Synthesis, 470-MHz 1H NMR spectra, and activity of delactonized derivatives of the anticancer drug etoposide.
The anticancer drug etoposide (VP 16-213, 1) contains a highly strained trans-fused gamma-lactone. This functionality is readily metabolized to an inactive ring-opened hydroxy acid (2). To prevent this detoxification of the drug and to investigate whether the lactone is essential for drug activity, we synthesized a cyclic ether analogue of etoposide (3) and tested it in the mouse leukemia L1210 system in vitro and in vivo. This ether analogue of etoposide was found to retain activity in the L1210 system, but the activity was reduced relative to the parent drug. A synthetic intermediate, the ring D opened diol of the reduced lactone (4), was also tested and found to be inactive in the L1210 system. The complete 470-MHz 1H NMR spectra of etoposide and its derivatives are reported. The usefulness of introducing deuterium at C-13 to determine J2,3 is also demonstrated. This coupling constant is characteristic of cis or trans stereochemistry across the C-D ring fusion.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D005047:Etoposide / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D011034:Podophyllotoxin / Q000031:analogs & derivatives*
D000970:Antineoplastic Agents; D005047:Etoposide; D011034:Podophyllotoxin