An intraperitoneal (IP) monotherapy in nu/nu mice with subcutaneous xenografts of a human prostate epithelial cancer cell line:DU145 was undertaken with an aldehyde dehydrogenase 3 inhibitor MATE, that is a potent apoptogen on (DU145) in culture but not on their human prostate epithelial normal counterparts [13] . Tumour growth was slowed down but treatment had to be done 5days/week. To try to potentiate the action of MATE in vivo, a bitherapy was undertaken based on the synergetic apoptotic effect that had been observed previously in culture on DU145 treated with a methional mimic METLICO and DIMATE, an inhibitor of ALDH1 and ALDH3 [19]. The bitherapy with METLICO/MATE administered IP was as effective as the monotherapy with MATE alone by IP, but at a 2-fold lower dose of MATE and at a dose of METLICO that had no growth-inhibitory effect as a monotherapy . Hence there was definite synergism with bitherapy. To try to increase the efficacy of bitherapy, it was administered by the intra-tumoral (IT) route using the recently developed 20-bars-pressurized microinjection system from CERMA [16, 17]. IT administration of the bitherapy was indeed more effective than that by IP as regards tumour volumes are concerned. Histopathological analysis of IT-treated tumours confirmed that there were many necrotized zones but intact cells were still present. Approaches for treating a wider zone of tumour tissue by IT-bitherapy are discussed.

6S,8S-Bis(3-methylthiopropanoyl) thiolesters of lipoic acid were synthesized with the carboxyl moiety of lipoate modified as methyl or water soluble choline esters. Evaluation on different cell lines in culture showed that they possessed modest antiproliferative activity. However, the 6-fold decrease in IC50 (from 270 to 45 microM) observed with the water soluble 6S,8S-bis(3-methylthiopropenoyl) thiolester dehydro derivative on a human epithelial prostate cancer cell line (DU145) argues in favor of 3-methylthiopropanoyl metabolites as endogenous growth regulatory (apoptogenic) compounds derived from methionine.

4-Amino-4-methyl-pent-2-ynthioc acid S-methyl ester (ampal thiolester: ATE) was used as a lead compound to synthesise new amino-substituted derivatives of alpha, beta acetylenic thiolester compounds as inhibitors of aldehyde dehydrogenase 1, (ALDH1). Of these compounds, the dimethyl derivative (DIMATE) was a competitive irreversible inhibitor (K(i) approximately 280 microM) of baker's yeast ALDH1 in vitro showing 80% inhibition at 400 microM when preincubated with the enzyme for 30min, whereas the trimethyl ammonium and the morpholine derivatives showed only 15% inhibition at 600 microM even after 60min preincubation. ATE inhibited ALDH1 activity in ALDH1-transfected L1210 T cells resistant to hydroperoxycyclophosphamide (HCPA) and inhibited growth synergistically in the presence of HCPA. In non-transfected L1210 counterparts ATE did not potentiate growth inhibition by HCPA. DIMATE was a 30-100-fold more effective growth inhibitor than ATE. Endogenous ALDH1 activities of BAF(3) cells over-expressing different levels of bcl(2) (0-100%) were similar (16-20mU/mg protein) and were all inhibited by DIMATE, reaching 20-30% at 4 microM. Up to 4 microM no apoptosis, as measured by DNA-fragmentation was observed, but at 8 and 10 microM DIMATE, DNA-fragmentation increased concomitantly with ALDH1 inhibition. No DNA-fragmentation was observed with ALDH1 irreversible inhibitors devoid of a thiolester group or with thiolesters which were not inhibitors of ALDH1. It was seen only with competitive irreversible inhibitors having the methanethiol and enzyme-inhibitory moieties. The methanethiol putatively released from DIMATE by ALDH1 esterase activity plays a role, albeit undefined, in lowering intramitochondrial glutathione levels which decreased by 47% as DNA-fragmentation increased.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

