Tumor necrosis factor (TNF)-A is present in the microenvironment of human tumors, including malignant pleural effusion (MPE). Although the cytokine is produced in the pleural cavity by both tumor and host cells, its effects on MPE formation are unknown. In these studies, we sought to determine the role of TNF-A in the pathogenesis of MPE and to assess the therapeutic effects of its neutralization in a preclinical model. For this, MPEs were generated in immunocompetent mice using intrapleural injection of mouse lung adenocarcinoma cells. The roles of tumor-and host-derived TNF-A were assessed using combined experimentation with TNF-a gene-deficient mice and in vivo TNF-A neutralization.
The bisorbicillinoids are a growing class of novel natural products endowed with unique biological
activity and are associated with fascinating hypotheses for their biosynthesis. A full account of our biomimetic
explorations toward the bisorbicillinoids including the total syntheses of bisorbicillinol (1), bisorbibutenolide
(2), and trichodimerol (4) from sorbicillin (3) is disclosed. Utilizing the novel dimerization reactions discovered
and fine-tuned en route to 1 and 4, several analogues of these natural products have been synthesized.
Furthermore, studies on the scope of these novel cycloaddition reactions and the isolation of a number of
unexpected products along with proposed mechanisms for their formation are reported. These findings add to
our knowledge of the largely unexplored chemistry of o-quinols and related aromatic systems.
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 p-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.
The structural variety of naturally occurring diaryl ethers is illustrated and the various synthetic methods employed for the construction of diaryl ether linkages in related total syntheses are reviewed. Examples of successful applications of each method (including reaction conditions, diaryl ether substitution pattern, and, when appropriate, the size of the ring formed) are given in tabular format.
The family of anthraquinone-fused
enediyne antitumor antibiotics
was established by the discovery of dynemicin A and deoxy-dynemicin
A. It was then expanded, first by the isolation of uncialamycin,
and then by the addition to the family of tiancimycins A–F
and yangpumicin A. This family of natural products provides
opportunities in total synthesis, biology, and medicine due to their
novel and challenging molecular structures, intriguing biological
properties and mechanism of action, and potential in targeted cancer
therapies. Herein, the total syntheses of tiancimycins A and
B, yangpumicin A, and a number of related anthraquinone-fused
enediynes are described. Biological evaluation of the synthesized
compounds revealed extremely potent cytotoxicities against a number
of cell lines, thus enriching the structure–activity relationships
within this class of compounds. The findings of these studies may
facilitate future investigations directed toward antibody–drug
conjugates for targeted cancer therapies and provide inspiration for
further advances in total synthesis and chemical biology.
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