3 research outputs found
Substrate-Initiated Synthesis of Cell-Penetrating Poly(disulfide)s
Lessons from surface-initiated polymerization are applied
to grow
cell-penetrating poly(disulfide)s directly on substrates of free choice.
Reductive depolymerization after cellular uptake should then release
the native substrates and minimize toxicity. In the presence of thiolated
substrates, propagators containing a strained disulfide from asparagusic
or, preferably, lipoic acid and a guanidinium cation polymerize into
poly(disulfide)s in less than 5 min at room temperature at pH 7. Substrate-initiated
polymerization of cationic poly(disulfide)s and their depolymerization
with dithiothreitol causes the appearance and disappearance of transport
activity in fluorogenic vesicles. The same process is further characterized
by gel-permeation chromatography and fluorescence resonance energy
transfer
Discovery of 3-((3-amino-<i>1H</i>-indazol-4-yl)ethynyl)-<i>N</i>-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (AKE-72), a potent Pan-BCR-ABL inhibitor including the T315I gatekeeper resistant mutant
BCR-ABL inhibition is an effective therapeutic approach for the treatment of chronic myeloid leukaemia (CML). Herein, we report the discovery of AKE-72 (5), a diarylamide 3-aminoindazole, as a potent pan-BCR-ABL inhibitor, including the imatinib-resistant mutant T315I. A focussed array of compounds 4a, 4b, and 5 has been designed based on our previously reported indazole I to improve its BCR-ABLT315I inhibitory activity. Replacing the morpholine moiety of I with the privileged tail (4-ethylpiperazin-1-yl)methyl afforded 5 (AKE-72) with IC50 values of WT and BCR-ABLT315I, respectively. Moreover, AKE-72 potently inhibited a panel of other clinically important mutants in single-digit nanomolar IC50 values. AKE-72 elicited remarkable anti-leukemic activity against K-562 cell line (GI50 AKE-72 strongly inhibited the proliferation of Ba/F3 cells expressing native BCR-ABL or its T315I mutant. Overall, AKE-72 may serve as a promising candidate for the treatment of CML, including those harbouring T315I mutation.</p
Dynamic Amphiphile Libraries To Screen for the “Fragrant” Delivery of siRNA into HeLa Cells and Human Primary Fibroblasts
Dynamic
amphiphiles are amphiphiles with dynamic covalent bridges
between their hydrophilic heads and their hydrophobic tails. Their
usefulness to activate ion transporters, for odorant release, and
for differential sensing of odorants and perfumes, has been demonstrated
recently. Here, we report that the same “fragrant” dynamic
amphiphiles are ideal to screen for new siRNA transfection agents.
The advantages of this approach include rapid access to fairly large
libraries of complex structures, and possible transformation en route
to assist uptake and minimize toxicity. We report single-component
systems that exceed the best commercially available multicomponent
cocktails with regard to both efficiency and velocity of EGFP knockdown
in HeLa cells. In human primary fibroblasts, siRNA-mediated enzyme
knockdown nearly doubled from >30% for Lipofectamine to >60%
for our
best hit. The identified structures were predictable neither from
literature nor from results in fluorogenic vesicles and thus support
the importance of conceptually innovative screening approaches