Richard Francis Langler

Chemical compounds that target thiol-disulfide groups on mononuclear phagocytes inhibit immune mediated phagocytosis of red blood cells

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.

Improving upon the in vitro biological activity of antithrombotic disulfides.

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.

New and More Potent Antifungal Disulfides

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.

Novel disulfides as anticancer/antimalarial agents

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 compounds had little or no antimalarial/anticancer activity while others were highly active with IC50 values in the low µM range. Three disulfides (3, 7, 9) show encouraging activity, viz: low activity against CHO (representative mammalian) cells and significantly higher activity against human malaria (Plasmodium falciparum) cells and human skin cancer (C32) cells.

Structure‐function studies for in vitro chemical inhibition of Fcγ receptor–mediated phagocytosis

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.

Ether Aryl Sulfonic Acid Esters with Improved Antimalarial/Anticancer Activities

Our previous report showed that our current benchmark agent, 4-methoxyphenyl p-toluenesulfonate, is a selective antimalarial/anticancer agent. A series of related sulfones and sulfonic acid esters is now examined. 4-Allyloxyphenyl p-toluenesulfonate is a superior antimalarial/anticancer agent. 4-Methoxyphenyl 4-nitrobenzenesulfonate is a superior antimalarial agent, but shows poorer inhibition of human skin cancer cells.

Optimizing disulfide fungitoxicity: Adjustment of hydrocarbon chain length

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.

Ionic Reactions of Sulfonic Acid Esters

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

The S2 oxygen atoms are essential for the pronounced fungitoxicity of the sulfur-rich natural product, dysoxysulfone

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.

Selected Sulfonyl Compounds as Anticancer/Antimalarial Agents

The synthesis and biological testing of a series of sulfonyl phenols and sulfonyl aryl methyl ethers has revealed that p-methoxyphenyl p-toluenesulfonate is a very selective and effective antimalarial agent which shows pronounced activity against human skin cancer cells. Application of a counter-attack strategy permits the direct preparation of the requisite tosylate ether from the bis(tosylate) of dihydroquinone.