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The synthesis and biological evaluation of novel sulfonate analogues of E-7010 are reported. Several of the compounds are potent inhibitors of cell proliferation and tubulin polymerization. Importantly, these compounds are also active against P-glycoprotein positive (+) cancer cells, which are resistant to many other antitumor agents.
alpha,beta-Unsaturated sulfones have been discovered from a combinatorial library as leads for a new series of inhibitors of inducible VCAM-1 expression. Although not essential, further conjugation of the sulfonyl group to another vinyl group or a phenyl group increases the potency dramatically.
The soluble polymer polyethylene glycol containing a traceless aryl alkyl sulfone linker was found to be resistant to reductive cleavage with sodium amalgam (Na/Hg). Detailed investigations revealed that the solvent plays an important role in the desulfonylation reaction; subsequently it was determined that MeOH/DMF (1/8) is an ideal solvent system for the cleavage of this traceless linker.
Protein tyrosine phosphatase inactivators are of interest as research tools and as therapeutic agents. In this study, the effect of sulfone analogue of naphthoquinone on the activities of PTP1B and other PTPs was examined. The results indicated that this compound selectively and irreversibly inactivated the PTP1B with the dissociation constant Ki of 3.5 microM and the inactivation rate constant kinact of 2.2 x 10(-2) sec-1.
A stable sulfone derivative of 2,4,6-trimethylcyclohexa-2,4-diene-1-one (7) undergoes facile ring cleavage under visible light to produce a ketene intermediate, which could be efficiently captured by amines to give amides even in the presence of competing nucleophiles such as water and ethanol.
Penicillin sulfones, which structurally incorporate both a 6-position alkylidene substituent and a 2'beta substituent, have been synthesized and evaluated as inhibitors of class C and class A serine beta-lactamases. Incorporation of the 2'beta-substituent generally improves inhibitory activity. Substituents that improve transport across the bacterial cell membrane have also been incorporated.
Three pyrrolyl heteroaryl sulfones (ethyl 1-[(1H-benzimidazol-2(3H)one-5-yl)sulfonyl]-1H-pyrrole-2-carboxyla te, ethyl 1-[(1H-benzimidazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate and ethyl 1-[(1H-benzotriazol-5(6)-yl)sulfonyl]-1H-pyrrole-2-carboxylate) were designed as novel HIV-1 reverse transcriptase non-nucleoside inhibitors using structure-based computational methods. Although these compounds were inactive in the cell-based assay, they inhibited the target enzyme with micromolar potency (IC50s = 2 microM, 3 microM and 9 microM, respectively).
A series of 1,3-dioxolane-based ligands, bearing ether, thioether and related sulfoxide and sulfone functionalities, were synthesised and tested as potential muscarinic antagonists. The compounds display moderate to low affinity for the three receptor subtypes M1-M3, with some of them showing a significant selectivity for the M1-M3 over the M2 subtype.
The peculiarities of molecular structures and the influence of reaction conditions on the folding efficiency of fusion proteins-biotechnological precursors of human insulin, expressed in Escherichia coli as inclusion bodies have been investigated. The fusion proteins contained proinsulin sequence with various leader peptides connected by an Arg residue to the insulin B-chain. The kind and the size of leader peptide do not have essential influence on folding efficiency. However, the efficiency of protein folding depends on the location of the (His)6 site, which is used for metal-chelating affinity chromatography. In our study the protein folding depends on the reaction medium composition (including additives), the presence of accompanied cell components, pH, temperature, concentrations of protein, and redox agents. A negative influence of nucleic acid and heavy metal ions on folding has been found. S-sulfonated fusion protein has proinsulin-like secondary structure (by CD-spectroscopy data) that is the key point for 95% efficient folding proceeding. Folded fusion proteins are transformed into insulin by enzymatic cleavage.
Recent studies have shown that mutations in two amino acid positions of the Pneumocystis carinii dihydropteroate synthase gene are significantly more common in immunocompromised patients with P. carinii pneumonia who fail sulfa or sulfone prophylaxis. This paper reviews the studies that suggest that these mutations may be responsible for some failures of prophylaxis in P. carinii.
Divinyl sulfone reacts at pH 8-9 with the alpha-amino groups of N-terminal residues, proline, the epsilon-amino groups of lysine, and the histidine side chains of peptides. This reaction leads to great enhancement of the abundance of the normally weak or missing "a(1)" fragment ion in MS/MS analysis defining the N-terminal residue of a peptide in a digest. This provides "one-step Edman-like" information that, together with a fairly accurately determined mass, often enables one to correctly identify a protein or family of proteins. The applicability of this procedure in proteomics was demonstrated with several peptides and tryptic digests of protein mixtures by LC-MS/MS experiments using a QTOF and MALDI-PSD analyses. Advantages of this approach are its simple chemistry, retention of charge multiplicity, and possibly, shortening of database search time. Used with other MS/MS data, it provides higher confidence in the scores and identification of a protein found in peptide mass fingerprinting. Moreover, this approach has an advantage in "de novo" sequencing due to its ability to decipher the first amino acid of a peptide whose information is normally unavailable in MS/MS spectra.
