Epidithiodioxopiperazine alkaloids possess an astonishing array of molecular architecture and generally exhibit potent biological activity. Nearly twenty distinct families have been isolated and characterized since the seminal discovery of gliotoxin in 1936. Numerous biosynthetic investigations offer a glimpse at the relative ease with which Nature is able to assemble this class of molecules, while providing synthetic chemists inspiration for the development of more efficient syntheses. Herein, we discuss the isolation and characterization, proposed fungal biogeneses, and total syntheses of epidithiodioxopiperazines.
The LREX’ prostate cancer model is resistant to the antiandrogen enzalutamide via activation of an alternative nuclear hormone receptor (NHR), glucocorticoid receptor (GR), which has similar DNA binding specificity to the androgen receptor (AR). Small molecules that target DNA to interfere with protein-DNA interactions may retain activity against enzalutamide-resistant prostate cancers where ligand binding domain antagonists are ineffective. We reported previously that a pyrrole-imidazole (Py-Im) polyamide designed to bind the consensus androgen response element half-site has antitumor activity against hormone-sensitive prostate cancer. In enzalutamide-resistant LREX’ cells, Py-Im polyamide interfered with both androgen receptor- and glucocorticoid receptor-driven gene expression, while enzalutamide interfered with only that of androgen receptor. Genomic analyses indicated immediate interference with the androgen receptor transcriptional pathway. Long-term treatment with Py-Im polyamide demonstrated a global decrease in RNA levels consistent with inhibition of transcription. The polyamide was active against two enzalutamide-resistant xenografts with minimal toxicity. Overall, our results identify Py-Im polyamide as a promising therapeutic strategy in enzalutamide-resistant prostate cancer.
The biomimetic total syntheses of both malbrancheamide and malbrancheamide B are reported. The synthesis of the two mono-chloro species enabled the structure of malbrancheamide B to be unambiguously assigned. The syntheses each feature an intramolecular Diels-Alder reaction of a 5-hydroxypyrazin-2(1H)-one to construct the bicyclo[2.2.2]diazaoctane core, which has also been proposed as the biosynthetic route to these compounds.
Inhibition of the 90 kDa heat shock protein (Hsp90) family of molecular chaperones represents a promising new chemotherapeutic approach toward the treatment of several cancers. Previous studies have demonstrated that the natural products, radicicol and geldanamycin, are potent inhibitors of the Hsp90 N-terminal ATP binding site. The cocrystal structures of these molecules bound to Hsp90 have been determined, and through molecular modeling and superimposition of these ligands, hybrids of radicicol and geldanamycin have been designed. A series of macrocylic chimeras of radicicol and geldanamycin and the corresponding seco-agents have been prepared and evaluated for both antiproliferative activity and their ability to induce Hsp90-dependent client protein degradation.
RNA polymerase II (pol II) encounters numerous barriers during transcription elongation, including DNA strand breaks, DNA lesions, and nucleosomes. Pyrrole-imidazole (Py-Im) polyamides bind to the minor groove of DNA with programmable sequence specificity and high affinity. Previous studies suggest that Py-Im polyamides can prevent transcription factor binding, as well as interfere with pol II transcription elongation. However, the mechanism of pol II inhibition by Py-Im polyamides is unclear. Here we investigate the mechanism of how these minor-groove binders affect pol II transcription elongation. In the presence of site-specifically bound Py-Im polyamides, we find that the pol II elongation complex becomes arrested immediately upstream of the targeted DNA sequence, and is not rescued by transcription factor IIS, which is in contrast to pol II blockage by a nucleosome barrier. Further analysis reveals that two conserved pol II residues in the Switch 1 region contribute to pol II stalling. Our study suggests this motif in pol II can sense the structural changes of the DNA minor groove and can be considered a "minor groove sensor." Prolonged interference of transcription elongation by sequence-specific minor groove binders may present opportunities to target transcription addiction for cancer therapy.Py-Im polyamide | transcription inhibition | minor groove | DNA I n eukaryotes, precursor mRNA synthesis is catalyzed by the RNA polymerase II holoenzyme (pol II), which frequently pauses during transcription elongation (1-3). In addition to regulatory factors that control pol II processivity, various obstacles encountered by pol II can also lead to stalling, and even backtracking, on the DNA template (4). Factors that affect pol II transcription elongation dynamics include intrinsic DNA sequences or structures (5, 6), endogenous epigenetic DNA modifications (7), embedded ribonucleotides (8), DNA lesions (9, 10), small-molecule DNA-binders (11, 12), DNA-binding proteins including nucleosomes (13), and even pol II itself (14, 15). Transient transcriptional pausing or short-lived transcriptional blockage can be rescued by the recruitment of transcription factor IIS (TFIIS) (16, 17), a transcription factor that facilitates the cleavage of backtracked transcript. In contrast, prolonged transcriptional arrest by some bulky DNA lesions triggers either ubiquitination and degradation of pol II, or transcription-coupled nucleotide excision repair, a special DNA repair pathway that preferentially repairs DNA lesions in the transcribed strand (17, 18). Structural, genetic, and biochemical studies have greatly advanced our understanding of how pol II copes with different kinds of covalent DNA lesions caused by oxidation (19, 20), alkylation (21-24), and photocyclo-addition (10). Less well understood are the interactions of the pol II machinery when confronted with a steric blockade by small molecules bound noncovalently in the minor groove of DNA (25-27).Pyrrole-imidazole (Py-Im) polyamides are a class of small molecules that c...
The enantiospecific synthesis of desthiochetomin, a putative biosynthetic intermediate of the epidithiodioxopiperazine natural product chetomin, is described. A diastereoselective N-alkylation was employed to form the key C3-N1’ bond of the heterodimeric indoline core, followed by peptide coupling and dioxopiperazine cyclization with the requisite N-methyl amino acids. A related sarcosine–derived dioxopiperazine was prepared in the same manner. The first proposed biosynthesis of chetomin is also detailed in the text.
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