Focusing on the step-by-step transformation of the traditional solid-phase peptide synthesis (SPPS) into an environmentally friendly process, we herein report the elimination of environmentally hazardous components (piperidine, DMF and DCM) from this technique.
We describe a polymer‐supported stereoselective synthesis of the (1S,5S)‐6‐oxa‐3,8‐diazabicyclo[3.2.1]octane‐bridged scaffold by tandem iminium ion cyclization/nucleophilic addition reactions. A series of resin‐bound acyclic intermediates bearing different substituents were prepared, and the scope and limitations of the chemical route leading to the bridged scaffold were evaluated. The Thr‐derived bridged scaffold was found to be substantially more stable in acid than the Ser‐derived scaffold, which was partially transformed into dihydropyrazinones. Substitution at the iminium‐forming nitrogen was critical for acid stability, and the N‐arylsulfonamides with electron‐withdrawing groups yielded the highest purity of the crude products prepared by acid‐mediated cleavage. The acid‐labile target compounds were synthesized by nucleophile‐mediated cleavage from the esterified Wang resin and cyclization in formic acid.
Traceless solid-phase synthesis represents an ultimate
sophisticated
synthetic strategy on insoluble supports. Compounds synthesized on
solid supports can be released without a trace of the linker that
was used to tether the intermediates during the synthesis. Thus, the
target products are composed only of the components (atoms, functional
groups) inherent to the target core structure. A wide variety of synthetic
strategies have been developed to prepare products in a traceless
manner, and this review is dedicated to all aspects of traceless solid-phase
organic synthesis. Importantly, the synthesis does not need to be
carried out on a linker designed for traceless synthesis; most of
the synthetic approaches described herein were developed using standard,
commercially available linkers (originally devised for solid-phase
peptide synthesis). The type of structure prepared in a traceless
fashion is not restricted. The individual synthetic approaches are
divided into eight sections, each devoted to a different methodology
for traceless synthesis. Each section consists of a brief outline
of the synthetic strategy followed by a description of individual
reported syntheses.
Inhibitors of cyclin-dependent kinases 9 have been developed as potential anticancer drugs for the treatment of multiple myeloma. We have previously prepared a library of arylazo-3,5-diaminopyrazole inhibitors of CDKs. Here, we describe a novel member, AAP1742 (CDK9 inhibition with IC(50) = 0.28 μm), that reduces the viability of multiple myeloma cell lines in low micromolar concentrations. Consistent with inhibition of CDK9, AAP1742 decreases the phosphorylation of RNA polymerase II and inhibits mRNA synthesis of anti-apoptotic proteins Mcl-1, Bcl-2, and XIAP, followed by apoptosis in the RPMI-8226 cell line in a dose- and a time-dependent manner. These results are consistent with the biochemical profile of AAP1742 and further suggest cellular inhibition of CDK9 as a possible target for anticancer drugs.
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