Copyright © 1996, 1997, 2000, 2001 by Galen Daryl Knight and VitaleTherapeutics, Inc.


Even though melting points and elemental analyses have not been provided for comparison, mass spectrometry, NMR, and IR data, alone, make it doubtful that sulfonates are generated in any appreciable quantities when the exemplary procedures are followed. At the same time, under slightly more oxidizing conditions than in the published procedures, a cyclic dimer of the sulfinate, differing from authentic sulfenate-linked "benzyl derivative" by only one additional "oxi"dation on each sulfur, seems possible. Assuming that the intramolecular nucleophilic requirement is fulfilled by contaminating amines or other solvated nucleophiles in other's "attempts" to synthesize authentic vitaletheine modulators, this would be consistent with i) observations of sultine formation in aqueous iodine solutions catalyzed by intramolecular nucleophiles, ii) with a peak in electrospray mass spectrometry at 755.89 obtained by others, and iii) with differences noted between the IR spectra of authentic vitaletheine modulators and those of the alleged sulfonates, CBZ-ß-alanyl-taurine and ß-alanyl-taurine, produced using modifications of other procedures. The IR spectra of the comparable sulfonate differs from IR spectra of authentic vitaletheine V4 in a fashion similar to the differences noted between the CBZ-ß-alanyl-taurine and authentic, sulfenate-linked benzyl derivative, i.e., there are more strong peaks in the S<=>O region of the spectra for the alleged sulfonates than there are C<->O peaks in the spectra of authentic vitaletheine V4 or in the sulfenate-linked benzyl derivative. Although not the only explanations for the observed differences between these two sets of data, these observations are somewhat theoretically consistent with overt (artifactual?) oxidation of the authentic benzyl derivative and vitaletheine V4 to the higher oxidation states when the synthetic protocols were modified in favor of more oxidizing conditions by others.

Although modifications to the exemplary synthetic protocols help to demonstrate the versatility of the published procedures in making a variety of compounds of the vitaletheine modulator family, there appears to be little genuine evidence that sulfonates are normally produced. One possible explanation for difficulties encountered by some in synthesizing the vitaletheine modulators is that halines previously have been observed to react with amines to form haloamines. This artifactual functional group may interfere with efforts to synthesize and maintain the free carbonimidate and carbamate tautomers of vitalethine and vitaletheine V4. For example, after exposure of the hydrogen bromide salts to DMSO and the subsequent formation of bromoamines, passage through the ion exchange (DEAE) column again would not be expected to remove catalytic amounts of bromine covalently-linked to the nitrogen of ß-alethine, and this bromine contamination can prevent or reverse phosgenation to vitalethine or vitaletheine V4. There appears to be little to no evidence for artifactual bromination of amines when the published and exemplary procedures are followed.

Thus, contamination of reaction mixtures with halides may help to explain why others believe the vitaletheine modulators are sulfonates. Iodine monobromides and presumably other mixed halines are excluded from appropriate steps in the exemplary procedures by chromatographically removing all bromide ions before continuing with the synthesis of the vitaletheine modulator. Unintentional contamination with halines can take place even if the reagents are pristine. For example, reaction products dried in the same desiccator with bromine-contaminated materials or hydrogen bromides containing residual DMSO could be exposed to volatile chlorines, bromines, iodines, and/or hydrogen halides. It is noteworthy that one of the masses evident in the spectrum of an alleged preparation of the benzyl derivative from one company appears to coincide with the mass expected for a bromo- derivative of vitaletheine V4, even though this material should never have been exposed to bromine and should not have rearranged to the proliferative agent, vitaletheine V4, under exemplary conditions. Under the circumstances, this company's claims that they have produced the benzyl derivative and vitaletheine V4 seem unjustified, since the procedures they used admittedly depart from the published ones and since the sulfonate structures assigned by them are inconsistent with the established chemical characteristics of the authentic compounds and with their own data. As noted above, even with departures from the exemplary procedures, their existing evidence indicates that oxidation probably does not exceed the level of sulfinic oxidation even when there is contamination with bromide, making their claims that the exemplary vitaletheine modulators are sulfonates unwarranted.

A problem similar to this one of "bromo" amines, encountered with "iodo"amine formation in reactions studying the iodination of tyrosyl peptides with a sulfenyl iodide and iodine generating systems, was overcome by reducing the non-specifically iodinated amines with bisulfite. Consistent with known reactions of sulfenyl iodides, amines uncouple this iodinating process presumably by reacting with sulfenyl iodides to form sulfenamides and iodide, the latter of which does not iodinate tyrosyl residues until reoxidized back to iodine or the sulfenyl iodide. This work will be published soon on VitaleTherapeutics' web site.

With the complexity of the chemical and biological considerations that are evolving, the controversy over the structures is not surprising, but it is not warranted. Two other companies (one chemical and one pharmaceutical) have admitted to exposing the zinc salts of the benzyl derivative and vitaletheine V4 to greatly reduced pressures for extended periods of time, conditions that may contribute to their dehydration, decarboxylation, and other rearrangements and decompositions. Others report relatively few problems with the syntheses. For example, a direct quote from received e-mail is "Regarding the benzyl derivative (benzyl carbamate) of vitalethine, a compound which in my opinion is easy to synthesize, our stock material is intended solely for laboratory use and must not be used for human." This message was sent in response to a query on behalf of a doctor in England who wanted to know the status of these therapies for treating dying human patients. Compound could not legally be supplied for these purposes under current FDA regulations.


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