Philippe Meresse

Etoposide: Discovery and Medicinal Chemistry

Etoposide is an antitumor agent currently in clinical use for the treatment of small cell lung cancer, testicular cancer and lymphomas. Since the introduction of etoposide in 1971, its mechanism of action and potent antineoplastic activity has served as the impetus for intensive research activities in chemistry and biology. This drug acts by stabilizing a normally transient DNA-topoisomerase II complex, thus increasing the concentration of double-stranded DNA breaks. This phenomenon triggers mutagenic and cell death pathways. The function of topoisomerase II is understood in some detail, as is the mechanism of inhibition of etoposide at a molecular level. Etoposide has shortcomings of limited neoplastic activity against several solid tumors such as non-small cell lung cancer, cross-resistance to MDR tumor cell lines and low bioavailability. The design and synthesis of etoposide analogs is an activity of fundamental interest to the field of cancer chemotherapy. In the first part, this article is a survey of the discovery of etoposide, the DNA topoisomerase II structure and mechanism, and the models for drug-enzyme interaction. The last part is concerned with the search for new etoposide analogs based upon an empirical design.

A one-pot, efficient synthesis of the potent cytotoxic podophyllotoxin derivative NPF

Abstract One-pot syntheses of 4′-demethylepipodophyllotoxin 7 and NPF 2 (4′- O -demethyl-4β-(4″-fluoroanilino)-4-deoxypodophyllotoxin) are described from podophyllotoxin 3 via a protocol using trimethylsilyl iodide in 72% and 52% overall yields, respectively.

Synthetic approaches to condensed aromatic analogues from etoposide. Synthesis of A-ring pyridazine picroetoposide

The studies feature the transformation of etoposide 1 into the pivotal intermediate (+)-19 for the elaboration of pyridazine-fused aromatic systems via a Stille cross-coupling. The synthesis of A-ring pyridazine picroetopiside (+)-21 has been achieved in 11 steps.

Synthesis of a highly functionalized γ-lactone as a precursor of 9-pentyl anthracyclines

Abstract The synthesis of non racemic chiral γ-lactone 7 from α-D-isosaccharino-1,4-lactone (+)- 8 , as a precursor of the A-ring of the targeted 3′-morpholinyl-9-pentyl anthracycline 6 , is described.