Full details of the total synthesis of the potent
antitumor antibiotic (−)-sandramycin (1), a
cyclic
decadepsipeptide possessing a 2-fold axis of symmetry, is described and
constitutes the first total synthesis of a
member of the growing class of naturally occurring agents now including
the luzopeptins and quinaldopeptin. Key
strategic elements of the approach include the late stage introduction
of the heteroaromatic chromophore thereby
providing access to analogs possessing altered intercalation
capabilities, symmetrical pentadepsipeptide coupling
and 32-membered macrocyclization conducted at the single secondary
amide site in superb conversion (90%), and
a convergent assemblage of the precursor pentadepsipeptide in which the
potentially labile ester linkage was introduced
in the final key coupling reaction. This approach also provided
the cyclic decadepsipeptides 24−26 lacking
both
chromophores and was extended to provide 32 lacking one of
the two chromophores. The characterization of the
DNA-binding properties of sandramycin vs 25 and
32 is detailed. The largest share of the binding is
derived from
the cyclic decadepsipeptide (ΔG° = −6.0 kcal/mol)
and the incremental addition of each chromophore increases
the
binding approximately 3.2 and 1.0 kcal/mol, respectively. This is
consistent with the representation of sandramycin
and the luzopeptins as minor groove binding cyclic decadepsipeptides
incrementally stabilized by mono and
bisintercalation. Following the same trends, sandramycin and
luzopeptin A were found to be nearly equivalent,
exceptionally potent cytotoxic agents (6−0.02 nM), 500−1000× more
potent than the cyclic decadepsipeptide 32
possessing a single chromophore, and ≥105× more potent
than the cyclic decadepsipeptides 24 and 25
lacking both
chromophores. DNase I footprinting studies revealed that
sandramycin and luzopeptin A behave comparably and
appear to bind best to regions containing alternating A and T residues.
Binding at other and perhaps all sites is
observed at modest agent concentrations with a perceptible preference
for 5‘-AT dinucleotide sequences many of
which were preceded by a 5‘-C, i.e. 5‘-CAT. Preliminary
studies of the 1:1 complex of sandramycin with 5‘-d(GCATGC)2 revealed that it maintains the 2-fold axis of
symmetry of the components with the agent sandwiching
the central two AT base pairs and adopting a compact conformation in
which the interchromophore distance is 10.1
Å. The cyclic decadepsipeptide is positioned in the minor groove
and the adopted conformation permits a rich array
of complementary hydrophobic contacts extending over much of the
interacting surface.
In this study, we identified antifolates with potent, targeted activity against whole-cell Mycobacterium tuberculosis (MTB). Liquid chromatography-mass spectrometry analysis of antifolate-treated cultures revealed metabolic disruption, including decreased pools of methionine and S-adenosylmethionine. Transcriptomic analysis highlighted altered regulation of genes involved in the biosynthesis and utilization of these two compounds. Supplementation with amino acids or S-adenosylmethionine was sufficient to rescue cultures from antifolate treatment. Instead of the "thymineless death" that characterizes folate pathway inhibition in a wide variety of organisms, these data suggest that MTB is vulnerable to a critical disruption of the reactions centered around S-adenosylmethionione, the activated methyl cycle.
Several phenyl substituted naphthalenes and isoquinolines have been identified as antibacterial agents that inhibit FtsZ-Zing formation. In the present study we evaluated the antibacterial of several phenyl substituted quinoxalines, quinazolines and 1,5-naphthyridines against methicillin-sensitive and methicillin-resistant Staphylococcus aureus and vancomycin-sensitive and vancomycin-resistant Enterococcus faecalis. Some of the more active compounds against S. aureus were evaluated for their effect on FtsZ protein polymerization. Further studies were also performed to assess their relative bactericidal and bacteriostatic activities. The notable differences observed between nonquaternized and quaternized quinoxaline derivatives suggest that differing mechanisms of action are associated with their antibacterial properties.
By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.
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