98184-57-7Relevant academic research and scientific papers
Nucleoside analogs. 14. The synthesis and antitumor activity in mice of molecular combinations of 5-fluorouracil and N-(2-chloroethyl)-N-nitrosourea moieties separated by a three-carbon chain
McElhinney, R. Stanley,McCormick, Joan E.,Bibby, Mike C.,Double, John A.,Radacic, Marco,Dumont, Patrick
, p. 1408 - 1412 (2007/10/03)
5-Fluorouracil (5-FU) seco-nucleosides having as the "sugar" moiety a two-carbon (C2) side chain carrying a N-(2-chloroethyl)-N-nitrosourea group were designed as molecular combinations of antimetabolite and alkylating agent, but hydrolytic release of free 5-FU was not fast enough for significant contribution to the high activity they showed against colon and breast tumors in mice. In the present study of the synthesis of the more reactive C3 seco-nucleosides, it emerged that, of various groups attached to the aldehydic center in the precursor phthalimides, only the alkoxy/uracil-1-yl type was conveniently obtained by the standard method. The methylthio/uracil-1-yl analog required relatively large amounts of reagent methanethiol, and exploration of alternatives involving α-chlorination of alkyl methyl sulfide or Pummerer rearrangement of its S-oxide, or successive hydrolysis and methylation of isothiouronium bromide, gave disappointing yields. For successful preparation of the alkoxy/ uracil-3-yl compounds, the route used for C2 homologs required considerable experimental modification. In addition to these O,N- and S,N-acetals, some N,N-acetals bearing two 5-FU residues were prepared. The new drugs have been tested against a panel of experimental tumors in mice. Although it is evident from a parallel study that even these C8 seco-nucleosides release free 5-FU too slowly in vivo, several of them have shown impressive anticancer activity. Reviewing their performance in comparison with earlier molecular combinations, a short list of seven [B.4152 (6), B.4015 (5), B.4030 (10), B.3999 (4), B.3995 (2), B.4083 (3), and B.3996 (the N3-substituted analog of 1)] should be investigated further. This is particularly appropriate in light of the present understanding of the mode of action of chloroethylating agents. Following a prolonged period of clinical impatience with nitrosoureas because of limited selectivity of action, a new era is confidently anticipated as these powerful drugs are increasingly studied in combination with O6-benzylguanine and other more efficient inhibitors of repair enzymes like O6-alkylguanine-DNA-alkyltransferase now being developed.
Synthesis of novel analogs of acetyl coenzyme A: Mimics of enzyme reaction intermediates
Martin, David P.,Bibart, Richard T.,Drueckhammer, Dale G.
, p. 4660 - 4668 (2007/10/02)
An improved method for the synthesis of analogs of coenzyme A (CoA) and its thioesters, which are modified in the thiol or thioester moiety, has been developed using a combination of chemical and enzymatic reactions. The enzymes catalyzing the last two steps of CoA biosynthesis were used to prepare a CoA analog (Ic) in which an amide bond is replaced by a thioester bond and the thiol group is replaced by a methyl group. Reaction of Ic with a primary amine in aqueous solution results in aminolysis of the thioester linkage to form the desired CoA analog. Reaction with different amines permits the introduction of a variety of functional groups in place of the normal thiol or thioester group. This methodology has been used in the synthesis of five new analogs of acetyl-CoA in which the thioester sulfur is replaced by a methylene group and the acetyl group is replaced by carboxylate (14a), nitro (14b), carboxamide (14c), methyl sulfoxide (14d), and methyl sulfone (14e) groups. 14a-c were designed to mimic the possible enolate or enol intermediate in the reaction of citrate synthase and related enzymes. 14a and 14c are potent inhibitors of citrate synthase, with K(i) values 1000- and 570-fold lower than the K(m) for acetyl-CoA, respectively. CD titrations indicate that 14a and 14c have low affinity for citrate synthase in the absence of oxaloacetate, consistent with their recognition as enol or enolate analogs. 14b is a poor inhibitor of citrate synthase, with affinity slightly lower than that for acetyl-CoA. These results are consistent with generation of the enol form of acetyl-CoA as the nucleophilic intermediate in the reaction of citrate synthase. 14d and 14e were designed to mimic the tetrahedral intermediate or transition state in the reaction of chloramphenicol acetyltransferase and related acetyl-CoA-dependent acetyltransferases. Both compounds are poor inhibitors of chloramphenicol acetyltransferase, with affinities slightly lower than that of acetyl-CoA, indicating that these compounds are not good mimics of the enzyme-bound tetrahedral intermediate or transition state.
Photochemistry of N-phthaloyl derivatives of methionine
Griesbeck, Axel G.,Mauder, Harald,Mueller, Ingrid,Peters, Eva-Maria,Peters, Karl,Von Schnering, Hans Georg
, p. 453 - 456 (2007/10/02)
Photocarboxylation of N-phthaloyl derivatives of methionine sulfoxide 1b and methionine sulfone 1c was observed in acetone as the major reaction. For 1a a fast electron transfer initiated cyclization which leads to the bicyclization product 3 (X-ray structure)was observed in the sensitized photolysis. Direct photolysis of 1a leads preferentially to the tricylic product 4 and the decarboxylation product 5. The methionine methyl ester 6a-c showed electon transfer initiated cyclization (for 6a) and disproportionation (for 6b), whereas 6c proved to be photostable.
Photochemistry of the Phthalimide System, 37. - Thiazacycloalkanols by Photocyclization of S-Substituted N-(Thioalkyl)phthalimides
Sato, Yasuhiko,Nakai, Hideo,Wada, Masao,Mizoguchi, Tomishige,Hatanaka, Yasumaru,et al.
, p. 1099 - 1118 (2007/10/02)
N-Substituted phthalimides (1,2) possessing a terminal thioether function in their side chain were irradiated with a high-pressure mercury lamp to give a variety of thiazacycloalkanol derivatives (3,7,9-13,16,17) with favored γ-, δ-, ε-, and ζ-hydrogen abstractions (Table 1), in moderate to fairly good yields.
