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Synthesis and antifungal testing of 2,4,5,7,9-pentathiadecane 9,9-dioxide has established that the absence of oxygen atoms on S2 significantly attenuates fungitoxicity in accord with our earlier proposal. Attempts to convert that compound into dysoxysulfone led to the discovery of a novel oxidative conversion of unsymmetrical γ-sulfonyl disulfides into the corresponding symmetrical γ-sulfonyl disulfides.

Nosylates of phenols can be selectively deprotected by thiocresol anions in DMSO. Successful deprotection can be accomplished in molecules containing aryl-appended halides, ethers, aldehydes, alkanesulfonates or arylsulfonates. Nosylate deprotection is accomplished by the CS bond rupture which is believed to proceed by nucleophilic aromatic substitution.

BACKGROUND We have investigated whether chemicals known to disrupt disulfide bonds are capable of altering immunoglobulin anti-D structure resulting in an increased efficacy of the chemically modified anti-D to inhibit Fcgamma receptor (FcgammaR)-mediated phagocytosis. If successful, this would provide a rationale to explore this mechanism of enhancing FcgammaR blockade for future use in immunoglobulin therapies for immune cytopenias. STUDY DESIGN AND METHODS Anti-D that was shown to block 50 percent of the FcgammaR-mediated phagocytosis of opsonized red blood cells (RBCs) using a monocyte monolayer assay (MMA) was combined with two different thiol-containing compounds, dithiothreitol (DTT) or p-toluenesulfonylmethyl mercaptan, with or without treatment with iodoacetamide, and allowed to react. Excess chemical was removed by extensive dialysis. FcgammaR blockade was assessed by MMA with dialyzed, untreated, or chemically treated anti-D using both D+ and D- opsonized target RBCs. Toxicity was determined by fluorescence-activated cell sorting. Aggregates and oligomerization of chemically treated anti-D were examined using gel filtration-high pressure liquid chromatography. RESULTS Using disulfide-reducing compounds to chemically modify anti-D significantly increases the efficacy of the anti-D to induce an FcgammaR blockade and decrease phagocytosis in vitro of opsonized D+ or D- RBCs. This effect was shown not due to unbound residual chemical, toxicity, or formation of immunoglobulin G oligomers. S-alkylation was required when using low concentrations of reducing compound. CONCLUSION Our results demonstrate that irreversible reduction of interchain disulfide bonds within the immunoglobulin anti-D results in a significantly increased efficacy to inhibit FcgammaR-mediated phagocytosis regardless of opsonized target cell. With the use of this strategy, more effective and less expensive immunoglobulin treatment for immune cytopenias such as immune thrombocytopenic purpura or autoimmune hemolytic anemia may be developed.

Degenerate substitution reactions (at carbon) between the appropriate sulfinic acid salts and tosylmethyl methyl or mesylmethyl methyl disulfides have formed symmetrical disulfone disulfides in moderate yields. These products form in a redox process involving sulfinate anions following partial skeletal disassembly arising from rupture of the SS bond. The reaction of mesylmethyl methyl disulfide and sodium methanesulfinate provides a natural product, dysoxysulfone, in low yield.

A pair of p-nitrophenyl disulfide carboxylic acids are shown to react rapidly in aqueous base to give p-nitrothiophenol-derived anions. Experimental and PM3 computational results support the view that hydroxide ions attack, in a bimolecular fashion, at the appropriate sulfenyl sulfur to produce p-nitrophenyl mercaptide anions.

The synthesis and biological testing of some phloroglucinol-derived trisulfonates and sulfonate methyl ethers has established that the tritosylate 12 is a good in vitro antimalarial agent and that the dinosylate methyl ether 19 is a superior agent for inhibiting human skin cancer cell lines.

Reaction between sulfinate anions and α -benzoate of dimethyl disulfide produces a novel α -thiolbenzoate disulfide. Thiolbenzoate appears to arise from the reaction of a contaminant, α -benzoate of dimethyl trisulfide, present in benzoate disulfide. Benzoate trisulfide is formed by the reaction of benzoic anhydride with dimethyl trisulfide, a contaminant in commercial dimethyl disulfide.

