On the Origin of Cytotoxicity of the Natural Product Varacin. A Novel Example of a Pentathiepin Reaction That Provides Evidence for a Triatomic Sulfur Intermediate

Abstract

A density functional theoretical study is presented, which implicates a novel S(3)-cleavage in the decomposition of a pentathiepin. This study predicts an interconversion between a pentathiepin and an open-chain polysulfur ion intermediate from which a key determinant in the chemistry then follows. Expulsion of diatomic sulfur, S(2), is unlikely from the unimolecular collapse of the open-chain polysulfur ion. Instead, S(3) can dissociate due to an unusually long and weak sulfur-sulfur (S4-S5) bond. A mechanistic picture now emerges which predicts that the novel S-S cleavage reaction and the unanticipated S(3) fragmentation are a result of delocalization of the negative charge within the remaining carbon-sulfur fragment. The computed results presented here reveal a new aspect to the chemistry of pentathiepins, that of S(3) unit transfer, which is proposed to have significance in the mechanism of cytotoxicity of the natural product varacin, 1.

Functionalization of pentagon–pentagon edges of fullerenes by cyclic polysulfides: A DFT study

“…2. The C-C bond lengths of pentathiepin rings on the considered compounds are calculated to be 1.585-1.588 and 1.570-1.580 Å in the S 5n -C 60 (D 3 ) and S 5n -C 70 (C 2v ), in agreement with those reported for varacin 6 derivatives [34,35]. S 5n -C 60 (D 3 ) and S 5n -C 70 (C 2v ) represent the C 60 (D 3 ) and C 70 (C 2v ) functionalized by 1, 2 and 3 pentathiepin rings (n=1, 2 and 3).…”

“…Fig. 1-Schlegel projections for a) the non-IPR isomer of C 60 fullerene with RSPI= (2,4,6,10,13,16,19,22,25,27,29,31) and D 3 symmetry b) the non-IPR isomer of C 70 fullerenes with RSPI= (1,2,10,13,15,18,22,23,28,29,32,35) and C 2v symmetry and c) C 60 fullerene with two Stone-Wales defects, including four Aps and RSPI= (2,4,13,14,16,17,19,20,22,24,26,30), in which all adjacent pentagons are highlighted with grey color. …”

“…1 [24]. Then, the C 60 (D 3 ) fullerene throughout this paper is referred to the non-IPR C 60 fullerene with D 3 symmetry and RSPI = (2,4,6,10,13,16,19,22,25,27,29,31), and C 70 (C 2v ) is referred to the non-IPR C 70 fullerene with C 2v symmetry and RSPI = (1,2,10,13,15,18,22,23,28,29,32,35). Schlegel diagrams of these structures together with their canonical spiral strips are shown in Fig.…”

Disulfide and multisulfide antitumor agents and their modes of action

“…Preliminary studies provided evidence that varacin derives its activity through DNA damage (Davidson et al, 1991;Barrows et al, 1991). Additional investigations using the interesting model compound, 7-methylbenzopentathiepin (54, Scheme 9), indicated that the biological activities of 54 may stem from DNA cleavage, which implies the origin of DNA damage by varacin Greer, 2001;Chatterji and Gates, 2003a). Consistent with these findings, it was reported as a direct proof that DNA cleavage by varacin was observed in the presence, but not in the absence, of thiols and the cleaving activity was enhanced by an increase in thiol concentration and a decrease in the pH (Lee et al, 2002a).…”

“…The ion 55 leads to the conversion of molecular oxygen to hydrogen peroxide probably through superoxide radical, and then to DNA-cleaving hydroxyl radicals by a trace-metal-dependent Fenton reaction (Chatterji and Gates, 2003a). In addition, the theoretical study using a model compound 56 implicates the generation of triatomic sulfur, S 3 , along with the hydrosulfide anions (Scheme 10), and the cytotoxic species, S 3 , was believed to represent significance for the cytotoxicity of varacin (Greer, 2001).…”