Biotransformation of Chrysin to Baicalein: Selective C6-Hydroxylation of 5,7-Dihydroxyflavone Using Whole Yeast Cells Stably Expressing Human CYP1A1 Enzyme

© 2017 American Chemical Society. Naturally occurring polyphenolic compounds are of medicinal importance because of their unique antioxidant, anticancer, and chemopreventive properties. Baicalein, a naturally occurring polyhydroxy flavonoid possessing a diverse range of pharmacological activities, has been used in traditional medicines for treatment of various ailments. Apart from its isolation from natural sources, its synthesis has been reported via multistep chemical approaches. Here, we report a preparative-scale biotransformation, using whole yeast cells stably expressing human cytochrome P450 1A1 (CYP1A1) enzyme that allows regioselective C6-hydroxylation of 5,7-dihydroxyflavone (chrysin) to form 5,6,7-trihydroxyflavone (baicalein). Molecular modeling reveals why chrysin undergoes such specific hydroxylation mediated by CYP1A1. More than 92% reaction completion was obtained using a shake-flask based process that mimics fed-batch fermentation. Such highly efficient selective hydroxylation, using recombinant yeast cells, has not been reported earlier. Similar CYP-expressing yeast cell based systems are likely to have wider applications in the syntheses of medicinally important polyphenolic compounds

Surfactant-free emulsion electrosynthesis via power ultrasound: electrocatalytic formation of carbon-carbon bonds

Proof-of-concept of the mediated electrosynthesis of carbon-carbon bonds in totally 'green' surfactant-free emulsion media generated by application of power ultrasound to a biphasic water-organic mixture is illustrated by reference to three systems, some requiring further activation by light, and each catalysed by vitamin B12. The voltammetry of aqueous vitamin B12 solutions at an electrode modified with microdroplets of the organic reactant is employed to gain an insight into the electrocatalytic pathway and readily permits the identification of optimum reaction parameters, such as starting material ratios and wavelength of light. The latter are employed in proof-of-concept emulsion electrosynthesis under conditions of triple activation (electron transfer, ultrasound and light)

Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor

Rohitukine (<b>1</b>), a chromone alkaloid isolated from Indian medicinal plant <i>Dysoxylum binectariferum</i>, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (<b>11d</b>) showed strong inhibition of Cdk-9/T1 (IC₅₀ 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI₅₀ < 1.0 μM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of <b>11d</b> for advancement in clinical studies

Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor

Rohitukine (<b>1</b>), a chromone alkaloid isolated from Indian medicinal plant <i>Dysoxylum binectariferum</i>, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (<b>11d</b>) showed strong inhibition of Cdk-9/T1 (IC₅₀ 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI₅₀ < 1.0 μM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of <b>11d</b> for advancement in clinical studies