Automated and Accelerated Synthesis of Indole Derivatives on a Nano-Scale

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  • TitleAutomated and Accelerated Synthesis of Indole Derivatives on a Nano-Scale
    Degree of recognitionInternational
    Media name/outletFaculty Opinions (formerly known as F1000Prime)
    Media typeWeb
    Duration/Length/Size1 page
    DescriptionDömling, Shaabani and coworkers use for the first time acoustic dispensing ejection (ADE) technology for the miniaturized, accelerated and automated synthesis of libraries of small molecules. They published an exciting trilogy of papers describing the synthesis of different scaffolds of small molecular weight on a nano scale.

    Providing small molecule libraries for high throughput screening in drug discovery is expensive and often a bottleneck. In pharma companies, libraries of hundreds of thousand up to several million compounds are stored and screened for biological activities. In academia most commercially available compound libraries are screened for biological activities. Often the libraries of pharma companies are based on historical collections of previously synthesized and purchased compounds. These libraries can be biased for certain target classes (e.g. GPCRs, kinases) and might not be suitable for new biological targets. Often such libraries are enriched with flat heterocyclic compound classes and do not take into account novel molecular architectures escaping flatland. Other chemotypes such as macrocycles (which might be suitable for protein-protein interactions) or covalent inhibitors are underrepresented or completely absent. Commercial libraries used in academia for screening are rather small in size and biased to certain chemotypes and limited diversity is available. Therefore, access to ‘on-the-fly’ (de novo) libraries based on fresh chemotype ideas for each biological screening project would be ideal. However, this is hampered by the complexity of organic synthesis and by the currently used large scale of synthesis in the milli mole range. Scale makes the synthesis of novel compounds very expensive due to the high price of building blocks and rather large numbers of building blocks required and generally very time-consuming synthesis. Even for large pharma companies the renewal of a million sized screening library is a very big and expensive undertaking.

    The approach by Dömling, Shaabani and coworkers can overcome the on-the-fly-synthesis obstacle by miniaturization, automation and acceleration of synthetic organic chemistry. They use touchless ADE technology to transport 2.5nL droplets from a 384-well source plate of building blocks to a destination plate of 384- or 1536-well format. In ADE, directed sound pulses are applied to a liquid and very small droplets of highly reproducible volume are formed. The speed of droplet ejection exceeds 200Hertz. Thus, library synthesis can be performed at very small volumes at unprecedented speed. The total material consumption for the synthesis of 384 novel small molecular weight compounds on a 500nmol scale including solvent is not more the 5mg. Are these amounts sufficient for early activity and screening and profiling? For reference: 2.5mmol of a compound (MW 400) gives 260mL of a 10mM solution and is the amount sufficient for ca. 1500 HTS and early compound profiling.

    In the first publication the team reported on the synthesis of several libraries of indole-based compounds. The interrupted Fischer indole synthesis combined with Ugi-type reactions yielded several attractive drug-like scaffolds. An unprecedented large number of building blocks was used for fast scope and limitation studies (68 isocyanides, 72 carboxylic acids). Multiple reactions were successfully repeated on a preparative mmol scale, showing scalability from nmol to mmol and thus synthetic utility. Miniaturization and analysis of the generated big synthesis data enabled deeper exploration of the chemical space and permitted the gain of knowledge that was previously impractical or impossible, such as the rapid survey of reactions, and building block and functional group compatibility.

    In two related publications, the Dömling group showed further interesting applications of ADE in the synthesis of large unbiased small molecular weight libraries in dense 384 or 1536 well format. In {1}, they describe the high-throughput automated nmol synthesis of novel isoquinolines via ADE technology leading to unprecedented fast exhaustive reaction evaluation and rapid scope and limitation. In {2}, the same technology was used to synthesize several thousand free boronic acids attached to multiple different scaffolds on a nano scale. Also, a screening application was shown and a covalent inhibitor of a Mycobacterium tuberculosis phosphatase was described.

    The work of Dömling, Shaabani and coworkers could lead a new way of future generation of chemical diversity on-the-fly, fresh compounds as opposed to screening the same historical library for each project. The automated and miniaturized synthesis technology platform when successfully combined with HTS could have a considerable impact on early drug discovery. It can be foreseen that the cycle time for the important hit-to-lead optimization through the design-make-test-analyze (DMTA) cycle can be shortened. For further reading, please see {1,2}.

    Acoustic droplet ejection enabled automated reaction scouting.

    Wang Y, Shaabani S, Ahmadianmoghaddam M, Gao L, Xu R, Kurpiewska K, Kalinowska-Tluscik J, Olechno J, Ellson R, Kossenjans M, Helan V, Groves M, Dömling A.

    ACS Cent Sci. 2019 Mar 27; 5(3):451-457

    PMID: 30937372
    Rapid approach to complex boronic acids.

    Neochoritis CG, Shaabani S, Ahmadianmoghaddam M, Zarganes-Tzitzikas T, Gao L, Novotná M, Mitríková T, Romero AR, Irianti MI, Xu R, Olechno J, Ellson R, Helan V, Kossenjans M, Groves MR, Dömling A.

    Sci Adv. 2019 Jul; 5(7):eaaw4607

    PMID: 31281893


    I have been collaborating for several years with the PI of this work, Dömling, on unrelated research.
    Cite this Recommendation:

    Holak T: Faculty Opinions Recommendation of [Shaabani S et al., Green Chem 2019 21(2):225-232]. In Faculty Opinions, 29 Aug 2019; 10.3410/f.736292016.793564196
    Producer/AuthorTadeusz Holak
    PersonsAlex Dömling