De novo branching cascades for structural and functional diversity in small molecules

Abstract

The limited structural diversity that a compound library represents severely restrains the discovery of bioactive small molecules for medicinal chemistry and chemical biology research, and thus calls for developing new divergent synthetic approaches to structurally diverse and complex scaffolds. Here we present a de novo branching cascades approach wherein simple primary substrates follow different cascade reactions to create various distinct molecular frameworks in a scaffold diversity phase. Later, the scaffold elaboration phase introduces further complexity to the scaffolds by creating a number of chiral centres and incorporating new hetero-or carbocyclic rings. Thus, employing N-phenyl hydroxylamine, dimethyl acetylenedicarboxylate and allene ester as primary substrates, a compound collection of sixty one molecules representing seventeen different scaffolds is built up that delivers a potent tubulin inhibitor, as well as inhibitors of the Hedgehog signalling pathway. This work highlights the immense potential of cascade reactions to deliver compound libraries enriched in structural and functional diversity.

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

“…[62] In the first study,a pproximately sixty molecules with over seventeen scaffold structures were screened for their ability to modulate the hedgehog pathway. [71] This pathway plays afundamental role during animal embryonic and post-embryonic development as well as in tumorigenesis as aberrant hedgehog signaling is detected in various cancers.T herefore,s mall-molecule modulators of the hedgehog pathway are well sought after for drug discovery as well as chemical-biology investigations.S creening the compound collection identified three molecules with three different scaffolds,n amely 156 a, 157 b,a nd 159 c,a s inhibitors of hedgehog signaling with IC 50 values of 0.79, 0.84, and 0.16 mm,r espectively (without influencing cell viability; Figure 5a,b).…”

“…[62] Interestingly,these simple substrates did not contain any of the ring systems contained in the diverse scaffolds formed by the domino reactions.I nt hat sense,t his approach resembles the de novo biosynthesis of diverse NPs from acyclicprimary substrates.Our strategy was based on the fact that anitrone (formed in situ) can be transformed into either abenzazepinone (153)oravinylindole (154)under different reaction conditions (Scheme 13). Thed ifferent reactive sites available on these intermediates could be exploited in diverse cyclization reactions by simply modifying the reaction conditions.Thus the three primary substrates N-phenylhydroxylamine (150), dimethyl acetylenedicarboxylate (151), and allene carboxylate 152 yielded seven distinct molecular frameworks in different cascade reactions under optimized reaction conditions in the "scaffold diversity phase" (Scheme 13).…”

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

“…To address this issue, synthetic community has been developing many DOS-based approaches for the generation of compound libraries embodying core scaffolds of natural products or its mimetics7891011. Natural products have inherent bioactivity and high bioavailability; thus, the natural product-inspired DOS libraries with biological relevance could be of great value for the identification of bioactive compounds121314.…”

Synthetic Small Molecule Inhibitors of Hh Signaling As Anti-Cancer Chemotherapeutics

“…A diversity oriented approach to design small molecules that occupy a wide-range of chemical space as potential therapeutic drugs was undertaken at the Max-Planck-Institut für Molekulare Physiologie [116]. Compounds prepared through this synthetic route were evaluated in several biological assays, including for their ability to inhibit Hh signaling.…”

“…13) is responsible for the anti-Hh activity of the scaffold (IC 50 ~ 0.5 μM). None of the compounds displaced BODIPY-Cyc from Smo in HEK293T cells, suggesting their inhibitory activity is mediated through a different mechanism than direct Smo antagonism [116]. …”