Strategies for the discovery of potential anticancer agents from plants collected from Southeast Asian tropical rainforests as a case study.

Covering up to early 2023The present review summarizes recent accomplishments made as part of a multidisciplinary, multi-institutional anticancer drug discovery project, wherein samples comprising higher plants were collected primarily from Southeast Asia, and also from Central America, and the West Indies. In the introductory paragraphs, a short perspective is provided on the current importance of plants in the discovery of cancer therapeutic agents, and the contributions of other groups working towards this objective are mentioned. For our own investigations, following their collection, tropical plants have been subjected to solvent extraction and biological evaluation for their antitumor potential. Several examples of purified plant lead bioactive compounds were obtained and characterized, and found to exhibit diverse structures, including those of the alkaloid, cardiac glycoside, coumarin, cucurbitacin, cyclobenzofuran (rocaglate), flavonoid, lignan, and terpenoid types. In order to maximize the efficiency of work on drug discovery from tropical plant species, strategies to optimize various research components have been developed, including those for the plant collections and taxonomic identification, in accordance with the requirements of contemporary international treaties and with a focus on species conservation. A major component of this aspect of the work is the development of collaborative research agreements with representatives of the source countries of tropical rainforest plants. The phytochemical aspects have included the preparation of plant extracts for initial screening and the selection of promising extracts for activity-guided fractionation. In an attempt to facilitate this process, a TOCSY-based NMR procedure has been applied for the determination of bioactive rocaglate derivatives in samples of Aglaia species (Meliaceae) collected for the project. Preliminary in vitro and in vivo mechanistic studies carried out by the authors are described for two tropical plant-derived bioactive lead compounds, corchorusoside C and (+)-betulin, including work conducted with a zebrafish (Danio rerio) model. In the concluding remarks, a number of lessons are summarized that our group has learned as a result of working on anticancer drug discovery using tropical plants, which we hope will be of interest to future workers.

Effects of Corchorusoside C on NF-κB and PARP-1 Molecular Targets and Toxicity Profile in Zebrafish.

The present study aims to continue the study of corchorusoside C (1), a cardenolide isolated from Streptocaulon juventas, as a potential anticancer agent. A mechanistic study was pursued in a zebrafish model and in DU-145 prostate cancer cells to investigate the selectivity of 1 towards NF-κB and PARP-1 pathway elements. Compound 1 was found to inhibit the expression of IKKα and NF-κB p65 in TNF-α induced zebrafish and inhibit the expression of NIK in vitro. The protein expression levels of XRCC-1 were increased and p53 decreased in DU-145 cells. XIAP protein expression was initially decreased after treatment with 1, followed by an increase in expression at doses higher than the IC50 value. The activity of caspase-1 and the protein expression levels of IL-18 were both decreased following treatment of 1. The binding interactions for 1 to NIK, XRCC-1, p53, XIAP, and caspase-1 proteins were explored in molecular docking studies. Additionally, the toxicity profile of 1 in zebrafish was favorable in comparison to its analog digoxin and other anticancer drugs at the same MTD in zebrafish. Overall, 1 targets the noncanconical NF-κB pathway in vivo and in vitro, and is well tolerated in zebrafish supporting its potential in the treatment of prostate cancer.

Spermidine alkaloid and glycosidic constituents of Vietnamese Homalium cochinchinensis.

Phytochemical investigation of the aerial parts of Homalium cochinchinensis led to the isolation of secondary metabolites belonging to the spermidine alkaloid, glycoside, depsidone and phenol classes. Of the eleven secondary metabolites isolated in this study, two spermidine alkaloids, dovyalicins H (1) and I (2), which belong to a rare group among this class, and six glycosides (3-8) are previously undescribed. The structures of all new isolates were determined by interpretation of spectroscopic and spectrometric data. In this report, the structural elucidation of these unprecedented secondary metabolites (1-8) is described.

Current status and contemporary approaches to the discovery of antitumor agents from higher plants.

Higher plant constituents have afforded clinically available anticancer drugs. These include both chemically unmodified small molecules and their synthetic derivatives currently used or those in clinical trials as antineoplastic agents, and an updated summary is provided. In addition, botanical dietary supplements, exemplified by mangosteen and noni constituents, are also covered as potential cancer chemotherapeutic agents. Approaches to metabolite purification, rapid dereplication, and biological evaluation including analytical hyphenated techniques, molecular networking, and advanced cellular and animal models are discussed. Further, enhanced and targeted drug delivery systems for phytochemicals, including micelles, nanoparticles and antibody drug conjugates (ADCs) are described herein.

