acylfulvene and Lung-Neoplasms

Illudin S and M (1, 2) are highly toxic sesquiterpenes found in the basidiomycete Omphalotus illudens. Illudins have a low therapeutic index, but acylfulvene derivatives display potent in vivo antitumor activity against a variety of multidrug resistant tumors. The lead acylfulvene (4), irofulven (5), in a randomized phase IIB clinical trial significantly increased overall survival in patients with metastatic hormone-refractory prostate cancer who failed prior treatment with two different standard chemotherapeutic regimens. Irofulven is unique, as the primary allylic hydroxyl group can undergo displacement with a variety of nucleophiles to produce analogues that retain key functional groups required for biological activity including the reactive cyclopropylmethyl carbinol and alpha,beta-unsaturated ketone. As described here, we synthesized a variety of urea, carbamate, and sulfonamide derivatives that retain key functional groups and display potent biological activity toward target solid tumor cells in vitro but are relatively nontoxic toward a nontarget B-cell derived cell line.

Topics: Adenocarcinoma; Animals; B-Lymphocytes; Carbamates; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Lung Neoplasms; Mice; Sesquiterpenes; Spiro Compounds; Structure-Activity Relationship; Sulfonamides; Urea

Reaction of the fungal sesquiterpene illudin S with excess paraformaldehyde in dilute H2SO4 gives (hydroxymethyl)acylfulvene. The primary allylic hydroxyl thus formed can undergo very facile replacement by a variety of nucleophiles. (Hydroxymethyl)acylfulvene (MGI.114) was more toxic than a precursor, acylfulvene, but less toxic than the parent compound illudin S to HL 60 cells.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Basidiomycota; Chromatography, Thin Layer; Crystallography, X-Ray; Drug Screening Assays, Antitumor; HL-60 Cells; Humans; Lung Neoplasms; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Polycyclic Sesquiterpenes; Sesquiterpenes

Acylfulvene, derived from the sesquiterpene illudin S by treatment with acid (reverse Prins reaction), is far less reactive to thiols than illudin S. However, it is reduced readily to an aromatic product, in the same way as illudin S. This may explain its greatly improved therapeutic index compared to that of the parent compound.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Humans; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Polycyclic Sesquiterpenes; Sesquiterpenes; Spiro Compounds