Gilvocarcin V exhibits both equilibrium DNA binding and UV light induced DNA adduct formation which is sequence context dependent

Abstract

The relative degree of both equilibrium binding and of ultraviolet light induced adduct formation for the antitumor antibiotic gilvocarin V with two hexaecamer DNA sequence isomers, d[ATATATAGCTATATAT]2 and d[AAAAAAAGCTTTTTTT]2, was assessed. The experiments reveal that gilvocarin V binds, under equilibrium conditions, and reacts, in the presence of exogenously applied UV light, more efficiently with the alternating purine:pyrimidine sequence hexadecamer than the homopurine:homopyrimidine duplex at identical gilvocarcin V to DNA duplex ratios. DNAse I digests of adduct containing duplexes derived from the d[AAAAAAAGCTTTTTTT]2 duplex, identified and isolated using gel shift assays employing denaturing polyacrylamide gels, confirm that gilvocarcin V adducts can be formed with thymine residues but suggest that adduct formation with either adenine or guanine residues is also possible.

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

“…First, a photochemical [2+2] cycloaddition of the vinyl side chain with thymine residues of DNA promoted by near-UV or visible blue light results in a covalent binding to DNA, which in turn leads to single-strand scissions. [2] Besides, the bioactivity of GV is also attributed to protein-DNA association resulting from an additional interaction with histone H3, a core component of the histone complex, for which the sugar moiety, D-fucofuranose, was proposed to form H-bonds. [3] The resulting tight interaction between the histone complex and DNA by these antibiotics leads to growth inhibition of cancer cells (Figure 1).…”

Aryl–Aryl Bond Formation by the Fluoride‐Free Cross‐Coupling of Aryldisiloxanes with Aryl Bromides

“…Keywords: biaryls · CÀC coupling · cross coupling · silicon · synthetic methods [ [4,5] gilvocarcin V is known to have antitumour activity [6] and fluorenone-based natural and synthetic compounds such as dengibsinin are of pharmaceutical interest. [7] Biaryl phosphane ligands such as 1 are widely employed in palladium-catalyzed amination reactions.…”

Structure, activity, synthesis and biosynthesis of aryl-C-glycosides

“…73 Additional in vitro studies have demonstrated the inhibition of topoisomerase II by 49, and this effect is also believed to be important for in vivo biological activity. 74 Initial activity screening of simocyclinones revealed the major metabolites from the producing strain, simocyclinone D4 (53) and D8 (54), to possess antibacterial activity against Grampositive bacteria and provide growth inhibition of various human tumor cell lines. 51 Recent work by Maxwell et al established 54 to be a potent inhibitor of gyrase.…”

“…97, 98 The classical example, actinorhodin (73) produced by S. coelicolor, has a unique dimeric structure with monomers connected by a C-C bond at C10. 99,100 Several other naturally occurring BIQs have been isolated and studied including the aryl-C-glycosides granaticin (74), granaticin B (75), and medermycin (lactoquinomycin A, 76) which will be the focus of interest here (Fig. 10A).…”