New Silybin Scaffold for Chemical Diversification: Synthesis of Novel 23-Phosphodiester Silybin Conjugates

Abstract

Silybin is the major component (ca. 30%) of the silymarin complex extracted from the seeds of Silybum marianum, with multiple biological activities operating at various cell levels. As an ongoing effort toward the exploitation of natural products as scaffolds for chemical diversification at readily accessible positions, we present here an efficient synthetic procedure to obtain new 23-phosphodiester silybin conjugates with different labels. A key point in our approach is the new 3,5,7,20-tetra-O-acetylsilybin-23-phosphoramidite, useful for a variety of derivatizations following a reliable and well-known chemistry. The feasibility of the procedure has been demonstrated by preparing new 23-silybin conjugates, exploiting standard phosphoramidite chemistry.Key words: natural products, flavonolignans, silybin, phosphorylation, drugs Flavonoids and flavonolignans are widely distributed among various citrus plants and are frequently found in the human diet. They may act as enzyme inhibitors, freeradical scavengers, antitumor agents, antibacterial agents, anti-inflammatory agents, and antioxidants. [1][2][3] Silybin (Figure 1) is the major component (ca. 30%) of the silymarin complex extracted from the seeds of Silybum marianum consisting of two diastereomers A and B in a ratio of approximately 1:1. Silybin is a natural compound with multiple biological activities operating at various cell levels most of them related to its radical-scavenging activity. Along with the beneficial activities resulting from the antioxidant and radical-scavenging properties, 3,4 silybin has recently received attention due to its anticancer and chemopreventive actions, 5,6 as well as hypocholesterolemic, cardioprotective, and neuroprotective activities. 3,7 In vivo applications of silybin are rather hampered by its very low bioavailability. In an attempt to improve its biological properties and facilitate in vivo applications of silybin, only limited structural modifications have been proposed 3,[8][9][10][11][12] and the available analogues are still unsatisfactory. Therefore new synthetic approaches for selectively modifying silybin are of interest. As a part of our continuing research effort towards the synthesis of new natural product analogues, 13,14 we present here the preliminary results of a efficient synthetic procedure to obtain new 23-phosphodiester silybin conjugates with different labels. The introduction of a phosphate group may bring pharmaceutical and pharmacokinetic benefits. 15 Conjugation is usually considered as an efficient route in drug discovery to improve the biological properties of a large number of drugs and can improve the bioavailability and delivery as well as the biological activity. We chose to start from the new 23-phosphoramidite building block 3 (Scheme 1) which could be transformed into a series of conjugates using a solution-phase parallel array protocol, exploiting standard and reliable phosphoramidite chemistry. 15 We initially converted silybin (1) into its 23-ODMT ether by a reaction with DMT...

Synthesis of new riboflavin modified ODNs: Effect of riboflavin moiety on the G-quadruplex arrangement and stability

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

“…Recently, a new family of flavonolignan dimers has been proposed by Romanucci et al [28]: Phosphate-Linked Silibinin dimers (PLSd). Inspired by oligoflavonoid structures [29] and exploiting phosphoramidite chemistry [30,31,32,33], they reported an efficient synthetic strategy to obtain new silibinin dimers in which the monomeric units are linked through phosphodiester bonds (Figure 7).…”

Cold-Active Lipase-Based Biocatalysts for Silymarin Valorization through Biocatalytic Acylation of Silybin

“…A new study on the bioavailability improvement was achieved through selective acylation of silybin in the 3-OH position with a 60% product yield in the presence of CeCl 3 •7H 2 O Lewis acid catalyst [8]. In order to obtain phosphorylated conjugates, Zarelli et al initially acetylated silybin in a complex three-step organic synthetic process with a 75% yield [15]. Moreover, there are encapsulated silymarin variants in matrices less toxic and much better accepted by the human organism [10,16].…”