DIazo transfer reaction onto γ‐butyrolactams (activated by α‐ethyloxalylation) gave rare α‐diazo γ‐butyrolactams. Decomposition of the latter by Rh2(OAc)4 in the presence of alcohols and water gave products of O–H insertion of the respective metal‐cabene species. Silver triflate (1 mol‐%) was found to convert the γ‐butyrolactams investigated into 1,5‐dihydro‐2H‐pyrrol‐2‐ones which represent versatile building blocks. Particular instability was noted for α‐diazo γ‐butyrolactams bearing alkyl or o‐substituted aryl substituents on the nitrogen atom. These were found to dimerize in solution or upon storage at room temperature to give fully conjugated bis‐hydrazones along with the loss of a nitrogen molecule.
Two
NIR-emitting platinum [Pt(N^N^C)(phosphine)] and iridium [Ir(N^C)2(N^N)]+ complexes containing reactive succinimide groups were synthesized
and characterized with spectroscopic methods (N^N^C,
1-phenyl-3-(pyridin-2-yl)benzo[4,5]imidazo[1,2-a]pyrazine, N^C, 6-(2-benzothienyl)phenanthridine, phosphine-3-(diphenylphosphaneyl)propanoic
acid N-hydroxysuccinimide ether, and N^N, 4-oxo-4-((1-(pyridin-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)butanoic
acid N-hydroxysuccinimide ether). Their photophysics
were carefully studied and analyzed using time-dependent density functional
theory calculations. These complexes were used to prepare luminescent
micro- and nanoparticles with the “core–shell”
morphology, where the core consisted of biodegradable polymers of
different hydrophobicity, namely, poly(d,l-lactic
acid), poly(ε-caprolactone), and poly(ω-pentadecalactone),
whereas the shell was formed by covalent conjugation with poly(l-lysine) covalently labeled with the platinum and iridium emitters.
The surface of the species was further modified with heparin to reverse
their charge from positive to negative values. The microparticles’
size determined with dynamic laser scanning varies considerably from
720 to 1480 nm, but the nanoparticles’ diameter falls in a
rather narrow range, 210–230 nm. The species with a poly(l-lysine) shell display a high positive (>30 mV) zeta-potential
that makes them essentially stable in aqueous media. Inversion of
the surface charge to a negative value with the heparin cover did
not deteriorate the species’ stability. The iridium- and platinum-containing
particles displayed emissions the spectral patterns of which were
essentially similar to those of unconjugated complexes, which indicate
retention of the chromophore nature upon binding to the polymer and
further immobilization onto polyester micro- and nanoparticles for
drug delivery. The obtained particles were tested to determine their
ability to penetrate into different cells types: cancer cells, stem
cells, and fibroblasts. It was found that all types of particles could
effectively penetrate into all cells types under investigation. Nanoparticles
were shown to penetrate into the cells more effectively than microparticles.
However, positively charged nanoparticles covered with poly(l-lysine) seem to interact with negatively charged proteins in the
medium and enter the inner part of the cells less effectively than
nanoparticles covered with poly(l-lysine)/heparin. In the
case of microparticles, the species with positive zeta-potentials
were more readily up-taken by the cells than those with negative values.
A hypothesis that simultaneous targeting cancer-related carbonic anhydrase hCA IX and hCA XII isoforms (whose overexpression is a cancer cell's defence mechanism against hypoxia) along with thioredoxin reductase (overexpressed in cancers as a defence against oxidative stress) may lead to synergistic antiproliferative effects was confirmed by testing combinations of the two inhibitor classes against pancreatic cancer cells (PANC-1). Combining both pharmacophoric motifs within one molecule led to a sharp increase of cytotoxicity. This preliminary observation sets the ground for a fundamentally new approach to anticancer agent design.
Decomposition of α‐diazo‐γ‐butyrolactams in the presence of aromatic and heteroaromatic amines, under Rh2(esp)2 catalysis, led to corresponding α‐arylamino‐γ‐butyrolactams, which are of significant value for medicinal chemistry. The reaction scope encompasses primary as well as secondary, diversely substituted anilines and heteroaromatic amines. Insertion into the anilinic amino group was shown to be selective over amide and sulfonamide N–H insertion.
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