Examination of [13C2]biphenylene formed by gas phase pyrolysis of doubly labelled benzyne precursors shows
that the principal pyrolytic process leads to overall
1,2→1,3 rearrangement of the C6H4 carbon skeleton
either in an intermediate C7H4O before decarbonylation or in benzyne
itself. A minor process involves an apparent 1,3-hydrogen shift. [1,2-13C2]Ethyne-1,2-diylbistrimethylsilane
was acylated with 3-(2,5-dihydro-1,1-dioxothien- 2-yl)propanoyl
chloride and the resulting ketone was desilylated to
yield 5-(2,5-dihydro-1,l-dioxo-thien-2-yl)[1,2-13C2]pent-1-yn-3-one.
Thermal elimination of sulfur dioxide and cyclization followed by
dehydrogenation yielded [7,7a-13C2]-2,3-dihydro-1H-inden-1-one which was oxidized and
dehydrated to give [3a,4-13C2]isobenzofuran-1,3-dione.
This doubly labelled phthalic
anhydride was diluted to approximately 5% 13C2 and the
resulting material was converted via benzenediazonium-
2-carboxylate into biphenylene at 84�, and pyrolysed at 830� to yield biphenylene,
and a sample diluted to 7.5% was converted into [2a,3-13C2]benzocyclobutenedione which was pyrolysed
at 650�, 750� and 830� to yield further samples of biphenylene.
The biphenylene samples were examined by mass
spectrometry at 20 eV to determine their isotopic composition and by 13C
n.m.r. spectroscopy to determine the distribution of labelling.
Flash vacuum pyrolysis of 2-(3′,3′-dimethyltriazenyl)benzoic acid (6) above 350? gives biphenylene and N,N- dimethylaniline. The acid (6) was synthesized with 13C2 labels placed as in (13) to generate [1,6- 13C2] benzyne. F.v.p . of labelled acid (13) from 400-850° gave biphenylene samples which showed 13C spectra consistent with an increasing extent of carbon rearrangement from [1,6-13C2] benzyne to [1,3-13C2] benzyne with increasing temperature. This is in accord with direct rearrangement of benzyne (Scheme 1) but it is probable that more than one mechanism is operating. The labelling evidence suggests that N,N- dimethylaniline is formed by re-addition of dimethylamine to benzyne.
We successfully repurpose the DNA repair protein methylguanine methyltransferase (MGMT) as an inducible degron for protein fusions. MGMT is a suicide protein that removes alkyl groups from the O 6 position of guanine (O 6 G) and is thereafter quickly degraded by the ubiquitin proteasome pathway (UPP). Starting with MGMT pseudosubstrates (benzylguanine and lomeguatrib), we first demonstrate that these lead to potent MGMT depletion while affecting little else in the proteome. We then show that fusion proteins of MGMT undergo rapid UPP-dependent degradation in response to pseudosubstrates. Mechanistic studies confirm the involvement of the UPP, while revealing that at least two E3 ligase classes can degrade MGMT depending on cell-line and expression type (native or ectopic). We also demonstrate the technique's versatility with two clinically relevant examples: degradation of KRAS G12C and a chimeric antigen receptor.
Die Pyrolyse der Benzocyclobutene (I) liefert über die Ester (II) die Aldehyde (III), die mit Ammoniak zu den Isochinolinen (IV) in durchweg hohen Ausbeuten kondensiert werden.
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