Mechanistic and chiroptical studies on the desulfurization of epidithiodioxopiperazines reveal universal retention of configuration at the bridgehead carbon atoms.

<p>The stereochemistry of the desulfurization products of chiral natural and synthetic 3,6-epidithiodiketopiperazines (ETPs) is specified inconsistently in the literature. Qualitative mechanisms have been put forward to explain apparently divergent stereochemical pathways, however the quantitative feasibility of such mechanistic pathways has not been assessed. We report a computational study which reveals that desulfurization of ETPs should occur universally with retention of configuration. While the majority of stereochemically assigned and reassigned cases fit this model, until now desulfurization of a synthetic gliotoxin analogue (7) has remained assigned as proceeding via inversion of configuration. Through detailed chiroptical studies, comparing experimentally obtained optical rotation values, electronic circular dichroism spectra, and vibrational circular dichroism spectra to their computationally simulated counterparts, as well as using chemical derivatization studies, we have unambiguously demonstrated that, contrary to its current assignment in the literature, the desulfurization of a synthetic ETP (7) also proceeds with retention of configuration.</p

A Scalable and Expedient Route to 1‑Aza[6]helicene Derivatives and Its Subsequent Application to a Chiral-Relay Asymmetric Strategy

A rapid route to diversely functionalized 1-aza[6]helicenes has been achieved via the development of a copper-mediated cross-coupling reaction, followed by PtCl₄-catalyzed cycloisomerization. Not only does this method allow access to these functionally important molecules on gram scale, but this strategy is also suitable for relaying the axial chirality of a key intermediate to the helicity of the product

Arylazopyrazoles: Azoheteroarene Photoswitches Offering Quantitative Isomerization and Long Thermal Half-Lives

Arylazopyrazoles, a novel class of five-membered azo photoswitches, offer quantitative photoswitching and high thermal stability of the <i>Z</i> isomer (half-lives of 10 and ∼1000 days). The conformation of the <i>Z</i> isomers of these compounds, and also the arylazopyrroles, is highly dependent on the substitution pattern on the heteroarene, allowing a twisted or planar geometry, which in turn has a significant impact on the electronic spectral properties of the compounds

Mechanistic and chiroptical studies on the desulfurization of epidithiodioxopiperazines reveal universal retention of configuration at the bridgehead carbon atoms.

<p>2,3,10,10-Tetramethyl-2,3-dihydro-1H-3,10a-epithiopyrazino[1,2-a]indole-1,4(10H)-dione (<strong>8</strong>). To a solution of gliotoxin analogue (7, 33 mg, 0.10 mmol) in dioxane (8 mL) was added PPh3 (33 mg, 0.16 mmol) and the resulting mixture was stirred overnight at room temperature. The solvent was then re-moved under reduced pressure and the pink residue was purified by column chromatography [PEEtOAc (100:0 to 95:5)] to afford a colorless oil (19 mg, 64%) which was recrystallized from CH2Cl2 to give a white solid: m.p. 58 60 C; IR (neat) 1720, 1456, 1387, 1288, 1134 cm-1; 1H NMR (400 MHz, CDCl3) 8.54 (app-d, J = 7.8 Hz, 1H), 7.25 (td, J = 7.8, 1.0 Hz, 1H), 7.20 (dd, J = 7.8, 1.0 Hz, 1H), 7.13 (td, J = 7.8, 1.0 Hz, 1H), 2.96 (s, 3H), 1.83 (s, 3H), 1.75 (s, 3H), 1.48 (s, 3H); 13C NMR (100 MHz, CDCl3) 172.5, 172.0, 139.7, 138.1, 128.1, 124.7, 122.4, 113.6, 86.6, 75.1, 43.5, 27.2, 26.3, 25.7, 13.3; MS (CI) m/z 289 (M+H)+, 306 (M+NH4)+; HRMS (CI) m/z calcd for C15H17N2O2S [(M+H)+] 289.1011, found: 289.1026. The obtained enantiomers could be separated by chiral HPLC (OD+ semiprep column, Hexane : Isopropanol, 90:10): First peak: [α]25D -47.5 (c 1.12, CH2Cl2), Second peak: [α]25D +34.4 (c 1.12, CH2Cl2).</p

Mechanistic and Chiroptical Studies on the Desulfurization of Epidithiodioxopiperazines Reveal Universal Retention of Configuration at the Bridgehead Carbon Atoms

The stereochemistry of the desulfurization products of chiral natural and synthetic 3,6-epidithiodiketopiperazines (ETPs) is specified inconsistently in the literature. Qualitative mechanisms have been put forward to explain apparently divergent stereochemical pathways, but the quantitative feasibility of such mechanistic pathways has not been assessed. We report a computational study revealing that desulfurization of ETPs should occur universally with retention of configuration. While the majority of stereochemically assigned and reassigned cases fit this model, until now desulfurization of the synthetic gliotoxin analogue shown has remained assigned as proceeding via inversion of configuration. Through detailed chiroptical studies comparing experimentally obtained optical rotation values, electronic circular dichroism spectra, and vibrational circular dichroism spectra to their computationally simulated counterparts as well as chemical derivatization studies, we have unambiguously demonstrated that contrary to its current assignment in the literature, the desulfurization of this synthetic ETP also proceeds with retention of configuration

Toward Photopharmacological Antimicrobial Chemotherapy Using Photoswitchable Amidohydrolase Inhibitors