An improved synthesis of phenacyl methyl disulfide is described. It led to conditions that efficiently furnish the ketal of phenacyl mercaptan. The ketal of phenacyl mercaptan appears to be the first known α -mercapto ketal. Phenacyl mercaptan is smoothly prepared from its ketal under standard conditions.

An overview of new synthetic methods for the construction of α-thiodisulfides is presented. α-Sulfone disulfide construction is prominently featured in the synthetic discussion. Biological test results on α-thiodisulfides, aryl disulfides, and thiosulfonates are reviewed and some organic-chemical mechanistic discussion is provided to rationalize them.

Three homologous ω-mercaptosulfones have been prepared and their crystal structures refined. When a single methylene (compound 3) was interposed between the p-toluenesulfonyl and thiol moieties, neither intramolecular nor intermolecular H-bonding was observed in the crystals. When an ethylene segment (compound 4) was interposed between the p-toluenesulfonyl and thiol moieties, one intermolecular H-bond per molecule was observed. When a propylene segment (compound 5) was interposed between the p-toluenesulfonyl and thiol moieties, H-bonded molecular dimers were formed in the crystal structure.

2,3,5-Trithiahexane reacts with the mercaptide anion derived from 1-propanethiol to furnish, inter alia, a family of trithiocarbonates. Key reaction products are identified and their yields determined by GCMS. A complete mechanism is proposed for the unexpected formation of these novel products.

The use and construction of a novel apparatus for a variant of conventional column chromatography is described. Relative to a single large conventional column, a bundled apparatus facilitates scale-up by accelerating fraction collection. The bundled approach permits prior knowledge of total running time, total solvent volume, and product location.

The addition of catecholborane (HBcat; cat = 1,2-O2C6H4) to a wide range of sulfoxides affords the corresponding sulfides, dihydrogen, and catBOBcat. The diboron compound catBOBcat acts like a Lewis acid and will coordinate one molecule of the starting sulfoxide. Although deoxygenations with bulky or electron withdrawing sulfoxides are slow, these reactions can be greatly accelerated with the use of excess HBcat or by employing a rhodium catalyst.

The antimalarial/anticancer (human skin cancer) properties of 11 small organosulfur compounds, some of which show antifungal and antileukemic activity, were determined using in vitro assays. Some c...

Categorizing even alternant hydrocarbons as joint or disjoint serves as the basis for differentiating between antiaromatic, Y-antiaromatic and very Y-antiaromatic structures. Both previously proposed methods for categorizing even alternant hydrocarbons as joint or disjoint are unreliable. A new approach is presented and shown to be both conveniently applicable and reliable. Because this topic bridges Huckel theory and modern structural concerns, it is suitable for inclusion in undergraduate Huckel theory courses.

Previously identified classes of antifungal disulfides are modified by extending alkyl substituents. Although, the principal focus is on f -sulfone disulfides, one nitrophenyl alkyl disulfide and a pair of f -ester disulfides were also prepared and examined. Optimum fungitoxicity is associated with structures which have seven to ten carbon atoms in the form of unbranched chains and/or phenyl rings.

Allenyl methyl ether (1) and (diphenylmethylene)cyclopropane (5) were ozonized with an ozone/oxygen mixture. Formation of the observed products cannot be satisfactorily rationalized via the familiar modified Criegee mechanism. However, a single-electron transfer (SET) mechanism provides a simple rationale.

New techniques are presented that permit the use of chemical graph theory to obtain secular equations for small molecules. The new techniques significantly accelerate manual calculations. A previously unrecognized relationship between the characteristic polynomial for a Huckel annulene and the secular equation for the corresponding Mobius annulene is deduced. The power of the graph-theoretical approach to illuminate chemically useful generalizations at the Huckel level is exemplified.

