Enzymatic Methylation and Structure–Activity‐Relationship Studies on Polycarcin V,a Gilvocarcin‐Type Antitumor Agent

Polycarcin V, a polyketide natural product of Streptomyces polyformus, was chosen to study structure–activity relationships of the gilvocarcin group of antitumor antibiotics due to a similar chemical structure and comparable bioactivity with gilvocarcin V, the principle compound of this group, and the feasibility of enzymatic modifications of its sugar moiety by auxiliary O‐methyltransferases. Such enzymes were used to modify the interaction of the drug with histone H3, the biological target that interacts with the sugar moiety. Cytotoxicity assays revealed that a free 2′‐OH group of the sugar moiety is essential to maintain the bioactivity of polycarcin V, apparently an important hydrogen bond donor for the interaction with histone H3, and converting 3′‐OH into an OCH₃ group improved the bioactivity. Bis‐methylated polycarcin derivatives revealed weaker activity than the parent compound, indicating that at least two hydrogen bond donors in the sugar are necessary for optimal binding.