We have previously shown that methional, CH3SCH2CH2CHO, an endogeneous cellular aldehyderived by the oxidative decarboxylation of 4-methylthio-2-oxobutanoic acid (B), an intermediate in the methionine salvage pathway is a potent inducer of apoptosis when added to cultures of mouse lymphoid cells BAF3 bo (Quash et al., 1995). MTOB a00 μM was also capable of alleviating the methionine dependence shown by transfed cells (Ogier et al., 1993) because of its ready transamination to methionine, with gamine as amine donor (Backlund et al., 1982). Further, the inhibition of this MTOB transaminase with novel transition state inhibitors such as methionine-ethyl ester- pyridoxal induced apoptosis in BAF3 bo cells but not in BAF3 bcl2 which had been trans- fected with the human bcl2 gene (Roch et al., 1996). When the reasons for this refractory behaviour of BAF3 bcl2 were investigated using[14C] MTOB it was found that the production of [14methional from [14C] MTOB was reduced by 50% in BAF3 bcl2 and that even the direct addition of 600μM methional could not induce apoptosis in BAF3 bcl2 (Roch and al, 19 Methional is itself further metabolised intracellularly [Figure 1] by 3 pathways: reduction by aldehyde reductase (ALR) to methionol, oxidation by aldehyde dehydro- genaseLDH1) to methyl thiopropionic acid and β-hydroxylation to malondialdehyde. We therefore tried to see whether the inhibition of the reductase or the dehydrogenase would uce apoptosis in methional treated BAF3 bcl2 cells. Using quercitin as an inhibitor of ALR increase in apotosis was observed in BAF3 bcl2, but this result is to be interpreted with caution as quercitin also induces DNA strand breaks directly.With disulfiram as an ibitor of ALDH a small increase was seen but experimentation could be carried out only with low concentrations (< 100μM) due to the intrinsic toxicity of this compound. It was therefore clear that more specific inhibitors of ALDH were required to try to determine if ALDH played a role in the resistance to the apoptosis-inducing activity of methio.

Transformation of N-carbamoyl or acetyl-4-trimethylsilyl-3-alkyn-1-amines to diversely substituted 2-pyrrolidinones, via a Wacker-type reaction, is described.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The carbopalladation of allenes in the presence of a 1,3-cycloalkanedione enolate leads, in certain cases with good yields, to 2-substituted 1,3-cycloalkanediones with an unsaturated chain with a 1,3-butadienyl moiety (compounds 1). Under acidic conditions, these compounds can. be readily cyclized with the formation of a cyclohexane ring if the substituents of the butadienyl framework exert sufficient stabilization on the electrodeficient carbon of the transition state. This methodology leads in a two-step sequence to steroids with an aromatic A-ring.

La carbopalladation des allenes en presence de l'enolate d'une cyclane-1,3-dione conduit, dans certains cas avec de bons rendements, a des cyclane-1,3-diones substituees en position 2 par une chaine insaturee comportant un motif buta-1,3-diene et repondant a la formule generale 1. En conditions acides, ces composes peuvent donner lieu a cyclisation vers un element cyclohexanique si les substituants de l'element dienique stabilisent suffisamment le carbone electroniquement deficient de l'etat de transition. Cette methodologie permet l'acces en deux etapes a des steroides possedant un cycle A aromatique.

The mechanisms by which ET-18-OCH3 (1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine) and other analogues of alkyl-lysophospholipids exert their antineoplastic effects are not yet fully elucidated. Possible interference with mechanisms involving intracellular pH (pH(i)) regulation was examined by measuring the effect of ET-18-OCH3 on the activity of the Na+/H+ exchanger in the breast cancer-derived cell line MCF-7. When ET-18-OCH3 was added to culture medium at 10 mu M (determined as a noncytotoxic but cytostatic concentration), it led to an intracellular acidification (0.15 pH unit). It also decreased the rate of pH(i) recovery by Na+/H+ exchange following artificial acidification. Kinetic parameters of the exchange indicated that this was due to a decrease in the affinity of the exchanger for both transported ions, rather than to a decrease in the number of exchanger proteins in the membrane (same maximal efflux rate for treated and untreated cells). These results suggest that Na+H+ exchanger inhibition and subsequent cytoplasmic acidification participate in the mode of action of ET-18-OCH3, and could be used for modulation of tumor-cell chemosensitivity or their subsequent commitment into programmed cell death.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Several alpha,alpha'-difunctional acetylenic compounds have been synthesized and shown to have marked and selective inhibitory effects on the growth of transformed cells, owing to their action as enzyme inhibitors.