Combining semi-synthesis with plant and microbial biocatalysis: new frontiers in producing a chemical arsenal against cancer

Abstract

Natural products (NPs) that exhibit anticancer activities are frequently not potent enough to be used clinically as therapeutics. Semi-synthesis and metabolic engineering are promising approaches for producing more efficacious derivatives of anticancer NPs (ACNPs), but each technique alone can be inefficient at obtaining specific ACNP derivatives that may be suspected to have enhanced anticancer activity. Here, we demonstrate that the methods of semi-synthesis and biocatalysis can be used as modules in succession and in different combinations to produce 6,8-dibromogenkwanin, a derivative of the ACNP apigenin. Further, we demonstrated that soybean seed coats can be used as a biocatalyst to convert brominated flavonoids into multiple derivatives. A strength of the combinatorial (bio)synthesis approach was that the order of the modules could be rearranged to increase the yield of the desired product. At lower treatment concentration (5 mM), 6,8-dibromogenkwanin exhibited enhanced antiproliferative activities against HT-29 colorectal adenocarcinoma cancer cells under normoxic and hypoxic conditions compared to its ACNP precursors, but not at higher concentrations. Dose-response analyses suggested that dibromogenkwanin had a distinct mode-of-action compared to apigenin. Thus, this proof-of-concept paper demonstrates combinatorial (bio)synthesis as an approach that can be used to produce novel chemistries for anticancer research.

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“…We recently demonstrated that an OMT from rice, namely OsNOMT, can methylate the 7-O-position of a semi-synthetic dibrominated derivative of the NP apigenin, despite that its natural substrate is naringenin [4]. We further demonstrated that the efficiency to produce our target molecule 6,8-dibromogenkwanin could be changed depending on the order in which semi-synthesis and biocatalysis 'modules' were employed [4].…”

Combining Biocatalysts and Semi-Synthesis to (Bio) Synthesize Recalcitrant Pharmaceuticals

“…We recently demonstrated that an OMT from rice, namely OsNOMT, can methylate the 7-O-position of a semi-synthetic dibrominated derivative of the NP apigenin, despite that its natural substrate is naringenin [4]. We further demonstrated that the efficiency to produce our target molecule 6,8-dibromogenkwanin could be changed depending on the order in which semi-synthesis and biocatalysis 'modules' were employed [4]. Based on this proof-of-concept, we propose that repositories of gene constructs that encode biocatalysts along with a database of their substrate specificities and semi-synthesis protocols could be assembled by the scientific community to facilitate the (bio)synthesis of 'recalcitrant' small molecules for bioactivity testing.…”