3 research outputs found
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
Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology
Small molecule toll-like receptor
(TLR) 7 agonists have gathered
considerable interest as promising therapeutic agents for applications
in cancer immunotherapy. Herein, we describe the development and optimization
of a series of novel TLR7 agonists through systematic structure–activity
relationship studies focusing on modification of the phenylpiperidine
side chain. Additional refinement of ADME properties culminated in
the discovery of compound 14, which displayed nanomolar
reporter assay activity and favorable drug-like properties. Compound 14 demonstrated excellent in vivo pharmacokinetic/pharmacodynamic
profiles and synergistic antitumor activity when administered in combination
with aPD1 antibody, suggesting opportunities of employing 14 in immuno-oncology therapies with immune checkpoint blockade agents
Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology
We have designed and developed novel and selective TLR7
agonists
that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion
of cytokines IL-6, IL-1β, IL-10, TNFa, IFNa, and IP-10 in human
and mouse whole blood. Pharmacokinetic and pharmacodynamic studies
in mice showed a significant secretion of IFNα and TNFα
cytokines. When combined with aPD1 in a CT-26 tumor model, the lead
compound showed strong synergistic antitumor activity with complete
tumor regression in 8/10 mice dosed using the intravenous route. Structure–activity
relationship studies enabled by structure-based designs of TLR7 agonists
are disclosed