Synthesis of Privileged Scaffolds by Using Diversity‐Oriented Synthesis

Abstract

An elegant reagent-controlled strategy has been developed for the generation of a diverse range of biologically active scaffolds from a chiral bicyclic lactam. Reduction of the chiral lactam with LAH or alkylation with LHMDS to trigger different cyclization reactions have been shown to generate privileged scaffolds, such as pyrrolidines, indolines, and cyclotryptamines. Their amenability to substitution allows us to create various compound libraries by using these scaffolds. In silico studies were used to estimate the drug-like properties of these compounds. Selected compounds were subjected to anticancer screening by using three different cell lines. In addition, all these compounds were subjected to antibacterial screening to gauge the spectrum of biological activity that was conferred by our DOS methodology. Gratifyingly, with no additional iterative cycles, our method directly generated anticancer compounds with potency at low nanomolar concentrations, as represented by spiroindoline 14.

Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification

“…3)22. Preliminary structure activity relationship (SAR) studies indicated that the aromatic or heteroaromatic functionality on the pyrrole moiety played a crucial role in imparting the inhibitory activity.…”

Diversity-Oriented Asymmetric Synthesis

“…They described a reagent-based DOS to afford spirocyclic and fused heterocyclic ring systems. 10,28,29 This strategy afforded biologically relevant molecular scaffolds such as cyclotryptamines, spirooxoindolones, tetrahydroquinolines, spiroindolanes and fused N-heterocycles. 30 The two-step sequence starts with bicy-…”

“…34 Among the various classes of compounds assayed, particularly interesting were the spiroindolanes, which inhibited cell proliferation of U-937, MCF-7 and HL-60 cell lines at 11-540 nM (with etoposide as control). 10,28 When screened against healthy BHK-1 (baby hamster kidney) cell line, these spiroindolanes required 100 times the concentration of their IC 50 to exhibit any cytotoxicity. The popularity of chiral auxiliaries as templates for DOAS was further exemplified by Sen and co-workers in 2012, via an Evans' chiral oxazolidinone based strategy for the asymmetric synthesis of quinolizidinones, piperizidinones and pyrrolidinones.…”

“…Diversity-oriented synthesis (DOS) is an efficient tool which has been utilized for quite some time to generate such structurally diverse libraries with exciting biological properties. [8][9][10] Its ulterior motive is to infiltrate an area of chemical space, which would enhance the biological diversity of the library, thereby augmenting the chances of discovering a compound with the desired bioactivity. 11 Focused libraries (based on molecular modeling) have proven to be very successful towards known biological targets; 12 however, they are unsuccessful for diseases related to protein-protein interactions and transcription factors, among others.…”

Network Measures for Chemical Library Design

“…The compounds thus obtained from the coupling step are again paired with another set of diverse reagents to end up with skeletal, stereochemical, and biologically diverse compounds. This approach has recently been applied to the synthesis of natural product‐inspired compounds [Galloway et al., ] and privileged scaffolds [Evans et al., ; Welsch et al., ; Surakanti et al., ].…”