Bridging the gap between natural product synthesis and drug discovery

Abstract

Covering: 1986 to 2020Natural products are an enduring source of chemical information useful for probing biologically relevant chemical space. Toward gathering further structure-activity relationship (SAR) information for a particular natural product, synthetic chemists traditionally proceeded first by a total synthesis effort followed by the synthesis of simplified derivatives. While this approach has proven fruitful, it often does not incorporate hypotheses regarding structural features necessary for bioactivity at the synthetic planning stage, but rather focuses on the rapid assembly of the targeted natural product; a goal that often supersedes the opportunity to gather SAR information en route to the natural product. Furthermore, access to simplified variants of a natural product possessing only the proposed essential structural features necessary for bioactivity, typically at lower oxidation states overall, is sometimes non-trivial from the original established synthetic route. In recent years, several synthetic design strategies were described to streamline the process of finding bioactive molecules in concert with fathering further SAR studies for targeted natural products. This review article will briefly discuss traditional retrosynthetic strategies and contrast them to selected examples of recent synthetic strategies for the investigation of biologically relevant chemical space revealed by natural products. These strategies include: diversity-oriented synthesis (DOS), biology-oriented synthesis (BIOS), diverted-total synthesis (DTS), analogue-oriented synthesis (AOS), two-phase synthesis, function-oriented synthesis (FOS), and computed affinity/dynamically ordered retrosynthesis (CANDOR). Finally, a description of pharmacophore-directed retrosynthesis (PDR) developed in our laboratory and initial applications will be presented that was initially inspired by a retrospective analysis of our synthetic route to pateamine A completed in 1998.

Figure 1.

Approximate timeline for the evolution of various synthetic strategies marrying natural product total synthesis and biological studies, including the gathering of structure-activity relationship information.

Figure 2.

Current front-line treatment for Chagas disease and drug lead realized from DOS library noting the stark contrast in molecular complexity especially in number of stereocenters and sp³-carbons.

Figure 3.

Dynemicin (26) and a FOS designed dynemicin mimic 27 and the targeted reactive arene diyl species involved in DNA scission by these enediyne antitumor antibiotics.

Figure 4.

PatA served as inspiration for development of pharmacophore-directed retrosynthesis. (IC₅₀ values for the interleukin-2 reporter gene assay using the same population of Jurkat cells.)

Figure 5.

a. Members of the spongiane family of diterpene natural products including gracilin A (34). b. Macfarlandin E (39) and t-butyl derivative 40 bearing a related masked 1,4-ketoaldehyde and shown to undergo Paal-Knorr pyrrole synthesis with lysine in simulated physiological conditions.

Figure 6.

Selected bioactivity data resulting from PDR applied to the gracilins highlighting the importance of C₁₀ stereochemisty and the superfluous exocyclic alkene.

Figure 7.

Cembranoid and norcembranoid natural products related to rameswaralide.

Figure 8.

Biological data obtained from preliminary stage I & II analogues showing increased potency compared to rameswaralide and intriguing selectivity toward HCT116 cells. ^aRameswaralide was previously assayed only against the A549 cell line (IC50 of 67 ± 3.7 μM).

Figure 9.

Structure of ophiobolins A & B. showing proposed pharmacophore (red).

Scheme 1.

a) Schreiber’s diversity-oriented synthesis (DOS) providing complex functionally and skeletally diverse molecules. b) Waldmann’s biology-oriented synthesis (BIOS) providing access to libraries based on “privileged” natural product skeletons.

Scheme 2.

a) Example natural products which show interesting bioactivity and contain an oxepane core. b) Short synthesis of oxepane core to allow rapid synthesis of a library of privileged oxepane containing scaffolds. c) Selected compounds resulting from oxepane based library which show intriguing activation of Wnt signaling (values shown are ED₅₀ in the reporter gene assay).

Scheme 3.

A generic view of diverted total synthesis (DTS).

Scheme 4.

Vanderwal’s analogue-oriented synthesis applied to the lissoclimides.

Scheme 5.

(a) A generic look at Baran's two-phase synthesis involving initial construction of the carbon skeleton followed by site-selective oxidation and functionalization to access intermediates and natural products of various oxidation state. (b) Application of two-phase synthesis to Taxol® providing access to various members of the taxane family.

Scheme 6.

Salvinorin A as an example case for improvement on chemical properties aiding in synthesis of bioactive natural product analogues using CANDOR.

Scheme 7.

Overview of various synthetic strategies bring biological function to the forefront including those employed to utilize bioactive natural products as starting points for biological studies building on ideas of FOS with comparison to PDR. The latter enables gathering of SAR information en route to a given natural product via target-oriented synthesis.

Scheme 8.

Various stages of PDR applied to gracilin A.

Scheme 9.

An overview of route used to complete stage I and II of the gracilin PDR route, showing intermediates both used for testing and as starting points for stage IV DTS.

Scheme 10.

PDR applied to rameswaralide (56) guided by the proposed pharmacophore consisting of the common 5,5,7-fused ABC ring system to be accessed in Stages I and II of PDR via the 5,5,6-fused ring system common to other family members.

Scheme 11.

Optimized synthetic sequence toward a potential rameswaralide precursor 69 involving a key Diels-Alder lactonization to deliver tricycle 63. Unanticipated reactions leading to by-products in a PDR strategy coupled with minimizing protecting groups and redox manipulation can result in direct access to interesting derivatives for bioactivity testing e.g. truncated ABC tricyclic derivatives 61, 67, 68.

Scheme 12.

PDR approach to ophiobolin A (71) guided by the 1,4-ketoaldehyde embedded in the 5,8-bicyclic (AB) ring system as the proposed pharmacophore.

Scheme 13.

Optimized synthesis of Stage II bicyclic target 74 and related bicycle 85.

Scheme 14.

Biological activity resulting from Stage I and initial Stage II application of PDR to Ophiobolin A (71).