Proximicins A, B, and C - Antitumor Furan Analogues of Netropsin from the Marine Actinomycete Verrucosispora Induce Upregulation of p53 and the Cyclin Kinase Inhibitor p21

摘要

Netropsin (1) and distamycin (2) are naturally occurring -peptides with antiviral and antibacterial activity (Figure 1).[1] Netropsin, formerly named congocidine, was isolated from S. netropsis in 1951,[2] while distamycin was isolated from S. distallicus in 1964.[3], [4] Both compounds bind in the minor groove of DNA, and they were arguably the first compounds for which AT-selective DNA binding was demonstrated.[5]-[8] The design of synthetic derivatives capable of addressing a specific sequence of DNA would allow the selective inhibition of gene expression and thus result in compounds that act as antitumor agents.[5] As a consequence, netropsin and distamycin were used as the basic structures for the synthesis of numerous analogues to enable the investigation and modulation of their minor-groove binding. This was also achieved by using combinatorial approaches.[5]-[11] A particular challenge was to generate selective binders for GC base pairs.[5]-[8] One approach was based on the assumption that the introduction of a hydrogen-bond acceptor in the pyrrole rings of netropsin might allow the drug to bind to GC-rich sequences.[5]-[8] By following this strategy, a large number of molecules were synthesized in which the N-methylpyrrole ring of netropsin was substituted by other heterocycles, for example, imidazole, thiazole, triazole, pyrazole, and furan.[5], [8] Since netropsin and distamycin lack selectivity and toxicity[8], [9] their use as drugs was prevented, except as an antiviral agent in a topical application.[12] Recent efforts have aimed to remedy these disadvantages.[9] A further important bioactivity of netropsin and distamycin is their inhibitory activities against the malaria-causing parasite Plasmodium falciparum.