Premithramycinone G, an Early Shunt Product of the Mithramycin Biosynthetic Pathway Accumulated upon Inactivation of Oxygenase MtmOII

摘要

Mithramycin (1, MTM, Scheme 1, also known as mithramycin A, mithracin, and plicamycin) is an aureolic acid anticancer agent produced by various soil bacteria of the genus Streptomyces, including Streptomyces argillaceus (ATCC 12956). It inhibits the growth of cancer cells by cross-linking GC-rich DNA, thereby shutting down specificity protein (Sp1 or Sp3) dependent pathways towards proto-oncogenes, such as c-myc,[1] APC,[2] and c-src.[3] The last gene is also associated with the unique hypocalcemic activity of mithramycin.[3] MTM has become a popular biochemical tool to study Sp-dependent signal-transduction pathways, but because of its toxic side effects is rarely used as an anticancer agent, except for the treatment of tumor hypercalcemia refactory to other chemotherapy.[4]-[8] However, MTM was recently identified as a potential lead drug against neurological diseases,[9], [10] arthritis,[11] and for the treatment of hematologic disorders.[12] All these new applications require only very small, less-toxic concentrations of the drug, although the mode-of-action in these contexts remains obscure.