Natural product–inspired cascade synthesis yields modulators of centrosome integrity

Abstract

In biology-oriented synthesis, the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is, in particular, met by the scaffolds of natural products selected in evolution. The synthesis of natural product-inspired compound collections calls for efficient reaction sequences that preferably combine multiple individual transformations in one operation. Here we report the development of a one-pot, twelve-step cascade reaction sequence that includes nine different reactions and two opposing kinds of organocatalysis. The cascade sequence proceeds within 10-30 min and transforms readily available substrates into complex indoloquinolizines that resemble the core tetracyclic scaffold of numerous polycyclic indole alkaloids. Biological investigation of a corresponding focused compound collection revealed modulators of centrosome integrity, termed centrocountins, which caused fragmented and supernumerary centrosomes, chromosome congression defects, multipolar mitotic spindles, acentrosomal spindle poles and multipolar cell division by targeting the centrosome-associated proteins nucleophosmin and Crm1.

Multi-Bond Forming Processes in Efficient Synthesis

“…[128,129] In the search for a library of potentially bioactive compounds, Waldmann and coworkers recently developed a three-component, one pot sequence that proceeds by a striking 12-step mechanism (Scheme 21). [130] The sequence involves two intermolecular Michael additions and various ring-closing and ring-opening steps. Overall yields of up to 80 % show control over the selectivity of this process, which involves three separate additions of reagents.…”

“…One-pot twelve-step cascade by Waldmann and coworkers. [130] Feldman utilised a double metathesis on a symmetrical substrate to obtain the linked bicyclic core of ent-lomaiviticin. [156] Twodirectional RCM reactions can also be performed as part of a domino sequence, for instance in the ring-opening metathesis/ double-RCM sequence employed in Phillips and Pfeiffer's elegant synthesis of (þ)-cyanthiwigin U (Scheme 25), [157] and the metathesis sequence employed in Nelson and coworkers' recent synthesis of molecular 'libraries'.…”

Scaffold Diversity Synthesis with Branching Cascades Strategy

“…Reactions with high conversions (consumption of 27) and relatively cleaner product profiles were then separately optimized (when required) for better results. The reaction screening revealed that 27-ketoesters were better Reaction of tryptamine with 27-ketoesters in dichloromethane followed by treatment with 10% trifluoroacetic acid (TFA) led to clean synthesis of biologically active centrocountins -the tetrahydroindoloquinolizines (53, see Chapter 16 for chemical biology of centrocountins) [56,57]. …”

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

“…To investigate this possibility, the compound collection was screened in two cell-based assays. In the first case, molecules were subjected to a high-content screen that monitors changes in cytoskeleton and DNA in the human cervical carcinoma HeLa cell line 51 . Treatment of cells with compounds at a concentration of 30 mM for 24 h and subsequent staining of DNA, actin filaments and microtubules revealed structurally similar molecules 17 and 45 causing the cells to round up as if they were entering mitosis ( Supplementary Figs 11 and 12).…”