- Effects of aromatic thiols on thiol-disulfide interchange reactions that occur during protein folding
The folding of disulfide containing proteins from denatured protein to native protein involves numerous thiol-disulfide interchange reactions. Many of these reactions include a redox buffer, which is a mixture of a thiol (RSH) and the corresponding disulfide (RSSR). The relationship between the structure of RSH and its efficacy in folding proteins in vitro has been investigated only to a limited extent. Reported herein are the effects of aliphatic and especially aromatic thiols on reactions that occur during protein folding. Aromatic thiols may be particularly efficacious as their thiol pKa values and reactivities match those of the in vivo catalyst, protein disulfide isomerase (PDI). This investigation correlates the thiol pKa values of aromatic thiols with their reactivities toward small molecule disulfides and the protein insulin. The thiol pKa values of nine para-substituted aromatic thiols were measured; a Hammett plot constructed using σp- values yielded ρ = -1.6 ± 0.1. The reactivities of aromatic and aliphatic thiols with 2-pyridyldithioethanol (2-PDE), a small molecule disulfide, were determined. A plot of reactivity versus pKa of the aromatic thiols had a slope (β) of 0.9. The ability of these thiols to reduce (unfold) the protein insulin correlates strongly with their ability to reduce 2-PDE. Since the reduction of protein disulfides occurs during protein folding to remove mismatched disulfides, aromatic thiols with high pKa values are expected to increase the rate not only of protein unfolding but protein folding as well.
- DeCollo,Lees
p. 4244 - 4249
(2007/10/03)
- DNA-Directed Alkylating Agents. 3. Structure-Activity Relationships for Acridine-Linked Aniline Mustards: Consequences of Varying the Length of the Linker Chain
Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability.The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons.Relationships were sought between chain length and biological properties.Within eachseries, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue.The in vivo antitumor activities of the compounds dependend to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive.However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not.Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation.
- Valu, Kisione K.,Gourdie, Trudi A.,Boritzki, Theodore J.,Gravatt, G. Lance,Baguley, Bruce C.,et al.
p. 3014 - 3019
(2007/10/02)