Combined Scaffold Evaluation and Systems‐Level Transcriptome‐Based Analysis for Accelerated Lead Optimization Reveals Ribosomal Targeting Spirooxindole Cyclopropanes

Abstract

With evolutionary drug resistance impacting efforts to treat disease, the need for small molecules that exhibit novel molecular mechanisms of action is paramount. In this study, we combined scaffold‐directed synthesis with a hybrid experimental and transcriptome analysis to identify bis‐spirooxindole cyclopropanes that inhibit cancer cell proliferation through disruption of ribosomal function. These findings demonstrate the value of an integrated, biologically inspired synthesis and assay strategy for the accelerated identification of first‐in‐class cancer therapeutic candidates.

Formal [4+1] Cyclization of ortho‐ or para‐Quinone Methides with 3‐Chlorooxindoles: Synthesis of 3,2′‐Tetrahydrofuryl Spirooxindoles

“…Aromatic ( 3 a – 3 g ), heteroaromatic ( 3 h ) and aliphatic ( 3 i‐3 k ) R 1 groups on 2‐sulfonylalkyl phenols proved to be suitable substituents. It should be noted that the spirooxindole 3 i has been reported by Ashfeld to have antitumor activity and to induce cell death [3a] . The method described here offers a straightforward and convenient way to synthesize this type of bioactive spirooxindole compounds.…”

Oxyphosphonium Enolate Equilibria in a (4+1)‐Cycloaddition Approach toward Quaternary C3‐Spirooxindole Assembly

“…The formation of 2 c proceeded in a 2 : 1 diastereomeric ratio, while 6 c was obtained in a 4 : 1 ratio of diastereoisomers. The formation of benzopyran was not altogether discouraging as bis‐spirooxindoles constitute an intriguing class of N ‐heterocyclic compounds known to exhibit promising biological activity as pharmaceutical agents [4e,13] . Attempts to generate exclusively dihydrobenzofuran 2 c through the slow addition of isatin 1 b via syringe pump (≥8 hours) at low concentrations failed to temper pyran formation.…”

“…Specifically, our efforts have focused on construction of the C3‐spirooxindole alkaloid scaffold, given its well‐established impact on drug discovery efforts in recent years [4] . Derivatives of this molecular core that contain a heterocyclic quaternary spirocenter at the 3‐position of the oxindole exhibit a variety of pharmacological effects, including analgesic, [5] anticancer, [4e] antituberculosis, [4c] and antimalarial properties (Figure 1). [4g] Additionally, the 2,3‐dihydrobenzofuran heterocyclic framework has generated substantial interest due to its functionality as a potential NaV1.7 blocker in the development of anti‐leukemia chemotherapeutics [6] …”

Hit Triage and Validation in Phenotypic Screening: Considerations and Strategies

“…While this co-clustering clearly suggested a specific MoA for those hits, it is worth noting that this suggested molecular MoA still needs to be validated as it could still be markedly differentiated from the known mechanisms (e.g., by modulating an upstream target on the same signaling pathway). This example highlights the utility of molecular profiling to filter hits to prioritize truly novel mechanisms (Drawnel et al, 2017;Rodriguez et al, 2019;Zoffmann et al, 2019).…”

“…2) Activity observed in primary cells from more than one human donor to avoid the trap of a narrowly relevant MoA. 3) Omics signature(s) supportive of differentiated MoA from both known, undesirable MoAs and the MoAs displayed by the other selected series to increase likelihood of success for the program (Tschapalda et al, 2016;Rodriguez et al, 2019). 4) Chemistry requirements are satisfied, including evidence of SAR, defined as >103 changes in activity based on chemical modifications, and no structural red flag (e.g., required reactive moieties likely incompatible with drug development).…”