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Synthesis 470 megahertz proton nmr spectra and activity of delactonized derivatives of the anti cancer drug etoposide

Synthesis 470 megahertz proton nmr spectra and activity of delactonized derivatives of the anti cancer drug etoposide

Journal of Medicinal Chemistry 25(9): 1077-1081

The anticancer drug etoposide (VP 16-213) contains a highly strained trans-fused .gamma.-lactone. This functionality is readily metabolized to an inactive ring-opened hydroxy acid. To prevent this detoxification of the drug and to investigate whether the lactone is essential for drug activity, a cyclic ether analog of etoposide was synthesized and tested in the mouse leukemia L1210 system in vitro and in vivo. This ether analog of etoposide retained 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, 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 was demonstrated. This coupling constant is characteristic of cis or trans stereochemistry across the C-D ring fusion.

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Accession: 006559971

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Synthesis, 470-MHz 1H NMR spectra, and activity of delactonized derivatives of the anticancer drug etoposide. Journal of Medicinal Chemistry 25(9): 1077-1081, 1982

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