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

Abstract

Polycarcin V, a polyketide natural product of Streptomyces polyformus, was chosen to study structure-activity-relationships of the gilvocarcin group of antitumor antibiotics, because of 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 H-bond donor for the interaction with histone H3, while 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 H-bond donors in the sugar are necessary for optimal binding.

Biosynthesis of natural and non-natural genistein glycosides

“…S12B and S13B †). According to previous reports, 27,35,36 the characteristic protons of 2-deoxy sugars were at 2.19 ppm (1H) and 1.60 ppm (1H), whereas other sugar protons were in the region from 3.0 ppm to 4.5 ppm in the compound with t R 18.1 min (Fig. S12A †).…”

“…To the best of our knowledge, these sugar O-methyltransferases were used for the rst time in the generation of methylated rhamnosyl avonoids, beside glycosylated phenolic compound polycarcins. 35 During the microbial production of these compounds using GT and SOMTs co-transformation from 12 mg L À1 (28. (Fig.…”

Biosynthesis of DNA-Alkylating Antitumor Natural Products

“…Antitumor antibiotic gilvocarcins are a subfamily of C -glycoside aromatic polyketides and are derived from the typical angucycline scaffold [ 138 ]. Part of gilvocarcin-type natural products including gilvocarcin V ( 174 ), chrysomycin A ( 175 ), and ravidomycin ( 176 ) ( Figure 23 A) possess the vinyl substituent at C-8 which mediates a photo-activated [2 + 2] photocycloaddition with the thymidyl residue on DNA ( Figure 23 B) [ 139 , 140 ].…”

Polycarcin V induces DNA-damage response and enables the profiling of DNA-binding proteins

“…These compounds exhibit remarkable light-activated antitumor activities [ 25 ] and their proposed mode of action is that they covalently cross-link to DNA upon ultraviolet (UV)-light irradiation [ 26 , 27 ]. Polycarcin V, one of the most potent gilvocarcins, is a C-aryl glycoside compound with an α-linked L-rhamnopyranose moiety [ 28 , 29 ] (Fig. 1A ) and it also has the capacity of binding to DNA [ 30 ].…”