A. Douglas Kinghorn’s research while affiliated with The Ohio State University and other places

The microbiota, comprising all the microorganisms within the body, plays a critical role in maintaining good health. Dysbiosis represents a condition resulting from an imbalance or alteration of the microbiota. This study comprehensively investigates the patent literature on dysbiosis over the past 20 years. image

Natural products have long been a cornerstone of drug discovery, providing diverse and biologically relevant chemical scaffolds. This work aims to guide newcomers to natural product research and, specifically, drug discovery by presenting a curated list of 30 key publications selected through an international survey of experts and critical evaluation by the authors. The selected works span textbooks, review articles, and original research papers, covering various aspects of natural product research, including chemistry, pharmacology, analytical sciences, emerging open science, and computational approaches. We discuss historical milestones in natural product drug discovery, highlighting the specific contributions of the U.S. National Cancer Institute in developing anticancer and anti-HIV agents. The present work also addresses current challenges and innovations in the field, emphasizing the importance of data quality, interdisciplinary collaboration, and the integration of artificial intelligence. By providing this carefully selected reading list and accompanying analysis, we aim to offer a comprehensive yet accessible entry point for researchers new to natural product-based drug discovery and highlight future directions and opportunities in this dynamic field.

Currently, clinically available cancer chemopreventive drug options are limited to mostly tamoxifen and its derivatives, such as raloxifene, and approved specifically for breast cancer. Thus, the availability of chemopreventive drug molecules for other types of malignant cancers would be desirable. In previous reports, the arils of Myristica fragrans (mace) have been found to exhibit cancer chemopreventive activity. Therefore, the purpose of the present study was to identify a natural product from this species with potential chemopreventive activity guided by chemoinformatic sample analysis via Global Natural Products Social (GNPS) molecular networking and molecular docking. The neolignan licarin A (1) was identified as a potential chemopreventive constituent, and subsequently submitted to several in vitro bioassays and a zebrafish toxicity evaluation. In this work, 1 afforded superior phosphoNF-κBp65 phosphorylation activity in DU-145 prostate cancer cells compared to isoliquiritigenin (2), which was used as a natural product chemopreventive control. Both 1 and 2 showed a longer-lasting reduction in cellular stress in a cell oxidative stress real-time dose–response assay than the positive control using Hepa1c1c7 mouse hepatoma cells. In addition, 1 displayed similar activities to 2, while also being less toxic to zebrafish (Danio rerio) than both this chalcone and the clinically used chemopreventive drug tamoxifen.

Cancer chemoprevention” is a term referring to the slowing or reversal of this disease, using nontoxic natural or synthetic compounds. For about 50 years, there has been a strong scientific interest in discovering plant-derived compounds to prevent cancer, and strategies for this purpose using a concerted series of in vitro , ex vivo , and in vivo laboratory bioassays have been developed. Five examples of the more thoroughly investigated agents of this type are described herein, which are each supported by detailed literature reports, inclusive of ellagic acid, isoliquiritigenin, lycopene, trans -resveratrol, and sulforaphane. In addition, extracts of the plants avocado ( Persea americana ), noni ( Morinda citrifolia ), açai ( Euterpe oleracea ), and mangosteen ( Garcinia mangostana ) have all shown inhibitory activity in an in vivo or ex vivo bioassay using a carcinogen and germane to cancer chemoprevention, and selected in vitro –active constituents are described for each of these 4 species.

Inhibition of translation initiation using eIF4A inhibitors like (−)-didesmethylrocaglamide [(−)-DDR] and (−)-rocaglamide [(−)-Roc] is a potential cancer treatment strategy as they simultaneously diminish multiple oncogenic drivers. We showed that human and dog osteosarcoma cells expressed higher levels of eIF4A1/2 compared with mesenchymal stem cells. Genetic depletion of eIF4A1 and/or 2 slowed osteosarcoma cell growth. To advance preclinical development of eIF4A inhibitors, we demonstrated the importance of (−)-chirality in DDR for growth-inhibitory activity. Bromination of DDR at carbon-5 abolished growth-inhibitory activity, while acetylating DDR at carbon-1 was tolerated. Like (−)-DDR, (±)-DDR, and (−)-Roc, (±)-DDR-acetate increased γH2A.X levels and induced G2/M arrest and apoptosis. Consistent with translation inhibition, these rocaglates decreased the levels of several mitogenic kinases, the STAT3 transcription factor, and the stress-activated protein kinase p38. However, phosphorylated p38 was greatly enhanced in treated cells, suggesting activation of stress response pathways. RNA sequencing identified RHOB as a top upregulated gene in both (−)-DDR- and (−)-Roc-treated osteosarcoma cells, but the Rho inhibitor Rhosin did not enhance the growth-inhibitory activity of (−)-DDR or (−)-Roc. Nonetheless, these rocaglates potently suppressed tumor growth in a canine osteosarcoma patient-derived xenograft model. These results suggest that these eIF4A inhibitors can be leveraged to treat both human and dog osteosarcomas.