Highly sweet compounds of plant origin: From ethnobotanical observations to wide utilization.

ETHNOPHARMACOLOGICAL RELEVANCE: Ethnobotanical studies have been of very great importance in recognizing plants that contain substances that modulate the heterodimer T1R2-T1R3 sweet taste receptor, inclusive of Stevia rebaudiana (Asteraceae) and Siraitia grosvenorii (Cucurbitaceae). AIM OF THE REVIEW: In addition to reviewing relevant ethnobotanical literature, inclusive of original field work conducted, the authors have provided a progress report on the ultimate regulatory acceptance of highly sweet ent-kaurane (steviol) diterpene glycosides from S. rebaudiana leaves ("stevia") and cucurbitane triterpene glycosides (mogrosides) from the fruits of S. grosvenorii (popularly known as "monk fruit"). Despite their relatively high prices relative to that of sucrose, the steviol glycosides and mogrosides are of current great interest for further more extensive utilization on the market as sweet-tasting non-caloric food additives, due to increases in the rates of obesity and diabetes all over the world. Recent phytochemical work on the sweet principles of these two species is highlighted, including the important "next-generation" sweetener, rebaudioside M, from S. rebaudiana. RESULTS: Initial observations on the ethnobotany of both S. rebaudiana and S. grosvenorii have proved crucial to indicating the presence of their sweet-tasting principles to the wider scientific community. CONCLUSIONS: Ethnobotanical observations have been pivotal in enabling the discovery of many sweet-tasting plant constituents, with those of S. rebaudiana and S. grosvenorii both being examples. Extractives prepared from these species are now commercially used widely in the U.S. as additives for the sweetening of foods and beverages.

Caspase-Dependent Apoptosis in Prostate Cancer Cells and Zebrafish by Corchorusoside C from Streptocaulon juventas.

Corchorusoside C (1), isolated from Streptocaulon juventas collected in Vietnam, was found to be nontoxic in a zebrafish ( Danio rerio) model and to induce cytotoxicity in several cancer cell lines with notable selective activity against prostate DU-145 cancer cells (IC50 0.08 µM). Moreover, corchorusoside C induced DU-145 cell shrinkage and cell detachment. In CCD-112CoN colon normal cells, 1 showed significantly reduced cytotoxic activity (IC50 2.3 µM). A preliminary mechanistic study indicated that 1 inhibits activity and protein expression of NF-κB (p50 and p65), IKK (α and ß), and ICAM-1 in DU-145 cells. ROS concentrations increased at 5 h post-treatment, and MTP decreased in a dose-dependent manner. Moreover, decreased protein expression of Bcl-2 and increased expression of PARP-1 was observed. Furthermore, corchorusoside C increased both the activity and protein levels of caspases 3 and 7. Additionally, 1 induced sub-G1 population increase of DU-145 cells and modulated caspases in zebrafish with nondifferential morphological effects. Therefore, corchorusoside C (1) induces apoptosis in DU-145 cells and targets the same pathways both in vitro and in vivo in zebrafish. Thus, the use of zebrafish assays seems worthy of wider application than is currently employed for the evaluation of potential anticancer agents of natural origin.

Antiproliferative Constituents of the Roots of Ethiopian Podocarpus falcatus and Structure Revision of 2α-Hydroxynagilactone F and Nagilactone I.

Bioassay-guided fractionation using the human colorectal adenocarcinoma (HT-29) cell line of the methanol extract of dried roots of Podocarpus falcatus led to the isolation of two new type C nagilactones, 16-hydroxynagilactone F (1) and 2ß,16-dihydroxynagilactone F (2), and the new totarane-type bisditerpenoid 7ß-hydroxymacrophyllic acid (4), along with the seven known compounds 2ß-hydroxynagilactone F (3), macrophyllic acid (5), nagilactone D (6), 15-hydroxynagilactone D (7), nagilactone I (8), inumakiol D (9), and ponasterone A (10). The structures of the new compounds were determined by 1D and 2D NMR, HRESIMS, UV, and IR and by comparison with the reported spectroscopic data of their congeners. The orientation of the C-2 hydroxy group of 3 and 8 was revised to be ß based on evidence from detailed analysis of 1D and 2D NMR data and single-crystal X-ray diffraction studies. Among the isolated compounds, the nagilactones, including the new dilactones 16-hydroxynagilactone F (1) and 2ß,16-dihydroxynagilactone F (2), were the most active (IC50 0.3-5.1 µM range) against the HT-29 cell line, whereas the bisditerpenoids (4 and 5) and the other known compounds 9 and 10 were inactive. The presence of the bioactive nagilactones in P. falcatus supports its traditional use.