4 research outputs found
Highly Regioselective Syntheses of Substituted Triphenylenes from 1,2,4-Trisubstituted Arenes via a Co-Catalyzed Intermolecular Alkyne Cyclotrimerization
Herein, we report the development
of a new method for the syntheses
of substituted triphenylenes from the corresponding 1,2,4-trisubstituted
arenes, which were themselves generated in a highly regioselective
manner according to an intermolecular alkyne cyclotrimerization reaction
that was catalyzed by a novel Co–TMTU complex. This highly
regioselective reaction for the formation of 1,2,4-trisubstituted
arenes will be a valuable addition to the plethora of tools already
available to synthetic chemists and encourage further mechanistic
studies of this important alkyne trimerization process
General Synthetic Approach to Functionalized Dihydrooxepines
A three-step sequence to access functionalized 4,5-dihydrooxepines from cyclohexenones has been developed. This approach features a regioselective Baeyer–Villiger oxidation and subsequent functionalization via the corresponding enol phosphate intermediate
Synthesis and Biological Investigation of Δ<sup>12</sup>-Prostaglandin J<sub>3</sub> (Δ<sup>12</sup>-PGJ<sub>3</sub>) Analogues and Related Compounds
A series of Δ<sup>12</sup>-prostaglandin
J<sub>3</sub> (Δ<sup>12</sup>-PGJ<sub>3</sub>) analogues and
derivatives were synthesized
employing an array of synthetic strategies developed specifically
to render them readily available for biological investigations. The
synthesized compounds were evaluated for their cytotoxicity against
a number of cancer cell lines, revealing nanomolar potencies for a
number of them against certain cancer cell lines. Four analogues (<b>2</b>, <b>11</b>, <b>21</b>, and <b>27</b>)
demonstrated inhibition of nuclear export through a covalent addition
at Cys528 of the export receptor Crm1. One of these compounds (i.e., <b>11</b>) is currently under evaluation as a potential drug candidate
for the treatment of certain types of cancer. These studies culminated
in useful and path-pointing structure–activity relationships
(SARs) that provide guidance for further improvements in the biological/pharmacological
profiles of compounds within this class
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