Polymorph prediction through observed structural isomorphism leading to a new crystalline form of cannabidiol

Straker, Hannah E; McMillan, Lynn; Mardiana, Lina; Hebberd, Glen Richard; Watson, Elle; Waddell, Paul G.; Probert, Michael R.; Hall, Michael J.

doi:10.1039/d3ce00041a

Cited by 4 publications

(1 citation statement)

References 23 publications

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“…Using liquid handling robotics, large numbers of ENaCt experiments can be set-up in parallel, using multiwell plate formats, allowing rapid screening of large volumes of the multi-dimensional experimental space. Successful ENaCt experiments provide single crystals suitable for SCXRD, with ENaCt being previously applied to the crystallization of Nheterocyclic carbenes, aromatic polyketides, a SARS-CoV-2 protease inhibitor and cannabidiol (Zhu et al, 2022;Al Subeh et al, 2022;Cooper et al, 2022;Straker et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

High-throughput nanoscale crystallization of dihydropyridine active pharmaceutical ingredients

Metherall,

Corner,

McCabe

et al. 2023

Acta Crystallogr Sect B

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Single-crystal X-ray diffraction analysis of small molecule active pharmaceutical ingredients is a key technique in the confirmation of molecular connectivity, including absolute stereochemistry, as well as the solid-state form. However, accessing single crystals suitable for X-ray diffraction analysis of an active pharmaceutical ingredient can be experimentally laborious, especially considering the potential for multiple solid-state forms (solvates, hydrates and polymorphs). In recent years, methods for the exploration of experimental crystallization space of small molecules have undergone a `step-change', resulting in new high-throughput techniques becoming available. Here, the application of high-throughput encapsulated nanodroplet crystallization to a series of six dihydropyridines, calcium channel blockers used in the treatment of hypertension related diseases, is described. This approach allowed 288 individual crystallization experiments to be performed in parallel on each molecule, resulting in rapid access to crystals and subsequent crystal structures for all six dihydropyridines, as well as revealing a new solvate polymorph of nifedipine (1,4-dioxane solvate) and the first known solvate of nimodipine (DMSO solvate). This work further demonstrates the power of modern high-throughput crystallization methods in the exploration of the solid-state landscape of active pharmaceutical ingredients to facilitate crystal form discovery and structural analysis by single-crystal X-ray diffraction.

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Section: Introductionmentioning

confidence: 99%

High-throughput nanoscale crystallization of dihydropyridine active pharmaceutical ingredients

Metherall,

Corner,

McCabe

et al. 2023

Acta Crystallogr Sect B

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Bioactivity-driven fungal metabologenomics identifies antiproliferative stemphone analogs and their biosynthetic gene cluster

Ayon,

Earp,

Gupta

et al. 2024

Metabolomics

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Introduction Fungi biosynthesize chemically diverse secondary metabolites with a wide range of biological activities. Natural product scientists have increasingly turned towards bioinformatics approaches, combining metabolomics and genomics to target secondary metabolites and their biosynthetic machinery. We recently applied an integrated metabologenomics workflow to 110 fungi and identified more than 230 high-confidence linkages between metabolites and their biosynthetic pathways. Objectives To prioritize the discovery of bioactive natural products and their biosynthetic pathways from these hundreds of high-confidence linkages, we developed a bioactivity-driven metabologenomics workflow combining quantitative chemical information, antiproliferative bioactivity data, and genome sequences. Methods The 110 fungi from our metabologenomics study were tested against multiple cancer cell lines to identify which strains produced antiproliferative natural products. Three strains were selected for further study, fractionated using flash chromatography, and subjected to an additional round of bioactivity testing and mass spectral analysis. Data were overlaid using biochemometrics analysis to predict active constituents early in the fractionation process following which their biosynthetic pathways were identified using metabologenomics. Results We isolated three new-to-nature stemphone analogs, 19-acetylstemphones G (1), B (2) and E (3), that demonstrated antiproliferative activity ranging from 3 to 5 µM against human melanoma (MDA-MB-435) and ovarian cancer (OVACR3) cells. We proposed a rational biosynthetic pathway for these compounds, highlighting the potential of using bioactivity as a filter for the analysis of integrated—Omics datasets. Conclusions This work demonstrates how the incorporation of biochemometrics as a third dimension into the metabologenomics workflow can identify bioactive metabolites and link them to their biosynthetic machinery.

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Oral delivery of cannabidiol: Revealing the formulation and absorption challenges

Sitovs,

Logviss,

Lauberte

et al. 2024

Journal of Drug Delivery Science and Technology

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Polymorph prediction through observed structural isomorphism leading to a new crystalline form of cannabidiol

Abstract: Cannabidiol (CBD) is a naturally occurring phytocannabinoid, approved for use in the US and other countries for the treatment of seizures associated with Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis...

Cited by 4 publications

References 23 publications

High-throughput nanoscale crystallization of dihydropyridine active pharmaceutical ingredients

High-throughput nanoscale crystallization of dihydropyridine active pharmaceutical ingredients

Bioactivity-driven fungal metabologenomics identifies antiproliferative stemphone analogs and their biosynthetic gene cluster

Oral delivery of cannabidiol: Revealing the formulation and absorption challenges

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