Diversity-oriented synthesis as a tool for chemical genetics

Abstract

Chemical genetics is an approach for identifying small molecules with the ability to induce a biological phenotype or to interact with a particular gene product, and it is an emerging tool for lead generation in drug discovery. Accordingly, there is a need for efficient and versatile synthetic processes capable of generating complex and diverse molecular libraries, and Diversity-Oriented Synthesis (DOS) of small molecules is the concept of choice to give access to new chemotypes with high chemical diversity. In this review, the combination of chemical genetics and diversity-oriented synthesis to identify new chemotypes as hit compounds in chemical biology and drug discovery is reported, giving an overview of basic concepts and selected case studies.

Figure 1

(a) Forward chemical genetics approach; (b) Reverse chemical genetics approach.

Figure 2

Illustration of forward and chemical genetics approaches used by Guy and co-workers for malaria drug discovery [14].

Figure 3

(a) Robotnikinin, a low µM sonic hedgehog inhibitor discovered by Schreiber’s group [33]; (b) Emmacin, a potent antibacterial compound with MIC₅₀ on the low µg/mL range discovered by Spring’s group [34,35].

Scheme 1

Synthesis of the tetracyclic scaffold 2 with tandem acylation/1,3-dipolar cycloaddition [36].

Scheme 2

Potential sites of functionalization and representative examples of compounds derived from template 3 by (a) cross-coupling reactions, (b) aminolysis of lactone moiety, (c) epoxide ring opening and (d) alcohol esterification [36,37].

Scheme 3

Split-and-pool DOS synthesis of the library based on template 3 [37].

Scheme 4

(a) Stereoselective synthesis of the spirooxindole scaffold 8; (b) Scaffold decoration by cross-coupling reactions (1), amide formations (2), N-acylations (3); (c) From this library, a potent enhancer of latrunculin B was discovered [49].

Scheme 5

Scaffold generated from phenyldiazoester compounds 10 (a) and 11 (b) [53].

Scheme 6

Library synthesis from the key intermediate 16. The exploration of the chemical space around scaffold 16 was achieved using (a) epoxidation, (b) dihydroxylation, (c) ring opening metathesis, (d) dihydroxylation/oxidative cleavage + reductive amination with dimethylamine, (e) dihydroxylation/oxidative cleavage + double reductive amination with primary amines, (f) dihydroxylation/oxidative cleavage + esterification, (g) Suzuki reactions [53].

Figure 4

(a–c) Comparative PCA plots of DOS library compounds (red, circles) vs. top-selling brand-name drugs (purple, squares) and natural products (blue, triangles); (d) PMI plot illustrating the molecular shape diversity of the DOS library (red, circles) and lowest-energy conformation of three representative DOS library members (15, 19, 21). Adapted by permission from Macmillan Publishers Ltd: ref. 53, copyright (2014).

Figure 5

The antimitotic compound, (S)-Dosabulin, discovered with forward chemical genetics approach [53].

Figure 6

(a) Strategic approaches for the synthesis of peptidomimetic scaffolds starting from sugar and amino acids derivatives; (b) Representative examples of bicyclic rigid scaffolds obtained with this strategy; (c) 6,8-dioxa-3-azabicyclo[3.2.1]octane scaffold as a constrained dipeptide isostere [80,81,82,83].

Figure 7

From a library 140 bicyclic peptidomimetics, a forward chemical genetics study allowed for the identification of 25 as a hit antifungal compound [75].

Scheme 7

Selected building blocks for the coupling step and skeletal diversity resulting from the cyclization step [90].

Scheme 8

Representative examples of library members obtained (a) from scaffold 31 and (b) from scaffold 33 [76].

Figure 8

Bidimensional scatter plots showing effects of library members on cell growth of selected deletant strains and structures of compounds 36 and 37 [76]. Cell growth inhibition on (a) wild-type strain; (b) ∆snq2 deletant strain; (c) ∆erg6 deletant strain; (d) ∆pdr3 deletant strain.