Activation of Leinamycin by Thiols:  A Theoretical Study

Abstract

Reaction of thiols with the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin (1) results in the conversion of this antitumor antibiotic to a DNA-alkylating episulfonium ion (5). While the products formed in this reaction have been rationalized by a mechanism involving initial attack of thiol on the central sulfenyl sulfur (S2') of the 1,2-dithiolan-3-one 1-oxide ring, the carbonyl carbon (C3') and the sulfinyl sulfur (S1') of this heterocycle are also expected to be electrophilic. Therefore, it is important to consider whether nucleophilic attack of thiol at these sites might contribute either to destruction of the antibiotic or conversion to its episulfonium ion form. To address this question, we have used computational methods to examine the attack of methyl thiolate on each of the three electrophilic centers in a simple analogue of the 1,2-dithiolan-3-one 1-oxide heterocycle found in leinamycin. Calculations were performed at the MP2/6-311+G(3df,p)//B3LYP/6-31G level of theory with inclusion of solvent effects. The results indicate that the most reasonable mechanism for thiol-mediated activation of leinamycin involves initial attack of thiolate at the S2'-position of the antibiotic's 1,2-dithiolan-3-one 1-oxide heterocycle, followed by conversion to the 1,2-oxathiolan-5-one intermediate (3).

Cellular Responses to the DNA Damaging Natural Compound Leinamycin

“…Previous studies have shown that along with DNA alkylation, leinamycin produces reactive oxygen species (ROS) from the persulfide species generated in the reaction of thiols with leinamycin [6,8]. A recent study in our lab showed that leinamycin was able to generate oxidative stress in the MiaPaCa human pancreatic cancer cell line [22].…”

“…Previous studies suggest that the 1, 2-dithiolan-3-one 1-oxide in leinamycin is the primary target of thiol attack as described in Figure 1 [6][7][8]. This reaction leads to the conversion of this heterocyle to a 1, 2-oxathiolan-5-one which undergoes a novel rearrangement reaction to produce a DNA attacking episulfonium ion [6][7][8]. This episulfonium ion associates noncovalently with the double stranded DNA and alkylates the N7 position of the guanine residue very efficiently [6][7][8][9][10].…”

“…Leinamycin has shown to have potent anticancer activity in both in vivo and in vitro tumor models and is currently under consideration to be developed as an anticancer agent [5]. Previous studies suggest that the 1, 2-dithiolan-3-one 1-oxide in leinamycin is the primary target of thiol attack as described in Figure 1 [6][7][8]. This reaction leads to the conversion of this heterocyle to a 1, 2-oxathiolan-5-one which undergoes a novel rearrangement reaction to produce a DNA attacking episulfonium ion [6][7][8].…”

“…This reaction leads to the conversion of this heterocyle to a 1, 2-oxathiolan-5-one which undergoes a novel rearrangement reaction to produce a DNA attacking episulfonium ion [6][7][8]. This episulfonium ion associates noncovalently with the double stranded DNA and alkylates the N7 position of the guanine residue very efficiently [6][7][8][9][10]. The guanine adduct is the only covalent DNA lesion which is formed by the reaction of thiol activated leinamycin with double stranded DNA.…”

“…For example, NAC attenuates cisplatin induced acute renal failure [29]. Leinamycin is a thiol dependent DNA damaging agent [6][7][8] and NAC is a thiol compound and precursor of reduced glutathione (GSH) [28]. Therefore, it is important to understand how NAC can modulate the cytotoxic effect of leinamycin in human cancer cells.…”