Advances in chemistry and bioactivity of parthenolide.

Review covering up to 07/2019(-)-Parthenolide is a germacrane sesquiterpene lactone, available in ample amounts from the traditional medical plant feverfew (Tanacetum parthenium). Acting as a covalently reactive compound, it displays anti-inflammatory, redox-modulating, and epigenetic activities, as well as selective cytotoxicity towards cancer stem and progenitor cells. Furthermore, parthenolide was found to modulate microtubule dynamics by interfering with the detyrosination of α-tubulin, a specific posttranslational modification of the cytoskeleton. This review interfaces recently achieved parthenolide syntheses with strategies for bioactivity-based derivatization. Furthermore, chemical probe development from parthenolide is discussed, leading to a qualified summary of reported biological activities and implicated or identified targets. Special emphasis is given to parthenolide-induced microtubule modulation and the recently characterized tubulin carboxypeptidase enzymes involved in nerve (re)growth, cardiac muscle cell function, and metastasis development.

Cornforth-Evans Transition States in Stereocontrolled Allylborations of Epoxy Aldehydes.

Allylboration reactions rank among the most reliable tools in organic synthesis. Herein, we report a general synthesis of trifunctionalized allylboronates and systematic investigations of their stereocontrolled transformations with substituted aldehyde substrates, in order to efficiently access diverse, highly substituted target substrates. A peculiar transition in stereocontrol was observed from the polar Felkin-Anh (PFA) to the Cornforth-Evans (CE) model for alkoxy- and epoxy-substituted aldehydes. CE-type transition states were uniformly identified as minima in advanced, DFT-based computational studies of allylboration reactions of epoxy aldehydes, conforming well to the experimental data, and highlighting the underestimated relevance of this model. Furthermore, a mechanism-based rationale for the substitution pattern of the epoxide was delineated that ensures high levels of stereocontrol and renders α,ß-epoxy aldehydes generally applicable substrates for target synthesis.

Synthesis and biological profiling of parthenolide ether analogs.

Parthenolide (PTL) strongly inhibits the detyrosination of microtubules and accelerates neuronal growth. In order to access cyclic ether derivatives of PTL, ring-closing metathesis (RCM) was investigated in comparison to intramolecular sulfone alkylation. Incompatibility of RCM with epoxides was found in this setting. Biological evaluation for tubulin carboxypeptidase inhibition indicated that the epoxide is crucial for parthenolide's activity.

Synthesis of (±)-4,5-dia-Parthenolide, an Unnatural Parthenolide Stereoisomer.

A short total synthesis of the novel unnatural parthenolide diastereomer (±)-4,5-dia-parthenolide was accomplished in 13 steps and an overall yield of 1.75% starting from commercially available (E,E)-farnesol. The challenging isopropenyl side chain oxidation was regioselectively achieved via a newly developed stepwise dihydroxylation procedure, employing a Bartlett-Smith iodocarbonate cyclization followed by iodide substitution and catalytic transesterification.

π-Extension of a 4-ethoxy-1,3-thiazole via aryl alkyne cross coupling: synthesis and exploration of the electronic structure.

A series of four donor aryl alkynyl substituted thiazole derivatives 3a-d and three similar aryl donor-acceptor systems 6a-c have been synthesized. All compounds bear different electron-donating groups in the 5-position of the thiazole core. The influence of both electron donor strength and the additional phenylethynyl unit on photophysical properties, i.e. UV/Vis absorption, fluorescence emission and fluorescence lifetime, has been evaluated. Additionally, theoretical calculations have been performed at the CAM-B3LYP/6-31+G(d,p) level and good agreement with the experimental data has been achieved. The new derivatives synthesized via palladium catalyzed cross coupling are characterised by moderately strong emission between 474 and 538 nm (ΦF = 0.35-0.39) and Stokes' shifts ranging from 0.54 to 0.79 eV (4392-6351 cm(-1)). The smaller chromophores of type 6 exhibit modest to high fluorescence emission (ΦF = 0.45-0.76) between 470 and 529 nm and their Stokes' shifts range from 0.59 to 0.65 eV (4765-5251 cm(-1)).

Nickel-Catalyzed 1,1-Aminoborylation of Unactivated Terminal Alkenes.

Herein, we disclose a Ni-catalyzed 1,1-difunctionalization of unactivated terminal alkenes that enables the incorporation of two different heteroatom motifs across an olefin backbone, thus streamlining the access to α-aminoboronic acid derivatives from simple precursors. The method is characterized by its simplicity and generality across a wide number of coupling counterparts.

Stereoselective total synthesis of parthenolides indicates target selectivity for tubulin carboxypeptidase activity.

The 2-(silyloxymethyl)allylboration of aldehydes was established to enable stereoselective access to α-(exo)-methylene γ-butyrolactones under mild conditions. Acid-labile functionality and chiral carbonyl compounds are tolerated. Excellent asymmetric induction was observed for ß,ß'-disubstituted α,ß-epoxy aldehydes. These findings led to the enantioselective total synthesis of the sesquiterpene natural product (-)-parthenolide, its unnatural (+)-enantiomer, and diastereoisomers. Among all the isomers tested in cell culture, only (-)-parthenolide showed potent inhibition of microtubule detyrosination in living cells, confirming its exquisite selectivity on tubulin carboxypeptidase activity. On the other hand, the anti-inflammatory activity of the parthenolides was weaker and less selective with regard to compound stereochemistry.

Nickelalactones with an allyl subunit - the effect of penta-coordination on structures and stability.

A series of allyl modified nickelalactone derivatives of the general formula [(L)nNi{CH2C(CH3)C(CH3)CH2COO}] was synthesized via ligand exchange reactions in order to investigate the influence of the neutral ligand L on the structure and stability of these complexes. While the square planar 1,8-diazabicyclo[5,4,0]undec-7-ene ligated derivative 1 is stable in the solid state and in solution at ambient temperature, the use of the chelating ligands 6-diphenylphosphino-1,8-diazabicyclo[5.4.0]undec-7-ene, 1,1-bis(dicyclohexylphosphino)methane and 1,2-bis(dicyclohexylphosphino)ethane (dcpe) led to square pyramidal derivatives 2, 4, and 5 with a novel ligand arrangement. In solution, these derivatives are fluxional and show increasing tendencies in the order 2 < 4 < 5 to decouple the nickelalactone moiety to 2,3-dimethylbutadiene (dmbd), CO2 and zero-valent nickel complexes. During the investigation of 5, the tetrahedral complex [(dcpe)2Ni] (6) and the trigonal planar derivative [(dcpe)Ni(dmbd)] (7) were observed as predominant decomposition products. In the case of the application of 1,1-bis(diphenylphosphino)methane as a neutral ligand, a dinuclear nickelalactone species [(µ-dppm)(Ni{CH2C(CH3)C(CH3)CH2COO})2] (3) was isolated in which the two nickel atoms realize different coordination geometries (SP-4 and SPY-5) in the solid state. The complexes were characterized by NMR techniques, single crystal X-ray diffraction measurements and infrared spectroscopy.