Podophyllotoxin-derivatives Lignans

Partially hydrogenated quinoline cores are also present in some important bioactive compounds. For example, the 4-aza-analogs of Podophyllotoxin, a plant lignan that inhibits microtubule assembly, revealed to be more potent and less toxic anticancer agents. In 2006, Ji s group reported a green multicomponent approach to a new series of these derivatives, consisting of the reaction of either tetronic acid or 1,3-indanedione with various aldehydes and substituted anilines in water under microwave irradiation conditions (Scheme 26) [107]. For this efficient and eco-friendly transformation, the authors proposed a mechanism quite similar to the one that was postulated for the synthesis of tetrahydroquinolines in the precedent section. 

The best example of a lignan used as a lead compound is podophyllotoxin, an antimitotic compound that binds to tubulin, although podophyllotoxin has not been isolated from Taxus species,. Etoposide and teniposide are well-known compounds derived from podophyllotoxin, and their antitumor activity is due to the inhibition of topoisomerase II. 

The alcohols formed from some cinnamic acid derivatives, namely /7-coumaryl alcohol, coniferyl alcohol (LI), and sinapyl alcohol (L2), commonly known as monolignols, undergo dimerization reactions that yield lignans such as (-l-)-pinoresinol (L3), (-l-)-sesamin (L4), (-)-matairesinol (L5), and podophyllotoxin (L6) (Fig. 13). Several thousand lignans are found to occur in nature. Lignins, the structural components of plant cell walls, are polymers of monolignols and/or lignans. 

The in vitro cytotoxicity of 5-methoxypodophyllotoxin, obtained from a root culture derived from Linum flavum, against EAT and HeLa cells was determined and compared with those of podophyllotoxin, etoposide, teniposide and 5-methoxypodophyllotoxin-4- 3-D-glucoside [106]. The tested lignans had about the same cytotoxic potency as podophyllotoxin (ED50 of 32 and 22 pg/mL versus 42.8 and 20.5 pg/mL, respectively against EAT and HeLa cells). However, in comparison with etoposide and teniposide they were clearly less potent (1.1 and 7.9 pg/mL, and 0.06 and 0.3 pg/mL, respectively). 

Stahelin H (1973) Activity of a new glycosidic lignan derivative (VP 16-213) related to podophyllotoxin in experimental tumors. Eur J Cancer 9 215-221... 

One of the most important discoveries made by the natural product chemist Kupchan was the unusual lignan-derived podophyllotoxin, which has clinical applications as a powerful and selective antineoplastic. The problem of synthesising it asymmetrically is solved elegantly using the chiral oxazoline auxiliary (see section 5.4.1). 

Interest in lignans and neolignans has risen sharply in the last few years. This is due chiefly to their powerful, varied biological activities (Table 7.3.1) exemplified by three of the most noteworthy representatives. First, the lignan podophyllotoxin (1), in the form of several semisynthetic derivatives, is one of the very few natural products from higher plants used clinically in cancer chemotherapy (30). Next kadsurenone (2), also isolated from an angiosperm species has been described as... 

A strong cytotoxic lignan is podophyllotoxin (Fig. 17) irom Podophyllum peltatum or P. hex-andrum (Berberidaceae). Podophyllotoxin has the same mechanism of action as the terpene indole alkaloids vinblastine and vincristine it inhibits cell division by binding to tubulin and preventing its polymerization. This lignan is used as treatment for warts, but is too toxic for systemic application. Derivatives with reduced toxicity are etoposide, etopophos, and tenipo-side. They are prepared semi-synthetically from 4 -demethylpodophyllotoxin and have an inverted stereochemistry at C-4. These changes lead to a new anticancer mechanism, the... 

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