We assessed the antithrombotic activity of some simple organosulfur compounds which have some of the functionality found in the disulfide ajoene, a pharmacologically active compound isolated from garlic. The results establish that antithrombotic activity is associated with disulfides directly attached to a phenyl ring and is further enhanced by an α-sulfonyl group. CH 3 SO 2 CH 2 SSPh proved to be a potent inhibitor of platelet aggregation with an IC 50 of 5 μM.

A semicircular mnemonic is described which permits one to anticipate the Huckel eigenvalue patterns for symmetrical contiguous nonfused bicycles (e.g., biphenyl). The mnemonic constitutes a new technique that is complementary to the existing Frost circle mnemonic for hydrocarbon monocycles. Pedagogically, the development of this semicircular mnemonic in class will serve to establish that the widespread practice of applying Huckel’s rule to polycycles is unsound.

Resonance energies are shown to be quasithermodynamic in character. Hence, they are generally unsuitable as bases for anticipating kinetic stabilities. Examples are provided, leading to the conclusion that those who intend the word 'aromatic' to mean chemically unreactive, need to carry out full Hückel calculations in order to rank hydrocarbons using the frontier orbital energies.

This review covers recent progress (since the late 1980's) in the solution phase reactions of sulfonic acid esters. Some discussion of reactions which have yet to be explored experimentally is also provided.

A previous report has established the intermediacy of a sulfide-sulfonate ester in the one-pot conversion of an aryl mercaptan and a sulfonate ester into the corresponding trithioorthoformate. This report describes evidence for the sequential intermediacy of a bissulfide-sulfonate ester and a dithiosulfène in the conversion of the sulfide-sulfonate ester into the trithioorthoformate. A new sulfonate ester is shown to give the highest yield of trithioorthoformate. Key words: single electron transfer, sulfonate esters, sulfenes.

Perturbation theory is applied to fully π-bonded non-alternant monocycles at the Hückel level. An effective "back-of-the-envelope" approach is developed that permits one to anticipate Hückel charge patterns for these monocycles. Very little modification is required to alter the basic approach so that it will permit rapid anticipation of AM1 -calculated charge patterns for such compounds. Keywords: hydrocarbon polarity, perturbation theory.

The one-pot conversion of a mercaptan and an aryl methanesulfonate into a trithioorthoformate is described. The intermediacy of a sulfide-sulfonate ester is firmly established. Experimental and computational results permit the formulation of a possible pathway for the formation of the intermediate sulfide-sulfonate ester. Keywords: single electron transfer, sulfonate esters, sulfide-sulfonate esters.

α-Thioboronate esters are obtained directly in high yield and selectivity from metal-catalyzed additions of B−X bonds (X = H, B) to thiocarbonyl compounds and vinyl sulfides.

Reaction between benzaldehyde and methyl α- benzylsulfonylacetate furnishes methyl (E)-α- benzylsulfonyl-β-phenylacrylate as the exclusive Knoevenagel adduct. The related condensations between α-benzylsulfonylacetonitrile and paraformaldehyde furnish trans-1-benzylsulfonyl-2-phenylcyclopropane-1-carbonitrile in modest yields. These product structures are established by X-ray crystallographic analysis. Phenylsulfene is ruled out as an intermediate in the formation of the cyclopropane.

Background Novel therapeutic agents that selectively induce tumor cell death are urgently needed in the clinical management of cancers. Such agents would constitute effective adjuvant approaches to traditional chemotherapy regimens. Organosulfur compounds (OSCs), such as diallyl disulfide, have demonstrated anti-proliferative effects on cancer cells. We have previously shown that synthesized relatives of dysoxysulfone, a natural OSC derived from the Fijian medicinal plant, Dysoxylum richi, possess tumor-specific antiproliferative effects and are thus promising lead candidates. Methods Because our structure-activity analyses showed that regions flanking the disulfide bond mediated specificity, we synthesized 18 novel OSCs by structural modification of the most promising dysoxysulfone derivatives. These compounds were tested for anti-proliferative and apoptotic activity in both normal and leukemic cells. Results Six OSCs exhibited tumor-specific killing, having no effect on normal bone marrow, and are thus candidates for future toxicity studies. We then employed mRNA expression profiling to characterize the mechanisms by which different OSCs induce apoptosis. Using Gene Ontology analysis we show that each OSC altered a unique set of pathways, and that these differences could be partially rationalized from a transcription factor binding site analysis. For example, five compounds altered genes with a large enrichment of p53 binding sites in their promoter regions (p < 0.0001). Conclusions Taken together, these data establish OSCs derivatized from dysoxysulfone as a novel group of compounds for development as anti-cancer agents.

