines.Peptides are unique and ubiquitous molecules since they modulate almost all the physiological and biochemical processes of living organisms. In this regard, the essence of this PhD thesis is mainly in the development of new cyclic peptide synthetic methodologies for catalytic and pharmaceutical areas. Cyclic peptide molecules have been prepared via the unique properties of the oxime resin, which allows a concomitant cyclization/cleavage step. This methodology has been applied for the synthesis of cyclic peptides by an on-resin cyclization, alternatively to conventional methods using in-solution cyclization. First, in block A, a library (95) of new bio-inspired peptides was prepared. These peptides have been used for the development of new eco-friendly chemical process, which is an enantioselective epoxidation in aqueous medium. The use of peptides as biocatalysts operating in water is very advantageous towards environmentally and economically aspects since these catalysts are inexpensive, generate few toxic waste and are reusable. The present study, separated into four main chapters in which catalysis is a central theme, makes us understand the optimal experimental conditions according to the use of cyclic peptides or linear oligopeptides for the enantioselective epoxidation of unsaturated ketones. Also, cyclic dipeptides have been used as key precursors for the synthesis of new piperazine-type diamino ligands as well as for the first total synthesis of chrysamide B, an integral part of block B. Finally, the last two blocks (C and D) aim to overcome the cyclization of peptides in solution for the synthesis of cyclic peptides. This is tedious and leads to low yields and purities. Our group is interested in developing a new methodology for cyclization/cleavage using oxime resin in order to offer a fast, general and efficient alternative to the cyclization of peptides in solution. The effectiveness of the strategy has allowed the total synthesis and characterization of more than 18 natural cyclic peptides, some of which have very interesting antimalarial activities. In addition, the study of the methodology allowed the development of a new strategy of head-to-side chain cyclization allowing the preparation of seven natural cyclic peptides, two anabaenopeptins and five pseudacyclins