We have synthesized a bifunctional vinyl sulfone-cysteineamido derivative of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) that can be conjugated to the sulfhydryls of mildly reduced recombinant antibody (chimeric anti-CEA antibody cT84.66) at pH 7 or to the amino groups of lysine residues at pH 9. The conjugation is sulfhydryl specific at pH 7 (case 1), and amino specific at pH 9 (case 2) as long as the antibody has no free sulhydryl groups. At a molar ratio of 50 BCA (bifunctional chelating agent) to mAb, the number of chelates conjugated is 0.8 for case 1, and 4.6 for case 2. The resulting conjugates can be radiolabeled with (111)In to high specific activity (5 mCi/mg) with high efficiency (>95%) at 43 degrees C in 60 min. The radiolabeled conjugates retained >95% immunoreactivity and are stable in serum containing 1mM DTPA over 3 d. When the radiolabeled conjugates were injected into nude mice bearing LS174T human colon tumor xenografts, over 40% ID/g accumulated in tumors during the period 24-72h. Tumor-to-blood ratios were 4.5, 3.5, and 2.5 for the sulfhydryl coupled conjugate at 24, 48, and 72 h, respectively, and 2.7, 2.5, and 2.3 for the amino-coupled conjugate at the same time points. For other organs the biodistributions were nearly identical whether the conjugates were attached via sulfhydryl or amino groups. These novel BCAs are easy to synthesize, offer versatile conjugation options, and give equivalent biodistributions that result in high tumor uptake and good tumor-to-blood ratios.
Two species resulting from the reaction of the SHV-1 class A beta-lactamase with the sulfone inhibitor tazobactam have been trapped at 100 K and mapped by X-ray crystallography at 2.0 A resolution. An acyclic form of tazobactam is covalently bonded to the catalytic Ser70 side chain, and a second species, a five-atom vinyl carboxylic acid fragment of tazobactam, is bonded to Ser130. It is proposed that the electron density map of the crystal is a composite picture of two complexes, each with only a single bound species. It is estimated that the two complexes exist in the crystal in approximately equal populations. Results are discussed in relation to the mechanism-based inhibition of class A beta-lactamases by the similar inhibitors sulbactam and clavulanic acid.
Our previous studies (Pattison, S. E., and Dunn, M. F. (1975), Biochemistry 14, 2733) have shown that the reaction of divalent metal ion chelators with the 140 000 mol wt mouse submaxillary nerve growth factor protein (7S NGF) activates the iota-subunit esteropeptidase activity ca. sevenfold. Ultraviolet-visible spectral studies with the chelator 2,2',2''-terpyridine (terpyridine) and fluorescence emission studies with 8-hydroxyquinoline-5-sulfonic acid (HQSA) in combination with both conventional and rapid-mixing stopped-flow kinetic techniques have been employed in the present study to investigate (a) the mechanism of the chelator-induced activation process, and (b) the identity of the divalent metal ion involved. The spectral studies confirm the presence of stoichiometrically significant amounts of tightly bound zinc ion in native 7S NGF (1-2 g-atoms of An2+/mol of 7S NGF). The kinetic studies show that the reaction of terpyridine with 7S NGF occurs via a two-step process involving first a rapid, apparent second-order step (k1 = 1 x 10(6) M-1 s-1) to form a 7S NGF-Zn2+-chelator monocomplex, then a slow step to form a bis(terpyridine)-Zn(II) complex and activated 7S NGF in an apparent first-order process (kobsd = 0.10 min-1). This rate is, within experimental error, identical with the apparent first-order rate constant for the chelator-induced activation process (monitored by the rate of change in the steady-state rate of hydrolysis of chromophoric substrate, alpha-N-benzoyl-D,L-arginine-p-nitroanilide). Kinetic studies of the reaction of HQSA with native 7S NGF show that, under the same conditions of concentration, the rate of formation of the tris(HQSA)-Zn(II) complex is identical with the rate of the HQSA-induced activation of the 7S NGF esteropeptidase. Thus, these studies unambiguously establish that zinc ion is the metal ion involved in the chelator-induced activation process, and that activation involves removal of zinc ion from native 7S NGF.
