Chemical derivatization of natural products: Semisynthesis and pharmacological aspects- A decade update

Natural withanolides, an update.

Plant steroids constitute a diverse group of natural products. Biosynthetically, they are derived from S-squalene-2,3-epoxide via acetate-mevalonate pathway. Among the plant steroids, phytosterols are ubiquitous in the plant kingdom. It is significant that some phytosterols have been reported to possess hypocholesterolemic activity. Withanolides are a large group of steroidal lactones with various biological activities. Brassinosteroids are a small group of plant steroids exhibiting plant growth hormonal activity. Phytoecdysteroids are polyhydroxylated plant steroids, many of which are known to exhibit anabolic effects with no undesirable side effects. Steroidal alkaloids are nitrogen-containing plant steroids with an array of biological activities. It is noteworthy that trace amounts of cholesterol and mammalian steroidal hormones including progesterone have been detected in some plants. Analyses of plant steroids mainly utilize chromatographic methods such as thin-layer chromatography (TLC), high performance liquid chromatography (HPLC), ultra high performance liquid chromatography (UHPLC), and gas liquid chromatography (GLC), while photodiode array (PDA), evaporative light scattering (ELS), and fluorescence (FL) detectors and mass spectrometry (MS) are commonly used for their detection, quantification, and identification. Some less common techniques employed for the analyses of plant steroids are immunoassays and biological assays.


Keywords:

plant steroids;
occurrence;
biological activity;
analysis;
thin-layer chromatography;
high performance liquid chromatography;
gas liquid chromatography;
mass spectroscopy;
biological assay;
immunoassay

Plant Steroids: Occurrence, Biological Significance and their Analysis

Along with surgery and chemotherapy, radiation therapy (RT) is an important modality in cancer treatment, and the development of radiosensitizers is a current key challenge in radiobiology to maximize RT efficiency. In this study, the radiosensitizing effect of a natural compound from the withanolide family, withanolide D (WD), was assessed. Clonogenic assays showed that a 1 h WD pretreatment (0.7 μM) before irradiation decreased the surviving fraction of several cancer cell lines. To determine the mechanisms by which WD achieved its radiosensitizing effect, we then assessed whether WD could promote radiation-induced DNA damages and inhibit double-strand breaks (DSBs) repair in SKOV3 cells. Comet and γH2AX/53BP1 foci formation assays confirmed that DSBs were higher between 1 and 24 h after 2 Gy-irradiation in WD-treated cells compared to vehicle-treated cells, suggesting that WD induced the persistence of radiation-induced DNA damages. Immunoblotting was then performed to investigate protein expression involved in DNA repair pathways. Interestingly, DNA-PKc, ATM, and their phosphorylated forms appeared to be inhibited 24 h post-irradiation in WD-treated samples. XRCC4 expression was also down-regulated while RAD51 expression did not change compared to vehicle-treated cells suggesting that only non-homologous end joining (NHEJ) pathways was inhibited by WD. Mitotic catastrophe (MC) was then investigated in SKOV3, a p53-deficient cell line, to assess the consequence of such inhibition. MC was induced after irradiation and was predominant in WD-treated samples as shown by the few numbers of cells pursuing into anaphase and the increased amount of bipolar metaphasic cells. Together, these data demonstrated that WD could be a promising radiosensitizer candidate for RT by inhibiting NHEJ pathway and promoting MC. Additional studies are required to better understand its efficiency and mechanism of action in more relevant clinical models.

/pdf/withanolide-d-enhances-radiosensitivity-of-human-cancer-cfdg56u5gi.pdf

Withanolide D Enhances Radiosensitivity of Human Cancer Cells by Inhibiting DNA Damage Non-homologous End Joining Repair Pathway.

Withanolides constitute a valuable class of bioactive natural products because some members of the class are known to exhibit cytotoxic activity and also induce a cytoprotective heat-shock response. In order to understand the relationship between their structures and these dual bioactivities of the withanolide scaffold, we obtained 25 analogues of withaferin A (WA) and withanolide D (WD) including 17 new compounds by semisynthesis involving chemical and microbial transformations. Hitherto unknown 16β-hydroxy analogues of WA and WD were prepared by their reaction with triphenylphosphine/iodine, providing unexpected 5β-hydroxy-6α-iodo analogues (iodohydrins) followed by microbial biotransformation with Cunninghamella echinulata and base-catalyzed cyclization of the resulting 16β-hydroxy iodohydrins. Evaluation of these 25 withanolide analogues for their cytotoxicity and heat-shock-inducing activity (HSA) confirmed the known structure–activity relationships for WA-type withanolides and revealed that WD analo...

Withaferin A and Withanolide D Analogues with Dual Heat-Shock-Inducing and Cytotoxic Activities: Semisynthesis and Biological Evaluation

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Withaferin A and Withanolide D Analogues with Dual Heat-Shock-Inducing and Cytotoxic Activities: Semisynthesis and Biological Evaluation