Cristina García-Ruiz

A Highly Stereoselective Synthesis of Glycidic Amides Based on a New Class of Chiral Sulfonium Salts: Applications in Asymmetric Synthesis

A new type of chiral sulfonium salts that are characterized by a bicyclic system has been designed and synthesized from α-amino acids. Their corresponding ylides, which were prepared by basic treatment of the sulfonium salts, reacted smoothly with a broad array of simple and chiral aldehydes to provide trans-epoxy amides in reasonable to very good yields and excellent stereoselectivities (>98%). The obtained epoxy amides were found to be useful as synthetic building blocks. Thus, they were reduced into their corresponding epoxy alcohols and subjected to oxirane-ring-opening reactions with different types of nucleophiles.

Exploring the Chemistry of Epoxy Amides for the Synthesis of the 2''-epi-Diazepanone Core of Liposidomycins and Caprazamycins

New synthetic strategies have been explored for the synthesis of the structural core of liposidomycins and caprazamycins, an intriguing class of complex nucleoside-type antibiotics. This structural core is comprised of a cyclic diazepanone system linked to an uridyl fragment. The various synthetic approaches have in common that they originate from an epoxy amide derived from uridine, obtained via reaction of uridyl aldehyde 19 with an amide-stabilized sulfur ylide. Two different strategies were shown to be efficient in constructing the diazepanone ring system: (a) a reductive amination of an epoxy aldehyde with N-methylamine with subsequent intramolecular oxirane ring opening and (b) a carbene insertion reaction of an acyclic diazoamine precursor.

Solid Phase Synthesis of Globomycin and SF-1902 A5

The syntheses of the natural lipocyclodepsipeptide-type antibiotics globomycin and SF-1902 A(5) are reported, utilizing solid phase technology for the construction of the peptidic fragment and a new asymmetric methodology of epoxidation for the preparation of the lipidic chain. The linkage between both fragments was successfully achieved in solid phase to complete the syntheses via a macrolactonization reaction executed prior to the cleavage of the acyclic precursors from the solid support. These syntheses provide access to the rapid generation of a library of analogues via modification of the amino acid residues as well as the lipidic chain, thus facilitating the identification of new antibiotics with interesting mechanisms of action based upon the inhibition of the enzyme signal peptidase II.

Epi-, Epoxy-, and C2-Modified Bengamides: Synthesis and Biological Evaluation

With the objective of investigating the influence of structural modifications of the polyketide chain of the bengamides upon their antitumoral activities, we targeted the preparation of bengamide E analogues with modification of the stereochemistry at C-2 and at C-3, the substituent at the C-2 position, and the presence of oxirane rings. For the synthesis of these analogues, a new synthetic method for asymmetric epoxidation, developed in our laboratories, was employed utilizing the chiral sulfonium salts 22 and 23. In order to access 2-epi-bengamide E from these epoxy amides, a synthetic methodology, developed by Miyashita, allowed an oxirane-ring-opening reaction with a double inversion of the configuration. Alternatively, an aldol reaction provided access to the same analogue in a shorter and more efficient manner. Finally, biological evaluation of all of these bengamide E analogues demonstrated that the polyketide chain is essential for the antitumor activity of these natural products, not being amenable to structural or configurational modifications.

Chemistry and Biology of Bengamides and Bengazoles, Bioactive Natural Products from Jaspis Sponges

Sponges corresponding to the Jaspidae family have proved to be a prolific source of bioactive natural products. Among these, the bengamides and the bengazoles stand out by virtue of their unprecedented molecular architectures and impressive biological profiles, including antitumor, antibiotic and anthelmintic properties. As a consequence, intense research activity has been devoted to these compounds from both chemical and biological standpoints. This review describes in detail the research into these classes of natural products and the benefits they offer in chemistry and biology.

An array of bengamide E analogues modified at the terminal olefinic position: synthesis and antitumor properties.

Based on our previously described synthetic strategy for bengamide E, a natural product of marine origin with antitumor activity, a small library of analogues modified at the terminal olefinic position was generated with the objective of investigating the effect of structural modifications on antitumor properties. Biological evaluation of these analogues, consisting of IC50 determinations against various tumor cell lines, revealed important aspects with respect to the structural requirements of this olefinic position for activity. Interestingly, the analogue possessing a cyclopentyl group displayed greater potency than the parent bengamide E, representing a key finding upon which to base further investigations into the design of new analogues with promising biological activities.

Stereoselective Total Synthesis of (-)-Depudecin.

The total synthesis of the natural product depudecin, an antiangiogenic microbial polyketide with inhibitory activity against histone deacetylases, is reported. Characterized by a highly oxidized 11-carbon chain containing two epoxides conjugated through a trans-disubstituted olefin, its total synthesis was efficiently accomplished by a novel asymmetric methodology of epoxide formation based on a new class of chiral sulfonium salts, allowing for the construction of the oxirane rings in an efficient and stereoselective fashion.

An Olefin Cross-Metathesis Approach to Depudecin and Stereoisomeric Analogues

A new total synthesis of the natural product (-)-depudecin, a unique and unexplored histone deacetylase (HDAC) inhibitor, is reported. A key feature of the synthesis is the utilization of an olefin cross-metathesis strategy, which provides for an efficient and improved access to natural depudecin, compared with our previous linear synthesis. Featured by its brevity and convergency, our developed synthetic strategy was applied to the preparation of the 10-epi derivative and the enantiomer of depudecin, which represent interesting stereoisomeric analogues for structure-activity relationship studies.

Silencing of Essential Genes within a Highly Coordinated Operon in Escherichia coli

ABSTRACT Essential bacterial genes located within operons are particularly challenging to study independently because of coordinated gene expression and the nonviability of knockout mutants. Essentiality scores for many operon genes remain uncertain. Antisense RNA (asRNA) silencing or in-frame gene disruption of genes may help establish essentiality but can lead to polar effects on genes downstream or upstream of the target gene. Here, the Escherichia coli ribF-ileS-lspA-fkpB-ispH operon was used to evaluate the possibility of independently studying an essential gene using expressed asRNA and target gene overexpression to deregulate coupled expression. The gene requirement for growth in conditional silencing strains was determined by the relationship of target mRNA reduction with growth inhibition as the minimum transcript level required for 50% growth (MTL50). Mupirocin and globomycin, the protein inhibitors of IleS and LspA, respectively, were used in sensitization assays of strains containing both asRNA-expressing and open reading frame-expressing plasmids to examine deregulation of the overlapping ileS-lspA genes. We found upstream and downstream polar silencing effects when either ileS or lspA was silenced, indicating coupled expression. Weighted MTL50 values (means and standard deviations) of ribF, ileS, and lspA were 0.65 ± 0.18, 0.64 ± 0.06, and 0.76 ± 0.10, respectively. However, they were not significantly different (P = 0.71 by weighted one-way analysis of variance). The gene requirement for ispH could not be determined due to insufficient growth reduction. Mupirocin and globomycin sensitization experiments indicated that ileS-lspA expression could not be decoupled. The results highlight the inherent challenges associated with genetic analyses of operons; however, coupling of essential genes may provide opportunities to improve RNA-silencing antimicrobials.