Reaction of n-Propanethiol with 3H-1,2-Benzodithiol-3-one 1-Oxide and 5,5-Dimethyl-1,2-dithiolan-3-one 1-Oxide: Studies Related to the Reaction of Antitumor Antibiotic Leinamycin with DNA

Entering the leinamycin rearrangement via 2-(trimethylsilyl)ethyl sulfoxides

“…[3][4][5][6] Initial attack of cellular thiols on leinamycin's 1,2-dithiolan-3-one 1-oxide "triggering unit" is believed to yield a key sulfenate intermediate (2) that undergoes intramolecular cyclization onto the neighboring carbonyl group. 7,8 The persulfide (3, RSS − ) ejected in this reaction causes oxidative stress, [9][10][11][12][13] while the resulting 1,2-oxathiolan-5-one derivative of leinamycin (4) undergoes further rearrangement to yield an episulfonium ion (5) that alkylates guanine residues in duplex DNA (Scheme 1). [8][9][10][11][12][13][14] The sulfenate ion (2) is proposed 7,8 to be a key intermediate in the thiol-triggered conversion of leinamycin to a DNA-alkylating episulfonium ion; however, to date, there is no experimental support for the existence of this entity.…”

“…7,8 The persulfide (3, RSS − ) ejected in this reaction causes oxidative stress, [9][10][11][12][13] while the resulting 1,2-oxathiolan-5-one derivative of leinamycin (4) undergoes further rearrangement to yield an episulfonium ion (5) that alkylates guanine residues in duplex DNA (Scheme 1). [8][9][10][11][12][13][14] The sulfenate ion (2) is proposed 7,8 to be a key intermediate in the thiol-triggered conversion of leinamycin to a DNA-alkylating episulfonium ion; however, to date, there is no experimental support for the existence of this entity. In an effort to fill this gap in our knowledge, we set out to generate discrete sulfenate ions related to 2 and determine whether these intermediates are, in fact, competent to enter the leinamycin rearrangement reaction manifold.…”

Possible chemical mechanisms underlying the antitumor activity of S-deoxyleinamycin

“…[1][2][3][4][5] Reaction of thiols with leinamycin leads to ejection of a persulfide intermediate (2) that generates cell-killing reactive oxygen species (Scheme 1). [6][7][8][9] In addition, the 1,2-oxathiolan-5-one derivative (3) formed in this reaction undergoes further rearrangement to an episulfonium ion (4) that efficiently alkylates guanine residues in duplex DNA. 6,10 The resulting 7-alkylguanine residues undergo rapid depurination to generate a burst of cytotoxic abasic sites in duplex DNA.…”

“…[6][7][8][9] In addition, the 1,2-oxathiolan-5-one derivative (3) formed in this reaction undergoes further rearrangement to an episulfonium ion (4) that efficiently alkylates guanine residues in duplex DNA. 6,10 The resulting 7-alkylguanine residues undergo rapid depurination to generate a burst of cytotoxic abasic sites in duplex DNA. [11][12][13] The reaction with thiols may be central to the potent biological activity of leinamycin because cells contain millimolar concentrations of the thiol-containing tripeptide glutathione 14 that can trigger the release of cell killing reactive intermediates from this natural product.…”

“…This result is informative because equilibrating mixtures of polysulfides have previously been observed as characteristic byproducts generated in the thiol-triggered production of reactive oxygen species (O 2 • − , H 2 O 2 , and HO•) by the leinamycin analogue 8. [6][7][8][9] Polysulfides result from the oxidation of a persulfide intermediate (RSS -) that is released from 8 by its reaction with thiols. [6][7][8][9] Analogous to the autooxidation of thiols, 46 this reaction likely involves metal-mediated oxidation of the sulfur anion (Eqn 2).…”