Structural Modification of Sylibin to Derivatives of Sylibin/Hydnocarpin D/Silandrin, and Evaluation of their Cytotoxicity against Cancer Cells.

BACKGROUND: Flavonolignans like silybin, hydnocarpin, and siliandrin are a group of natural compounds combining the structural moieties of flavonoid and phenylpropanoid (lignan). Hydnocarpin and silandrin have been less explored because of their trace occurrence in nature. OBJECTIVE: The present study aimed at chemical conversion of silybin to hydnocarpin and siliandrin. Another objective was to synthesize a series of amide derivatives and biologically evaluate them with regard to their anti-cancer effects. METHODS: In order to selectively convert silybin to 23-iodo silybin, 23-iodo hydnocarpin D and 23- iodo isosilandrin, the ratio of Ph3P, imidazole and molecular iodine was meticulously adjusted. These three iodide compounds were converted into amide compounds by chemical transformation. MTT method was applied to evaluate their anti-cancer potency. The binding affinity to related proteins was calculated by molecular docking. RESULTS: A total of 45 new amido-derivatives were synthesized and structurally characterized by NMR and HRMS. Some of them showed moderate to good antiproliferative potency against cancer cells. The activity of compound 10j was further testified by colony formation assay and molecular docking. CONCLUSION: The synthesis of 23-iodo silybin, 23-iodo hydnocarpin D and 23-iodo isosilandrin from silybin was successfully accomplished by one simple iodination reaction. Some of the amide derivatives of sylibin/hydnocarpin D /silandrin exhibited a remarkable inhibitory effect of proliferation on cancer cells compared to silybin. These results would pave the way for further investigation on the derivatives of flavonolignans for the treatment of cancer.

Exploring Mitochondria-Mediated Intrinsic Apoptosis by New Phytochemical Entities: An Explicit Observation of Cytochrome c Dynamics on Lung and Melanoma Cancer Cells.

Hydnocarpin (Hy) is a flavonoid isolated and purified from the seeds of Hydnocarpus wightiana Blume. Herein, we have developed a built-in semi-synthetic modification on Hy by one-pot multi-component reaction and a [3 + 2] cycloaddition strategy to append five membered isoxazole and isoxazolone as new phytochemical entities (NPCEs). Two selected NPCEs viz Hy-ISO-VIII and Hy-ISO-G from the library of 20 newly synthesized derivatives after in vitro screening unveiled promising cytotoxicity and induced caspase-mediated apoptosis against the human lung and melanoma cancer cells which were well supported by virtual screening based on ligand binding affinity and molecular dynamic simulations. As a new insight, we introduced surface-enhanced Raman spectroscopy to identify the chemo-marker molecular fingerprint to confirm the cellular uptake, cytochrome c release, and DNA fragmentation in a label-free manner. The present findings throw up a surfeit of seminal reasons behind the semi-synthetic modification of Hy, stepping forward to cancer chemotherapy.

1,4-Benzodioxane Lignans: An Efficient, Asymmetric Synthesis of Flavonolignans and Study of Neolignan Cytotoxicity and Antiviral Profiles.

1,4-Benzodioxane lignans are a class of bioactive compounds that have received much attention through the years. Herein research pertaining to both 1,4-benzodioxane flavonolignans and 1,4-benzodioxane neolignans is presented. A novel synthesis of both traditional 1,4-benzodioxane flavonolignans and 3-deoxyflavonolignans is described. The antiviral and cytotoxic activities of 1,4-benzodioxane neolignans were then investigated; eusiderins A, B, G, and M, deallyl eusiderin A, and nitidanin, which contain the 1,4-benzodioxane motif but lack the chromanone motif found in the known antiviral flavonolignans, were tested. Notably, it was found that all eusiderin 1,4-benzodioxane neolignans exhibited greater antiviral activity than the potent and well-known silybin flavonolignans. While most modifications of the C-1' side chain did not significantly alter the cytotoxicity or antiviral activity, eusiderin M and nitidanin, which contain an allylic alcohol side chain, had lower cytotoxicity. All the eusiderins had similar antiviral activities, with eusiderin B having the best selectivity index. These results show that the chromanone moiety of the flavonolignans is not essential for bioactivity.