The EPXH2 gene encodes for the soluble epoxide hydrolase (sEH), a homodimeric enzyme with each monomer containing two domains with distinct activities. The C-terminal domain, containing the epoxide hydrolase activity (Cterm-EH), is involved in the metabolism of arachidonic acid epoxides, endogenous chemical mediators that play important roles in blood pressure regulation, cell growth, and inflammation. We recently demonstrated that the N-terminal domain contains a Mg2+-dependent lipid phosphate phosphatase activity (Nterm-phos). However, the biological role of this activity is unknown. The inability of known phosphatase inhibitors to inhibit the Nterm-phos constitutes a significant barrier to the elucidation of its function. We describe herein sulfate, sulfonate, and phosphonate lipids as novel potent inhibitors of Nterm-phos. These compounds are allosteric competitive inhibitors with K(I) in the hundred nanomolar range. These inhibitors may provide a valuable tool to investigate the biological role of the Nterm-phos. We found that polyisoprenyl phosphates are substrates of Nterm-phos, suggesting a possible role in sterol synthesis or inflammation. Furthermore, some of these compounds inhibit the C-terminal sEH activity through a noncompetitive inhibition mechanism involving a new binding site on the C-terminal domain. This novel site may play a role in the natural in vivo regulation of epoxide hydrolysis by sEH.
The catalytic portion of the chloroplast ATP synthase (CF1) is structurally asymmetric. Asymmetry of the otherwise symmetrical alpha3beta3 heterohexamer is induced by the presence of tightly bound nucleotides and interactions with the single-copy, smaller subunits. Lucifer Yellow vinyl sulfone (4-amino-N-[3-(vinylsulfonyl)phenyl]naphthalimide-3,6-disulfonic acid) rapidly and covalently binds to lysine 378 on one alpha subunit [Nalin, C. M., Snyder, B., and McCarty, R. E., (1985) Biochemistry 24, 2318-2324] [Shapiro, A. B. (1991) Ph.D. Thesis, Cornell University, Ithaca, NY). The asymmetrical binding of Lucifer Yellow to CF1 provides a method to investigate the cause of asymmetry in the alpha subunits. The reaction of CF1 with Lucifer Yellow was monitored by total fluorescence of bound Lucifer Yellow as well as by quantitative determination of Lucifer Yellow bound to the tryptic peptide that contains lysine 378 of the alpha subunit. The total binding of Lucifer Yellow to CF1 was not affected by the presence of tightly bound nucleotides or nucleotide in the medium. Neither the total binding of Lucifer Yellow to CF1 nor the reaction of alpha-lysine 378 with Lucifer Yellow was changed by the removal of the epsilon subunit, the delta subunit, or both subunits. The extent of incorporation of Lucifer Yellow into lysine 378 of the alpha subunit in (alphabeta)n was about three times that of Lucifer Yellow incorporation into CF1. Reconstitution of (alphabeta)n with gamma restored the binding of one Lucifer Yellow per alpha3beta3gamma. Therefore, the interactions between gamma and the alphabeta heterohexamer are important in conferring asymmetry to the alpha subunits of CF1.
The catalytic portion of the chloroplast ATP synthase (CF(1)) consists of five different polypeptides in the stoichiometry alpha(3)beta(3)gammadeltaepsilon and is structurally asymmetric. Asymmetry is readily apparent in the properties of the six nucleotide binding sites and the single-copy, smaller subunits. Asymmetry is also detected in the alpha subunits by the rapid and covalent binding of Lucifer Yellow vinyl sulfone (LY) to one of the three chemically identical alpha subunits. The binding of LY to a single alpha subunit has allowed the investigation of whether asymmetry in the alpha subunits is a permanent feature of CF(1). The development of an electrochemical proton gradient across illuminated thylakoid membranes and the preincubation of CF(1) in solution with Mg(2+)-ATP were found to alter the LY distribution such that multiple alpha subunits were labeled with LY. Illumination of thylakoid membranes doubled the extent of LY labeling, and fluorescence resonance energy transfer measurements indicated that LY was bound to more than one alpha subunit. Since the change in LY distribution was inhibited by proton ionophores (uncouplers), alteration of alpha conformation by illumination is a result of the generation of a proton gradient. Preincubation of CF(1) in solution with Mg(2+)-ATP had no effect on the extent of LY labeling but resulted in multiple alpha subunits binding LY as determined by fluorescence resonance energy transfer measurements. Adenine nucleotides at substrate level concentrations inhibit the reaction of LY with the alpha subunits. No increase in LY labeling was observed when thylakoids were illuminated under conditions in which CF(1) was catalytically active.
The aim of this work is to obtain a chemically cross-linked hydrogel from hyaluronic acid and cellulose derivatives that exhibits sensitivity to variation of the composition of the external absorbing medium and an equilibrium sorption capacity higher than a common hyaluronic acid-based hydrogel, in view of its potential use in prevention of postsurgical soft tissue adhesion. This has been achieved by chemical stabilization of hyaluronic acid (HA) and cellulose derivatives, hydroxyethylcellulose (HEC) and carboxymethylcellulose (CMCNa) through the difunctional cross-linker divinyl sulfone. Significant increase in sorption capacity, both in water and in water solutions at different ionic strength, has been observed for these samples in comparison with hydrogels obtained through chemical stabilization of hyaluronic acid. Moreover, different dehydration procedures adopted for the xerogel synthesis have been used, which resulted in a modulation of the equilibrium sorption capacity. Hyaluronic acid stability has been confirmed by means of NMR analysis.