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Studies with plant cell cultures and synthetic chemistry: routes to etoposide

University of British Columbia

The studies presented in this thesis involve investigations in the use of plant cell cultures in combination with synthetic chemistry to provide efficient routes for the synthesis of novel aryltetralin analogues of the podophyllotoxin family as well as intermediates for the synthesis of etoposide (1) and teniposide (2), two important anticancer agents. The present study is also devoted to providing a better understanding with regard to the use of biotransformation by plant cell cultures as a novel tool in the synthesis of podophyllotoxin analogues and closely related lignans. The initial phases involved the use of readily available aromatic aldehydes 226, 280 and 286, which after derivatization were employed in a "one-pot" 1,4-addition-enolate alkylation or 1,4-addition-enolate aldol reaction in the preparation of several dibenzybutanolide analogues, such as 266, 267, 272-279. Although the syntheses to 266 and 267 have been previously established in this laboratory, other intermediates 272 - 279 in the synthesis to 4'- demethylepipodophyllotoxin analogues were required and thus investigated. Further studies of the present research involved biotransformation of dibenzylbutanolides 266, 267, 272, 273, 274, 275 and 276 to analogues of the lignan, 4'-demethylepipodophyllotoxin (16), by means of plant cell cultures from Podophyllum peltatum and Nicotiana sylvestris, as well as horseradish peroxidase enzymes as catalysts in the cyclization reactions of dibenzylbutanolides. The results, obtained from these studies, suggested that compounds bearing a methylene group at C-7" of the basic dibenzylbutanolide skeleton are suitable precursors in the enzyme catalyzed cyclizations to isopodophyllotoxin analogues, 268 and 309, as potentially active antineoplastic agents. In contrast, the presence of a hydroxyl group at C-7" restricted the enzymatic process to partial oxidation and complete suppression of the cyclization process. An alternative approach in the preparation of the aryltetralin compounds of the podophyllotoxin series was achieved by chemical conversion of 277, 278 and 279, utilizing Lewis and protic acids. The products obtained from these experiments possessed either podophyllotoxin (3) or isopodophyllotoxin (52) configuration. The later stages of the present studies concentrated on the preparation of compounds 6 and 331, bearing the 4'-demethylpodophyllotoxin (6) configuration, represented in the Etoposide (1) molecule. [Figures.]

Thesis/Dissertation

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2009-07-02

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http://hdl.handle.net/2429/10010

Chemistry

University of British Columbia

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