Emmanuel Bertounesque

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.

Chromium(II) chloride: a new reagent for cross-aldol reactions

Abstract The proposed cross aldolization of α-bromoketones with aldehydes in presence of Chromium (II) chloride is an excellent stereospecific reaction. One exception to the stereospecific orientation is reported.

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.

Erythro selective cross aldol reaction via α-silyl trimethylsilyl esters.

Various fluoride ion mediated reactions of aliphatic α-silyl trimethylsilyl esters 1 with benzaldehyde have been investigated. Moderate erythro stereoselectivity is observed.

Synthesis of podophyllotoxin A-ring pyridazine analogue

Abstract Podophyllotoxin A-ring pyridazine analogue 3 has been constructed in nine steps from (−)-podophyllotoxin. The Stille reaction was exploited to generate the key intermediate 4 .

Synthesis of aryl phosphates based on pyrimidine and triazine scaffolds

The syntheses of the triazinyl-based bis-aryl phosphates 2 and 3, and of the aminopyrimidyl-based aryl phosphate 4 are described. Each compound contains a diaryl ether-phosphate structural motif. The synthetic route to bis-aryl phosphates 2 and 3 consisted in two nucleophilic substitution reactions with amines from cyanuric chloride, followed by a Suzuki coupling with the resulting 2,4-diamino-6-chloro-1,3,5-triazine derivative 12 to introduce the diaryl ether functionality. Aryl phosphate 4 was obtained via condensation of aryl guanidine 34 with aryloxyphenyl butenone 31. These de novo-designed aryl phosphates were evaluated as potential inhibitors of the Grb2-SH2 domain using an ELISA assay. The water-soluble sodium salt 26 of 3 gave an IC(50) value in the high micromolar range. Molecular modeling studies were subsequently performed upon modifying the 1,3,5-trisubstituted triazine scaffold of 3. Non-phosphate derivatives encompassing cyclopropane, pyrrole, keto-acid, and IZD fragments were thus step-wise designed and their Grb2-SH2 complexes were modeled by molecular dynamics. Some derivatives gave rise to an enriched pattern of H-bonds and cation-pi interactions with Grb2-SH2.

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 picropodophyllin homolactone

Abstract Based on a Wittig olefination strategy, the first synthesis of picropodophyllin homolactone 2 is described in nine steps and 30% overall yield from podophyllotoxine 1 . The relative configuration of 2 was unambiguously determined using 2D NOESY NMR and a Monte Carlo search protocol. This work corrects the literature on the synthesis of 2 .

New development of the Mukaiyama reaction: One pot synthesis of β-chloro acids and esters

The titanium tetrachloride reaction of ketene silyl acetals with benzaldehyde has been investigated. Through an aldolization-chlorination process, using two equivalents of TiCl4, β-chloro acids and esters are obtained in good yields.

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.