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Dibromoderivatives of benzofused chalcogen-nitrogen heterocycles are important precursors in the synthesis of various photovoltaic materials. 4,7-Dibromobenzo[d][1,2,3]thiadiazole is a practically unexplored compound in this series. In this communication, it was shown that the nucleophilic substitution of 4,7-dibromobenzo[d][1,2,3]thiadiazole with morpholine gave selectively 4-substituted product—4-(7-bromobenzo[d][1,2,3]thiadiazol-4-yl)morpholine. The structure of the newly synthesized compound was established by means of elemental analysis, high resolution mass-spectrometry, 1H, 13C NMR, and IR spectroscopy, mass-spectrometry, and X-ray analysis.

The 11a,12-dihydrobenzo[b]benzo[5,6][1,4]oxazino[2,3-e][1,4]oxazine heterocyclic system has been used in the construction of heteropropellanes, which attracted much attention not only on the possible modification of drugs, but also for novel materials with unusual and important physical properties. In this communication, the reaction of ethyl 2-(hydroxyimino)propanoate 1 with disulfur dichloride and o-aminophenol, which gave ethyl 11a,12-dihydrobenzo[b]benzo[5,6][1,4]oxazino[2,3-e][1,4]oxazine-5a(6H)-carboxylate in moderate yield, was described. The structure of the newly synthesized compound was established by means of elemental analysis, high resolution mass-spectrometry, 1H, 13C NMR and IR spectroscopy, mass-spectrometry and X-ray analysis.

The synthesis of [1,3]dithiolo[4,5-d]dithiazolium salts from readily available zinc chelate has been developed. Chlorination of 2-oxo and 2-(dicyanomethylene) (2-oxo-1,3-dithiole-4,5-diyl) diethanethioates with SO2Cl2 followed by condensation with Me3SiN3 produced 1,2,3-dithiazolium chlorides. The structure of 5-(dicyanomethylene)[1,3]dithiolo[4,5-d][1,3,2]dithiazol-1-ium tetrafluoroborate was confirmed by powder X-ray diffraction, and its chemical bonding pattern as well as charge transfer were studied within the QTAIM framework applied to the results of plane wave DFT periodic calculations. Reduction with triphenylantimony and electrochemical reduction of [1,3]dithiolo[4,5-d]dithiazolium salts by cyclic voltammetry, chronoamperometry, and microelectrolysis at a controlled potential on a platinum electrode in acetonitrile revealed the formation of [1,3]dithiolo[4,5-d]dithiazolyl radicals, which were characterized by EPR spectroscopy.

A synthesis of thieno[2,3-d][1,3,2]dithiazolium salts from commercial tetrahydrothiophene has been developed. The reaction of thieno[2,3-f][1,2,3,4,5]pentathiepin with LiAlH4 in THF at −15 °C, after treatment with acetyl chloride, led to 2,3-(bisacetylthio)thiophene in high yield. Bis(acetylthio)thiophene reacted with sulfuryl chloride and then trimethylsilyl azide was added to afford a 1,3,2-dithiazolium chloride which was converted into a soluble tetrafluoroborate. Electrolytic reduction under controlled potential yielded a thieno[2,3-d][1,3,2]dithiazolyl radical which was characterized by EPR in frozen methylene dichloride.

Dihalogenated derivatives of [1,2,5]chalcogenadiazolo[3,4-d]pyridazines are of interest as precursors for both photovoltaic materials and biologically active compounds. In this communication, 4,7-dichloro[1,2,5]oxadiazolo[3,4-d]pyridazine 1-oxide was prepared via the reaction of 3,6-dichloro-5-nitropyridazin-4-amine with oxidizing agents; the best yield of the target compound was achieved in the reaction with (diacetoxyiodo)benzene in benzene by heating at reflux for two hours. The structure of the newly synthesized compound was established by means of 13C-NMR and IR spectroscopy, mass-spectrometry and elemental analysis.

Histone deacetylases (HDACs) play a pivotal role in epigenetic regulation through post translational modifications of histone core and other critical proteins in cellular pathways. The HDACs class III, sirtuins (SIRTs) 1-7, possess limited deacetylase activity. Each of these nicotinamide dinucleotide (NAD+) dependent enzymes have unique structures of catalytic sites that prefer larger lysine-modifying groups as substrates (i.e., glutaryl, succinyl, lipoyl, crotanyl, myristoyl). In particular, SIRT2 is a key regulator of nuclear H4K16 and cytoplasmic alpha-tubulin proteins, thereby acting as a mitotic exit regulator. From the literature, it is clear that SIRT2 plays a pivotal role in the regulation of cancers, so much so that it may switch between tumor suppressor and regulator at different stages of tumor progression. For this reason, SIRT2 has been identified as a possible target for cancer therapy but due to the pleiotropic roles of SIRT2 under normal and pathologic conditions, it is important to assess its activity during pharmacomodulation (i.e. activation or inhibition). Therefore, non-invasive PET imaging using SIRT2-specific substrate-type radiotracers may aid in the development of new SIRT2 inhibitors for therapy of cancer. Herein, we report novel synthesis of a focused library of compounds to assess the structure activity relationship (SAR) of SIRT2 with fluoroalkyl chain length varying between 3 and 16 carbons. The preliminary screening was performed with the tert-butyloxycarbonyl-lysine-aminomethylcoumarin (Boc-lys-AMC) backbone and Fluor-de-lys assay [1] to determine the chain length for optimal SIRT2 catalytic efficiency. Based on the analysis of Michealis-Menten kinetics of each substrate, myristoyl (14-carbon carboxylic acid) was cleaved most efficiently, followed by 12-fluorododecanoic and 10-fluorodecanoic acids (kcat/km = 4E-3, 1E-4, 8.9E-5 s-1uM-1, respectively). For in vivo PET imaging radiotracer development, we linked the 12-fluorododecanoic acid with the aminohexanoicanilide (AHA) backbone [2]. This compound was developed with a terminal bromine (precursor), iodine, fluorine, and F-18 (12-[18F]DDAHA). In vitro cellular uptake studies demonstrated a three-fold increase in accumulation of 12-[18F]DDAHA in U87 glioma cells as compared to MiaPaCa, MDA-MB-231, and MCF10A cell lines. The increased accumulation in the U87 glioma cells indicates that this compound may prove useful for detection of brain gliomas and for monitoring therapies with novel SIRT2 specific inhibitors. This insight into the catalytic activity of SIRT2 provides a basis for the development of a SIRT2-specific PET imaging agent to further probe the role of SIRT2-mediated epigenetic regulation in normal physiology and cancer. Citation Format: Robin E. Bonomi, Aleksandr Shavrin, Vadim Popov, Thomas Mangner, Juri G. Gelovani. Elucidating structure-activity relationships of SIRT2 and fluoroalkyl chain length to identify the lead candidate substrate radiotracer for PET imaging. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4234.

N-Acyl tryptophan isopeptides undergo acyl transfer in chemical ligations via 7-, 10-, 11- and 12-membered cyclic transition states to yield natural peptides, representing the first examples of successful isopeptide ligations from N-acyl tryptophan units.