A New Class of Synthetic Flavonolignan-Like Dimers: Still Few Molecules, but with Attractive Properties.

In recent years, there has been increasing interest in dimeric molecules due to reports of their promising therapeutic value in the treatment of numerous diseases (such as cancer, HIV, Alzheimer's and, malaria). Many reports in the literature have highlighted the ability of these molecules to interact not only with specific biologic receptors but also to induce a biological response that more than doubles the results of the corresponding monomeric counterpart. In this regard, flavonolignan dimers or simply bi-flavonolignans are an emerging class of dimeric compounds that unlike bi-flavonoids, which are very widespread in nature, consist of synthetic dimers of some flavonolignans isolated from the milk thistle Silybum marianum [L. Gaertn. (Asteraceae)]. This mini-review will discuss recent developments in the synthesis, characterization and antioxidant activity of new families of flavonolignan dimers, in light of emerging medicinal chemistry strategies.

Chemoenzymatic Synthesis, Characterization, and Scale-Up of Milk Thistle Flavonolignan Glucuronides.

Plant-based therapeutics, including herbal products, continue to represent a growing facet of the contemporary health care market. Mechanistic descriptions of the pharmacokinetics and pharmacodynamics of constituents composing these products remain nascent, particularly for metabolites produced following herbal product ingestion. Generation and characterization of authentic metabolite standards are essential to improve the quantitative mechanistic understanding of herbal product disposition in both in vitro and in vivo systems. Using the model herbal product, milk thistle, the objective of this work was to biosynthesize multimilligram quantities of glucuronides of select constituents (flavonolignans) to fill multiple knowledge gaps in the understanding of herbal product disposition and action. A partnership between clinical pharmacology and natural products chemistry expertise was leveraged to optimize reaction conditions for efficient glucuronide formation and evaluate alternate enzyme and reagent sources to improve cost effectiveness. Optimized reaction conditions used at least one-fourth the amount of microsomal protein (from bovine liver) and cofactor (UDP glucuronic acid) compared with typical conditions using human-derived subcellular fractions, providing substantial cost savings. Glucuronidation was flavonolignan-dependent. Silybin A, silybin B, isosilybin A, and isosilybin B generated five, four, four, and three monoglucuronides, respectively. Large-scale synthesis (40 mg of starting material) generated three glucuronides of silybin A: silybin A-7-O-ß-D-glucuronide (15.7 mg), silybin A-5-O-ß-D-glucuronide (1.6 mg), and silybin A-4´´-O-ß-D-glucuronide (11.1 mg). This optimized, cost-efficient method lays the foundation for a systematic approach to synthesize and characterize herbal product constituent glucuronides, enabling an improved understanding of mechanisms underlying herbal product disposition and action.

Mechanistic study of the biomimetic synthesis of flavonolignan diastereoisomers in milk thistle.

The mechanism for the biomimetic synthesis of flavonolignan diastereoisomers in milk thistle is proposed to proceed by single-electron oxidation of coniferyl alcohol, subsequent reaction with one of the oxygen atoms of taxifolin's catechol moiety, and finally, further oxidation to form four of the major components of silymarin: silybin A, silybin B, isosilybin A, and isosilybin B. This mechanism is significantly different from a previously proposed process that involves the coupling of two independently formed radicals.

[Synthesis of structural fragments of natural flavonoids and flavolignans from 2'-hydroxychalcones].

Structural analogues of natural flavonoids and flavolignans - new 2'-OAc-chalcones and 2-hetaryl-3-aminochromons with the remnants of a 6-halogen-1,3-benzodioxane, 1,4-benzodioxane and 1,5-benzodioxepan were synthesized. Structure of the obtained compounds was confirmed by the 1H NMR data.