Photopharmacological agents exhibit light-dependent biological activity and may have potential in the development of new antimicrobial agents/modalities. Amidohydrolase enzymes homologous to the well-known human histone deacetylases (HDACs) are present in bacteria, including resistant organisms responsible for a significant number of hospital-acquired infections and deaths. We report photopharmacological inhibitors of these enzymes, using two classes of photoswitches embedded in the inhibitor pharmacophore: azobenzenes and arylazopyrazoles. Although both classes of inhibitor show excellent inhibitory activity (nM IC₅₀ values) of the target enzymes and promising differential activity of the switchable <i>E</i>- and <i>Z</i>-isomeric forms, the arylazopyrazoles exhibit better intrinsic photoswitch performance (more complete switching, longer thermal lifetime of the <i>Z</i>-isomer). We also report protein–ligand crystal structures of the <i>E</i>-isomers of both an azobenzene and an arylazopyrazole inhibitor, bound to bacterial histone deacetylase-like amidohydrolases (HDAHs). These structures not only uncover interactions important for inhibitor binding but also reveal conformational differences between the two photoswitch inhibitor classes. As such, our data may pave the way for the design of improved photopharmacological agents targeting the HDAC superfamily

Thienopyrimidinone Based Sirtuin‑2 (SIRT2)-Selective Inhibitors Bind in the Ligand Induced Selectivity Pocket

Sirtuins (SIRTs) are NAD-dependent deacylases, known to be involved in a variety of pathophysiological processes and thus remain promising therapeutic targets for further validation. Previously, we reported a novel thienopyrimidinone SIRT2 inhibitor with good potency and excellent selectivity for SIRT2. Herein, we report an extensive SAR study of this chemical series and identify the key pharmacophoric elements and physiochemical properties that underpin the excellent activity observed. New analogues have been identified with submicromolar SIRT2 inhibtory activity and good to excellent SIRT2 subtype-selectivity. Importantly, we report a cocrystal structure of one of our compounds (<b>29c</b>) bound to SIRT2. This reveals our series to induce the formation of a previously reported selectivity pocket but to bind in an inverted fashion to what might be intuitively expected. We believe these findings will contribute significantly to an understanding of the mechanism of action of SIRT2 inhibitors and to the identification of refined, second generation inhibitors

On the Histone Lysine Methyltransferase Activity of Fungal Metabolite Chaetocin

Histone lysine methyltransferases (HKMTs) are an important class of targets for epigenetic therapy. <b>1</b> (chaetocin), an epidithiodiketopiperazine (ETP) natural product, has been reported to be a specific inhibitor of the SU­(VAR)­3-9 class of HKMTs. We have studied the inhibition of the HKMT G9a by <b>1</b> and functionally related analogues. Our results reveal that only the structurally unique ETP core is required for inhibition, and such inhibition is time-dependent and irreversible (in the absence of DTT), ultimately resulting in protein denaturation. Mass spectrometric data provide a molecular basis for this effect, demonstrating covalent adduct formation between <b>1</b> and the protein. This provides a potential rationale for the selectivity observed in the inhibition of a variety of HKMTs by <b>1</b> in vitro and has implications for the activity of ETPs against these important epigenetic targets

Development of a Photo-Cross-Linkable Diaminoquinazoline Inhibitor for Target Identification in <i>Plasmodium falciparum</i>

Di­amino­quina­zolines represent a privileged scaffold for antimalarial discovery, including use as putative <i>Plasmodium</i> histone lysine methyltransferase inhibitors. Despite this, robust evidence for their molecular targets is lacking. Here we report the design and development of a small-molecule photo-cross-linkable probe to investigate the targets of our di­amino­quina­zoline series. We demonstrate the effectiveness of our designed probe for photoaffinity labeling of <i>Plasmodium</i> lysates and identify similarities between the target profiles of the probe and the representative di­amino­quina­zoline BIX-01294. Initial pull-down proteomics experiments identified 104 proteins from different classes, many of which are essential, highlighting the suitability of the developed probe as a valuable tool for target identification in <i>Plasmodium falciparum</i>

Defining the Mechanism of Action and Enzymatic Selectivity of Psammaplin A against Its Epigenetic Targets

Psammaplin A (<b>11c</b>) is a marine metabolite previously reported to be a potent inhibitor of two classes of epigenetic enzymes: histone deacetylases and DNA methyltransferases. The design and synthesis of a focused library based on the psammaplin A core has been carried out to probe the molecular features of this molecule responsible for its activity. By direct in vitro assay of the free thiol generated upon reduction of the dimeric psammaplin scaffold, we have unambiguously demonstrated that <b>11c</b> functions as a natural prodrug, with the reduced form being highly potent against HDAC1 in vitro (IC₅₀ 0.9 nM). Furthermore, we have shown it to have high isoform selectivity, being 360-fold selective for HDAC1 over HDAC6 and more than 1000-fold less potent against HDAC7 and HDAC8. SAR around our focused library revealed a number of features, most notably the oxime functionality to be important to this selectivity. Many of the compounds show significant cytotoxicity in A549, MCF7, and W138 cells, with the SAR of cytotoxicity correlating to HDAC inhibition. Furthermore, compound treatment causes upregulation of histone acetylation but little effect on tubulin acetylation. Finally, we have found no evidence for <b>11c</b> functioning as a DNMT inhibitor