pactamycin and 1-1-dimethylurea

An advanced intermediate in a projected synthesis of pactamycin has been prepared. Early installation of the C1-dimethylurea functionality allows for its participation in a diastereoselective, chelation-controlled addition of organometal nucleophiles to the C5 prochiral ketone. Four of the molecule's six stereocenters are set with a ketone functional handle provided for subsequent manipulation.

Topics: Antibiotics, Antineoplastic; Catalysis; Ketones; Methylurea Compounds; Molecular Structure; Pactamycin; Stereoisomerism

Pactamycin, one of the most densely functionalized aminocyclitol antibiotics, has pronounced antibacterial, antitumor, antiviral, and antiplasmodial activities, but its development as a clinical drug was hampered by its broad cytotoxicity. Efforts to modulate the biological activity by structural modifications using synthetic organic chemistry have been difficult because of the complexity of its chemical structure. However, through extensive biosynthetic studies and genetic engineering, we were able to produce analogs of pactamycin that show potent antimalarial activity, but lack significant antibacterial activity, and are about 10-30 times less toxic than pactamycin toward mammalian cells. The results suggest that distinct ribosomal binding selectivity or new mechanism(s) of action may be involved in their plasmodial growth inhibition, which may lead to the discovery of new antimalarial drugs and identification of new molecular targets within malarial parasites.

Topics: Amino Acid Sequence; Anti-Bacterial Agents; Antimalarials; Gene Knockout Techniques; Gene Silencing; Genetic Engineering; HCT116 Cells; Humans; Malaria; Methylurea Compounds; Pactamycin; Plasmodium falciparum; Streptomyces; Transferases