From a design principle described in an earlier paper, a new series of substituted aryl methyl disulfides have been prepared and tested against Aspergillus niger and Aspergillus flavus. Methyl p-nitrophenyl disulfide is more potent (by an order of magnitude) than the fungitoxic natural product (CH3SCH2S)2. With the present rationale in hand, one can anticipate which Polycarpamine is an effective antifungal agent.

Graph-theoretical arguments have produced an approach to generating antiaromatic hydrocarbon bicyclic structures. The newly recognized antiaromatic structures feature strategically located odd acyclic substituents. PM3-calculated ΔST values are used to support the assignment of antiaromatic character to appropriate structures. Manuscript received: 26 June 2000. Final version: 12 June 2001.

Relative gas phase stabilities of pairs of planar regioisomeric thioacyl-substituted carbocations have been calculated using the MNDO method. These systems are stabilized by good π donors. The role of S π-electron population as a gauge of substituent effects is examined. Similar results were obtained using isodesmic reactions to gauge substituent effects. Results of this and earlier studies are consistent with the resonance saturation effect. Keywords: semiempirical calculations, carbonium ions.

Sodium hydride reductions of aryl methanesulfonates afford dimeric sulfone-sulfonate esters as well as products arising from SO bond rupture. SO bond rupture becomes more competitive as the LUMO energy of the sulfonate ester declines. Exploration of the chemistry of a sulfone-sulfonate ester revealed a complex novel reaction that resulted in the formation of, inter alia, a dichloromethanesulfonate ester and a trichloromethanesulfonate ester. The first successful approaches to the synthesis of the heretofore unknown trichloromethanesulfonates and dichloromethanesulfonates are reported. Key words: sodium hydride reductions, sulfenes, sulfone-sulfonate esters

AM1 and 3–21G computations, on the lowest singlet state of selected π-ylides, support the earlier conclusion that π-ylides are highly polar with highly reactive side-chains. The computations also indicate that the corresponding triplet states are lower in energy and have substantially reduced polarity. Contrary to the expectations derived from Huckel calculations, AM1 and 3–21G calculations suggest that the best π-ylide structures have non-aromatic rings. The heats of isomerization contradict earlier conclusions reached using topological resonance energies. π-Ylides are expected to afford different product structures depending on the electronic state of the π-ylide involved in a given cycloaddition reaction.

An attempt to explore aromatic sulfonate esters as agents for the condensation of alcohols with mercaptans revealed an unusual process for sulfonate esters: CS bond rupture. Two mechanistic possibilities for CS bond rupture are explored: (i) radical anion intermediacy via single electron transfer and (ii) nucleophilic aromatic substitution. Both experiments and molecular orbital computations are presented to support the conclusion that nucleophilic aromatic substitutions are occurring. Keywords: sulfonyl esters, nitrobenzenesulfonates, CS bond rupture.

An MNDO study has been carried out on a variety of S-substituted carbon radicals. Computations using the half-electron approximation and unrestricted Hartree-Fock (UHF) computations were done on each radical studied. The half-electron approximation gives unacceptable results for phenyl-substituted radicals. UHF computations do not give pure doublets for phenyl- or vinyl-substituted radicals. Relative gas-phase stabilities have been calculated for a selection of regioisomeric S-substituted carbon radicals. Results indicate that substituent stabilization in the radicals is generally smaller than in thionium ions previously reported.

