16 research outputs found
Asymmetric Total Synthesis of Neoxaline
A first
asymmetric total synthesis and determination of the absolute
configuration of neoxaline has been accomplished through the highly
stereoselective introduction of a reverse prenyl group to create a
quaternary carbon stereocenter using (−)-3a-hydroxyfuroindoline
as a building block, construction of the indoline spiroaminal via
cautious stepwise oxidations with cyclizations from the indoline,
assembly of (<i>Z</i>)-dehydrohistidine, and photoisomerization
of unnatural (<i>Z</i>)-neoxaline to the natural (<i>E</i>)-neoxaline as the key steps
Actinoallolides A-E, new anti-trypanosomal macrolides, produced by an endophytic actinomycete, actinoallomurus fulvus MK10-036
d broth of Actinoallomurus fulvus MK10-036. The structures of the actinoallolides, including absolute stereochemistry, were elucidated by a combination of spectroscopic analyses and a series of chemical derivatization studies. Actinoallolide A showed the most potent and selective in vitro anti-trypanosomal activity without cytotoxicity. A new class of promising lead compounds was identified for the development of drugs for both sleeping sickness and Chagas disease
Total Synthesis and Determination of the Absolute Configuration of Naturally Occurring Mangromicin A, with Potent Antitrypanosomal Activity
An
enantioselective total synthesis of (+)-mangromicin A has been
accomplished. The tetrahydrofuran ring of mangromicin A, possessing
a tetrasubstituted carbon center, was constructed by Mukaiyama-type
vinylogous alkylation via a cyclic oxocarbenium intermediate derived
from a γ-hydroxy ketone with ideal stereoselectivity, and the
4-hydroxydihydropyrone scaffold was generated via Dieckmann cyclization
at a late stage of the total synthesis. The reliable asymmetric synthesis
of (+)-mangromicin A has revealed the absolute configuration of naturally
occurring mangromicin A
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Molecular Insights into the Biosynthesis of Guadinomine: A Type III Secretion System Inhibitor
Guadinomines are a recently discovered family of anti-infective compounds produced by Streptomyces sp. K01-0509 with a novel mode of action. With an IC(50) of 14 nM, guadinomine B is the most potent known inhibitor of the type III secretion system (TTSS) of Gram-negative bacteria. TTSS activity is required for the virulence of many pathogenic Gram-negative bacteria including Escherichia coli , Salmonella spp., Yersinia spp., Chlamydia spp., Vibrio spp., and Pseudomonas spp. The guadinomine (gdn) biosynthetic gene cluster has been cloned and sequenced and includes 26 open reading frames spanning 51.2 kb. It encodes a chimeric multimodular polyketide synthase, a nonribosomal peptide synthetase, along with enzymes responsible for the biosynthesis of the unusual aminomalonyl-acyl carrier protein extender unit and the signature carbamoylated cyclic guanidine. Its identity was established by targeted disruption of the gene cluster as well as by heterologous expression and analysis of key enzymes in the biosynthetic pathway. Identifying the guadinomine gene cluster provides critical insight into the biosynthesis of these scarce but potentially important natural products
Isolation and Total Synthesis of Hoshinolactam, an Antitrypanosomal Lactam from a Marine Cyanobacterium
In
the search for new antiprotozoal substances, hoshinolactam,
an antitrypanosomal lactam, was isolated from a marine cyanobacterium.
The gross structure was elucidated by spectroscopic analyses, and
the absolute configuration was determined by the first total synthesis.
Hoshinolactam showed potent antitrypanosomal activity with an IC<sub>50</sub> value of 3.9 nM without cytotoxicity against human fetal
lung fibroblast MRC-5 cells (IC<sub>50</sub> > 25 μM)
Synthesis and Evaluation of Antibacterial Activity of Bottromycins
Total
synthesis of bottromycin A<sub>2</sub> can be accomplished
through a diastereoselective Mannich reaction of a chiral sulfinamide,
mercury-mediated intermolecular amidination, and cyclization of a
constrained tetracyclic peptide. Exploitation of this process allowed
the synthesis of several novel bottromycin analogs. The antimicrobial
activity of these analogs was evaluated in vitro against Gram-positive
bacteria, such as methicillin resistant <i>Staphylococcus aureus</i> (MRSA) and vancomycin resistant <i>enterococci</i> (VRE).
Structure–activity relationships were explored taking into
consideration the unique three-dimensional structure of the compounds.
Notably, one of the new analogs devoid of a methyl ester, which is
known to lower the in vivo efficacy of bottromycin, exhibited antibacterial
bioactivity comparable to that of vancomycin
Aogacillins A and B Produced by <i>Simplicillium</i> sp. FKI-5985: New Circumventors of Arbekacin Resistance in MRSA
Aogacillins A and B, capable of overcoming arbekacin resistance in methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), were isolated from a culture broth of <i>Simplicillium</i> sp. FKI-5985. Their structures were elucidated by NMR spectroscopic studies and ECD analyses. The aogacillins possessed a novel carbon skeleton, including a β-keto-γ-methyliden-δ-lactone ring connected to a 2-ethyl-6-methylcyclohexane ring by spiro conjugation
Design and <i>De Novo</i> Synthesis of 6‑Aza-artemisinins
Development
of designer natural product variants, 6-aza-artemisinins,
enabled us to achieve structural modification of the hitherto unexplored
cyclohexane moiety of artemisinin and concise <i>de novo</i> synthesis of the tetracyclic scaffold in just four steps from the
modular assembly of three simple building blocks. This expeditious
catalytic asymmetric synthetic approach generated lead candidates
exhibiting superior <i>in vivo</i> antimalarial activities
to artemisinin