The semisynthesis and biological activity of paclitaxel (Taxol) analogues in which the oxygen atom in ring D is substituted by a sulfur or a selenium atom is presented. These derivatives were synthesized and tested in order to make more transparent the role of the oxetane ring in the biological activity of paclitaxel. The sulfur derivatives were found to be less active than paclitaxel in biological assays, while the selenium derivative could not be converted to its 4-acyl analogue. The results with the sulfur analogues suggest that the oxygen atom in the oxetane ring plays an important role in the mechanism by which paclitaxel exhibits its anticancer activity.

The structure of the title compound (1), isolated from Hortiaregia, was established by nuclear magnetic resonance spectroscopy. The investigation demonstrates the value of indirect shift correlation experiments. The compound was further characterized by chemical and spectroscopic methods.

Derivatives of alpha-conidendrin, podophyllotoxin, and sikkimotoxin were prepared to evaluate the cytotoxic contributions of C-4 configuration and pendant and fused arene substitutions. Dimethyl-alpha-conidendryl alcohol (5), 9-deoxypodophyllol (6), and 9-deoxysikkimol (17) were dehydrated to their respective oxolane derivatives 4, 3, and 9. Diols 5 and 6 were converted via oxabicyclo[3.2.1]octanols 10 and 14 to target oxolanes 8 and 7 where C-4 had been inverted relative to that in 3 and 4. Cytotoxicities of the five oxolanes were determined in two drug-sensitive human leukemia and two multidrug-resistant cell lines expressing P-glycoprotein or multidrug-resistance associated protein (MRP). Changing the pendant arene configuration or replacing a m-methoxy by hydrogen resulted in a 100-fold cytotoxicity loss. Replacing a methylenedioxy group in the fused arene by two methoxy substituents reduced cytotoxicity by 10-fold. Drug-resistant cell lines were equally resistant to compounds 3, 4, 8, and 9 indicating that these four compounds do not serve as substrates of the transport proteins P-glycoprotein and MRP.