BACKGROUND: Previous studies [Transfusion 2005;45:384] showed that certain chemical compounds containing sulfur-reactive groups can inhibit Fcγ receptor (FcγR)-mediated phagocytosis in vitro. These studies, however, did not prove that only sulfur functionality–induced reactivity was efficacious. In an effort to develop a drug-based approach for the future treatment of immune-mediated cytopenias, these earlier findings have now been extended and this chemically induced interference with FcγR-mediated phagocytosis of anti-D-coated red cells (RBCs) was examined to assess the optimal structural requirements for the inhibitory effect. STUDY DESIGN AND METHODS: Chemical compounds were purchased or synthesized and used for the assessment of which chemical moiety(-ies) were required for successful inhibition of in vitro phagocytosis of anti-D-coated RBCs with a monocyte monolayer assay. RESULTS: Using compounds having similar structures but differences in reactive moieties, it was proved that the only chemical moiety that was required for inhibition of FcγR-mediated phagocytosis in vitro was a disulfide bond. It is also shown, however, that a p-nitrophenyl group provides significant enhancement to the inhibitory effect of disulfide-containing compounds. Involvement of carbonyl and hydroxyl functional groups was also able to be ruled out. CONCLUSION: Our results confirm and extend previous studies that suggested that only those compounds that target free sulfhydryl groups on the monocyte-macrophage are most effective at blocking phagocytosis of antibody-coated RBCs in vitro. It is also shown that p-nitrophenyl substituent groups have an enhancing effect on the efficacy of disulfide bond-containing compounds. These findings should aid in the design of a drug-based approach for the future treatment of immune cytopenias.

BACKGROUND: Patients having immune cytopenias produce antibodies that target hematopoietic cells resulting in their phagocytosis and intracellular destruction. Early reports suggested that phagocytosis could be inhibited by interfering with membrane thiol (SH) groups on phagocytes. Thus, whether chemical compounds that interact with SH or disulfide (SS) groups on mononuclear phagocytes can inhibit phagocytosis of antibody-coated cells was examined. STUDY DESIGN AND METHODS: A monocyte monolayer assay (MMA), which examines the in vitro monocyte-macrophage (Mφ) interaction with anti-Rh(D)-coated red cells (RBCs), was used to study the ability of different SH and SS chemicals to inhibit the Fc receptor–mediated phagocytosis of sensitized RBCs. The compounds examined included thimerosal, dithiothreitol (DTT), pentane-1-thiol, and two recently described SH and two SS chemicals that have been synthesized. RESULTS: All compounds were found to be able to inhibit phagocytosis to varying degrees correlating to the structure of the molecule. In general, those compounds that interact with free SH groups to inhibit phagocytosis were found better than SH-containing compounds that interact with SSs. Thimerosal and p-nitrophenyl methyl disulfide were the most effective compounds inhibiting phagocytosis. Both chemicals showed greater than 50 percent inhibition at concentrations as low as 10−9 mol per L. DTT was the least effective compound tested. Only thimerosal showed significant toxicity, as determined by decreased cell viability and increased apoptosis, but only at concentrations of 10−8 mol per L. The effect of chemical treatment was on attachment rather than on phagocytosis itself. Fcγ receptor–independent endocytosis was not affected by the chemical treatment. CONCLUSION: These studies indicate that pharmacologic strategies that target SH groups on mononuclear phagocytes may have future efficacy for the treatment of immune cytopenias.

Several sulfur-containing compounds, isolated from garlic, have been implicated as highly active antithrombotic agents. We have prepared 10 new aromatic disulfides and an aromatic thiosulfonate in order to determine the in vitro response of human platelets to dosages of these compounds. The poor biological activity of PhSSCH3 was enhanced by the introduction of, inter alia, a nitro group onto the aromatic ring. The nitro group increased potency by activating the disulfide linkage. Anti-platelet aggregation activity was also enhanced by increasing the lipophilicity of one test compound. The ability of an aromatic disulfide to inhibit platelet aggregation can be enhanced by appending an electron-withdrawing group to the aromatic ring. The results presented establish that the aromatic thiosulfonate is a very effective inhibitor of platelet aggregation.