Novel Broccoli Sulforaphane-Based Analogues Inhibit the Progression of Pancreatic Cancer without Side Effects.

The naturally occurring isothiocyanate sulforaphane, found in Brassicaceae vegetables, is promising in cancer treatment, e.g., by the normalization of enhanced levels of NF-κB-signaling in tumor stem cells. We chemically synthesized seven sulforaphane analogues by substitution of the sulfinyl group (S(O)) to either sulfimidoyl (S(NR)) or sulfonimidoyl (S (O) (NR)) groups, and characterized them in the cell lines of pancreatic cancer and several other tumor entities, including the NCI-60 cell panel. MTT and colony forming assays, flow cytometry, immunohistochemistry, microRNA arrays, bioinformatics, tumor xenotransplantation, and Kaplan Meier survival curves were performed. Compared to sulforaphane, the analogue SF102 was most efficient in inhibition of viability, colony formation, tumor growth, and the induction of apoptosis, followed by SF134. Side effects were not observed, as concluded from the body weight and liver histology of chick embryos and survival of C. elegans nematodes. Among 6659 differentially regulated microRNAs, miR29b-1-5p, and miR-27b-5p were downregulated by sulforaphane compared to controls, but upregulated by SF102 and SF134 compared to sulforaphane, suggesting differential signaling. Each substance was involved in the regulation of several NF-κB-related target genes. In conclusion, sulforaphane analogues are promising for the development of highly active new drugs in cancer treatment.

Additions to N-Sulfinylamines as an Approach for the Metal-free Synthesis of Sulfonimidamides: O-Benzotriazolyl Sulfonimidates as Activated Intermediates.

Sulfonimidamides are obtained in moderate to very good yields from the key intermediates O-benzotriazolyl sulfonimidates, which are formed by reacting aryldiazonium tetrafluoroborates, N-tritylsulfinylamine, and N-hydroxybenzotriazole hydrate in a process mediated by a tertiary amine. The formation of the sulfonimidate proceeds in inexpensive and environmentally benign dimethyl carbonate as the solvent, it does not require anhydrous conditions, and the product yields generally exceed 70 %. The substrate scope is broad, and a wide range of sensitive organic functionalities is well tolerated. The reactions probably proceed via aryl radicals formed from diazonium cations with assistance from both the tertiary amine and the sulfinylamine.

Hemithioindigos for Cellular Photopharmacology: Desymmetrised Molecular Switch Scaffolds Enabling Design Control over the Isomer-Dependency of Potent Antimitotic Bioactivity.

Druglike small molecules with photoswitchable bioactivity-photopharmaceuticals-allow biologists to perform studies with exquisitely precise and reversible, spatial and temporal control over critical biological systems inaccessible to genetic manipulation. The photoresponsive pharmacophores disclosed have been almost exclusively azobenzenes, which has limited the structural and substituent scope of photopharmacology. More detrimentally, for azobenzene reagents, it is not researchers' needs for adapted experimental tools, but rather protein binding site sterics, that typically force whether the trans (dark) or cis (lit) isomer is the more bioactive. We now present the rational design of HOTubs, the first hemithioindigo-based pharmacophores enabling photoswitchable control over endogenous biological activity in cellulo. HOTubs optically control microtubule depolymerisation and cell death in unmodified mammalian cells. Notably, we show how the asymmetry of hemithioindigos allows a priori design of either Z- or E- (dark- or lit)-toxic antimitotics, whereas the corresponding azobenzenes are exclusively lit-toxic. We thus demonstrate that hemithioindigos enable an important expansion of the substituent and design scope of photopharmacological interventions for biological systems.

2,2,6,6-Tetramethylpiperidin-1-yloxycarbonyl: A Protecting Group for Primary, Secondary, and Heterocyclic Amines.

The 2,2,6,6-tetramethylpiperidin-1-yloxycarbonyl (Tempoc) protecting group is readily introduced by the reaction of amines with a new acyl transfer reagent, 4-nitrophenyl (2,2,6,6-tetramethylpiperidin-1-yl) carbonate (NPTC). Tempoc has a reactivity profile that complements the commonly used t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) protecting groups. Deprotection can be achieved under mild reductive conditions with in situ generated Cu(I) species or by thermolytic cleavage at 135 °C. Mechanistic studies on the deprotection of Tempoc-indole suggest a combination of ionic and radical fragmentation pathways under thermal conditions.