Reductive alkylation of DNA by mitomycin A, a mitomycin with high redox potential

Abstract

The mitomycins are a group of antitumor antibiotics that covalently bind to DNA upon reductive activation. Mitomycin A (lb; MA) is more toxic than its clinically useful cousin, mitomycin C (la; MC).The greater toxicity of mitomycin A has been previously attributed to its higher reduction potential. In this report, the DNA alkylation products of reductively activated MA were isolated and characterized by conversion to the known 7-amino mitosene-deoxyguanosine adducts. The three major adducts formed were identified as a monoadduct, 7V2-(2"/3-amino-7"-methoxymitosen-l"a-yl)-2,-deoxyguanosine (5), a decarbamoyl monoadduct, A2-(2///3-amino-10"-decarbamoyl-7"-methoxymitosen-1 "a-yl)-2'-deoxyguanosine (6), and a bisadduct, /V2-(2"/3-amino-10//-deoxyguanosin-Á2-yl-7-methoxymitosen-1 "a-yl)-2'-deoxyguanosine (7). Under all reductive activation conditions employed, MA selectively alkylated the 2-amino group of guanine in DNA, like MC. In addition, both MA and MC alkylated DNA and cross-linked oligonucleotides to a similar extent. However, variations in the reductive activation conditions (H2/Pt02, Na2S204, or enzymatic) affected the distribution of the three major MA adducts in a different manner than the distribution of MC adducts was affected. A mechanism is proposed wherein the 7-methoxy substituent of MA allows initial indiscriminate activation of either of the drugs' two electrophilic sites. While oxygen inhibited cross-linking by MC, similar aerobic conditions exhibited little influence on the cross-linking ability of MA. Hence, the greater toxicity of MA may be influenced by increased and nonselective activation and cross-link formation in both aerobic and anaerobic cells. This effect is a direct consequence of the higher redox potential of MA as compared to MC. Kohn et al., Hoey et al. (1988)]. Finally, structures of the major alkylation products between reduced MC and DNA, two monoadducts (2 and 3) (Tomasz et al., 1986a(Tomasz et al., ,b, 1988a) and one bisadduct (4), (Tomasz et al., 1987) have been determined. The latter was shown to constitute the interstrand cross-links of DNA by MC (Borowy-Borowski et al., 1990a). Studies into the forces governing the relative ratios of these adducts have demonstrated that the reduction conditions influence the cross-link to monoadduct ratio (Tomasz et al., 1987(Tomasz et al., , 1988b.

Mitomycinoid Alkaloids: Mechanism of Action, Biosynthesis, Total Syntheses, and Synthetic Approaches

“…[125,131] This affect as it relates to the comparison between MMC and MMA has been proposed to be a direct consequence of their different redox potentials, with MMA showing an initial indiscriminate activation of either electrophilic site (Scheme 9). [136] …”

The generation and reactions of quinone methides

“…108 Reduction of mitomycin A and C in vitro by H 2 /PtO 2 or by Na 2 S 2 O 4 gives 62 which then breaks down to the quinone methide 63A . 109 This quinone methide reacts with DNA to give a complex mixture of alkylated DNA and cross-linked oligonucleotides. Mitomycin A is both more easily reduced and more toxic than mitomycin C, and there is some evidence that the toxicity of mitomycin A is related to the greater ease of is nonselective reductive activation.…”

“…Mitomycin A is both more easily reduced and more toxic than mitomycin C, and there is some evidence that the toxicity of mitomycin A is related to the greater ease of is nonselective reductive activation. 109 The Cr(ClO 4 ) 2 -mediated reduction of mitomycin C in aqueous solutions to give 62C has also been studied. 110 McClelland and Lam examined the elimination of methanol from reduced quinone 62 and obtained strong evidence for a stepwise reaction mechanism though an iminium ion reaction intermediate (Scheme 29).…”

The role of bioreductive activation of doxorubicin in cytotoxic activity against leukaemia HL60-sensitive cell line and its multidrug-resistant sublines

“…On the other hand, there is an increasing body of evidence that the reductive activation of antitumour drugs, for example, mitomycin C, tirapazamine and indoloquinone, could result in covalent binding to DNA (McGuinness et al, 1991;Adams and Stratford, 1994;Bailey et al, 2001) and lead to the important increase in the cytotoxic activity of these compounds against tumour cells (Patterson et al, 1995(Patterson et al, , 1997Chinje et al, 1999;Cowen et al, 2003). Many investigations are also focused on the bioreductive activation of DOX (Bartoszek and Wolf, 1992;Taatjes et al, 1997;Bartoszek, 2002).…”