4 research outputs found
Total Synthesis of (+)-Ileabethoxazole via an Iron-Mediated Pauson–Khand [2 + 2 + 1] Carbocyclization
Studies
describe the total synthesis of (+)-ileabethoxazole (<b>1</b>) using a Stille cross-coupling reaction of propargylic stannanes
with 5-iodo-1,3-oxazoles to produce 1,1-disubstituted allenes (<b>11</b>). An iron-mediated [2 + 2 + 1] carbocyclization yields
a novel cyclopentenone for elaboration to <b>1</b>. Site-selective
palladium insertion reactions allow for regiocontrolled substitutions
of the heterocycle. Asymmetric copper hydride reductions are examined,
and strategies for the formation of the central aromatic ring are
discussed
Experimental Evolution of Diverse Strains as a Method for the Determination of Biochemical Mechanisms of Action for Novel Pyrrolizidinone Antibiotics
The continuing rise
of multidrug resistant pathogens has made it
clear that in the absence of new antibiotics we are moving toward
a “postantibiotic” world, in which even routine infections
will become increasingly untreatable. There is a clear need for the
development of new antibiotics with truly novel mechanisms of action
to combat multidrug resistant pathogens. Experimental evolution to
resistance can be a useful tactic for the characterization of the
biochemical mechanism of action for antibiotics of interest. Herein,
we demonstrate that the use of a diverse panel of strains with well-annotated
reference genomes improves the success of using experimental evolution
to characterize the mechanism of action of a novel pyrrolizidinone
antibiotic analog. Importantly, we used experimental evolution under
conditions that favor strongly polymorphic populations to adapt a
panel of three substantially different Gram-positive species (lab
strain <i>Bacillus subtilis</i> and clinical strains methicillin-resistant <i>Staphylococcus aureus</i> MRSA131 and <i>Enterococcus faecalis</i> S613) to produce a sufficiently diverse set of evolutionary outcomes.
Comparative whole genome sequencing (WGS) between the susceptible
starting strain and the resistant strains was then used to identify
the genetic changes within each species in response to the pyrrolizidinone.
Taken together, the adaptive response across a range of organisms
allowed us to develop a readily testable hypothesis for the mechanism
of action of the CJ-16 264 analog. In conjunction with mitochondrial
inhibition studies, we were able to elucidate that this novel pyrrolizidinone
antibiotic is an electron transport chain (ETC) inhibitor. By studying
evolution to resistance in a panel of different species of bacteria,
we have developed an enhanced method for the characterization of new
lead compounds for the discovery of new mechanisms of action
Enantioselective Total Synthesis of Antibiotic CJ-16,264, Synthesis and Biological Evaluation of Designed Analogues, and Discovery of Highly Potent and Simpler Antibacterial Agents
An
improved and enantioselective total synthesis of antibiotic
CJ-16,264 through a practical kinetic resolution and an iodolactonization
reaction to form the iodo pyrrolizidinone fragment of the molecule
is described. A series of racemic and enantiopure analogues of CJ-16,264
was designed and synthesized through the developed synthetic technologies
and tested against drug-resistant bacterial strains. These studies
led to interesting structure–activity relationships and the
identification of a number of simpler, and yet equipotent, or even
more potent, antibacterial agents than the natural product, thereby
setting the foundation for further investigations in the quest for
new anti-infective drugs
Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations
From the enediyne class of antitumor
antibiotics, uncialamycin
is among the rarest and most potent, yet one of the structurally simpler,
making it attractive for chemical synthesis and potential applications
in biology and medicine. In this article we describe a streamlined
and practical enantioselective total synthesis of uncialamycin that
is amenable to the synthesis of novel analogues and renders the natural
product readily available for biological and drug development studies.
Starting from hydroxy- or methoxyisatin, the synthesis features a
Noyori enantioselective reduction, a Yamaguchi acetylide-pyridinium
coupling, a stereoselective acetylide-aldehyde cyclization, and a
newly developed annulation reaction that allows efficient coupling
of a cyanophthalide and a <i>p</i>-methoxy semiquinone aminal
to forge the anthraquinone moiety of the molecule. Overall, the developed
streamlined synthesis proceeds in 22 linear steps (14 chromatographic
separations) and 11% overall yield. The developed synthetic strategies
and technologies were applied to the synthesis of a series of designed
uncialamycin analogues equipped with suitable functional groups for
conjugation to antibodies and other delivery systems. Biological evaluation
of a select number of these analogues led to the identification of
compounds with low picomolar potencies against certain cancer cell
lines. These compounds and others like them may serve as powerful
payloads for the development of antibody drug conjugates (ADCs) intended
for personalized targeted cancer therapy