Acylfulvene analogs with a spiro-cyclobutane ring and peptide, estrogen prodrugs of illudin

Illudin S and M are sesquiterpenes first isolated in the 1940s. Their structures were determined in 1962 and they were proposed to be biosynthesized from three molecules of mevalonic acid. They were shown to be toxic to a series of cancer cells but they have a low therapeutic index. By studying their metabolism, cellular targets and chemical reactivity towards thiols, they were proposed to function as alkylating agents of macromolecules. Modification of the parent structure led to a series of analogs with better efficacy. Among those, irofulven was shown to have excellent efficacy and it is being tested in a series of phase I and II clinical trials.; Most of the analogs of illudins are derivatives of the natural products made by modification of their 5-membered ring. Their efficacy was found to parallel activity towards thiols. Replacement of the cyclopropane ring with a spiro-cyclobutane ring was intended to reduce their chemical activity and, it was hoped, to improve their selectivity among macromolecular targets. Analogs with a spiro-cyclobutane ring were therefore synthesized and their biological activity was compared with that of the cyclopropane counterparts. It was found that this structure change did reduce the cytotoxicity compared to that of previously synthesized cyclopropane analogs. However the in vitro test results did not indicate that they would have better efficacy than the cyclopropane analogs.; Targeted drug delivery of illudins to certain tissue could increase their efficacy by reducing their toxic effect to other tissue or organs. Conjugates of illudins with peptides, which are substrates of PSA (prostate specific antigen), were synthesized. These compounds were designed to utilize PSA to release illudin in the prostate cancer tissue. A related kind of delivery might also be realized by conjugating illudin with estrogens. The estrogen receptor in some cells such as breast cancer cells might help the conjugates localize selectively by recognizing the estrogen part of the conjugates. Some estrogen conjugates of illudin have been synthesized. These two types conjugates are under investigation for evaluation of their biological activity.