Organometallic conjugates consisting of a gold(I) N‐heterocyclic carbene (NHC) moiety and a naphthalimide were prepared and investigated as cytotoxic agents that interact with both DNA and the disulfide reductase enzyme thioredoxin reductase (TrxR). The complexes were potent DNA intercalators related to their naphthalimide partial structure, inhibited TrxR as a consequence of the incorporation of the gold(I) moiety, and triggered efficient cytotoxic effects in MCF‐7 breast and HT‐29 colon adenocarcinoma cells. Strong effects on tumor cell metabolism were noted for the most cytotoxic complex, chlorido[1‐(3′‐(4′′‐ethylthio‐1′′,8′′‐naphthalimid‐N′′‐yl))‐propyl‐3‐methyl‐imidazol‐2‐ylidene]gold(I) ( 4 d ). In conclusion, the conjugation of naphthalimides with gold(I) NHC moieties provided a useful strategy for the design of bioorganometallic anticancer agents with multiple modes of action. 相似文献
Noscapine is a phthalideisoquinoline alkaloid isolated from the opium poppy Papaver somniferum. It has long been used as an antitussive agent, but has more recently been found to possess microtubule‐modulating properties and anticancer activity. Herein we report the synthesis and pharmacological evaluation of a series of 6′‐substituted noscapine derivatives. To underpin this structure–activity study, an efficient synthesis of N‐nornoscapine and its subsequent reduction to the cyclic ether derivative of N‐nornoscapine was developed. Reaction of the latter with a range of alkyl halides, acid chlorides, isocyanates, thioisocyanates, and chloroformate reagents resulted in the formation of the corresponding N‐alkyl, N‐acyl, N‐carbamoyl, N‐thiocarbamoyl, and N‐carbamate derivatives, respectively. The ability of these compounds to inhibit cell proliferation was assessed in cell‐cycle cytotoxicity assays using prostate cancer (PC3), breast cancer (MCF‐7), and colon cancer (Caco‐2) cell lines. Compounds that showed activity in the cell‐cycle assay were further evaluated in cell viability assays using PC3 and MCF‐7 cells. 相似文献
A series of 3,5‐bis(benzylidene)‐4‐piperidones 3 were converted into the corresponding 3,5‐bis(benzylidene)‐1‐phosphono‐4‐piperidones 5 via diethyl esters 4 . The analogues in series 4 and 5 displayed marked growth inhibitory properties toward human Molt 4/C8 and CEM T‐lymphocytes as well as murine leukemia L1210 cells. In general, the N‐phosphono compounds 5 , which are more hydrophilic than the analogues in series 3 and 4 , were the most potent cluster of cytotoxins, and, in particular, 3,5‐bis‐(2‐nitrobenzylidene)‐1‐phosphono‐4‐piperidone 5 g had an average IC50 value of 34 nM toward the two T‐lymphocyte cell lines. Four of the compounds displayed potent cytotoxicity toward a panel of nearly 60 human tumor cell lines, and nanomolar IC50 values were observed in a number of cases. The mode of action of 5 g includes the induction of apoptosis and inhibition of cellular respiration. Most of the members of series 4 as well as several analogues in series 5 are potent multi‐drug resistance (MDR) reverting compounds. Various correlations were noted between certain molecular features of series 4 and 5 and cytotoxic properties, affording some guidelines in expanding this study.相似文献
Summary: Polyelectrolyte hydrogels containing diprotic acid moieties sensitive to ionic strength changes of the swelling medium were synthesized from N,N‐diethylaminoethyl methacrylate (DEAEMA), N‐vinyl‐2‐pyrrolidone (VP) and itaconic acid (IA) by using ammonium persulfate (APS) as a free radical initiator in the presence of the cross‐linker, methylenebisacrylamide (MBAAm). The swelling behavior of the ionic poly[(N,N‐diethylaminoethyl methacrylate)‐co‐(N‐vinyl‐2‐pyrrolidone)] [P(DEAEMA/VP)] hydrogels were investigated in pure water; in NaCI solutions with pH 4 and 9; and in water‐acetone mixtures depending on the IA content in the hydrogel. The average molecular mass between cross‐links ( ) and polymer‐solvent interaction parameter (χ) of the hydrogels were determined from equilibrium swelling values. The pulsatile swelling behavior was also observed in response to solvent changes between the solution in water and in acetone. The equilibrium swelling ratio of these hydrogels was basically unaffected with change in temperature. The swelling variations were explained according to the swelling theory based on the hydrogel chemical structure.
Pulsatile swelling behavior of ionic P(DEAEMA/VP) hydrogels in response to solvent changes between water and acetone at 25 °C. 相似文献
This paper reports the structural modification of Hoveyda–Grubbs complexes through the introduction of either an N‐alkyl‐N′‐mesityl heterocyclic carbene, an N‐alkyl‐N′‐(2,6‐diisopropylphenyl) heterocyclic carbene, or an N‐alkyl‐N′‐alkyl heterocyclic carbene. The effect of the modified N‐heterocyclic carbene (NHC) ligand was investigated in representative ring‐opening metathesis polymerization (ROMP), ring‐closing metathesis (RCM) and cross metathesis (CM) reactions. A pronounced influence on both catalyst activity and selectivity was found to be exerted by the NHC amino substituents, which emphasizes that a rigorously selected steric environment is critical in olefin metathesis catalyst design. 相似文献
γ‐Glutamylcyclotransferase (GGCT) depletion inhibits cancer cell proliferation. However, whether the enzymatic activity of GGCT is critical for the regulation of cancer cell growth remains unclear. In this study, a novel diester‐type cell‐permeable prodrug, pro‐GA, was developed based on the structure of N‐glutaryl‐l ‐alanine (GA), by structure optimization using temporary fluorophore‐tagged prodrug candidates. The antiproliferative activity of pro‐GA was demonstrated using GGCT‐overexpressing NIH‐3T3 cells and human cancer cells including MCF7, HL‐60, and PC3 cells. By contrast, normal cells were not significantly affected by pro‐GA treatment. Moreover, pro‐GA administration exhibited anticancer effects in a xenograft model using immunocompromised mice inoculated with PC3 cells. These results indicate that the enzymatic activity of GGCT accelerates tumor growth and that GGCT inhibition is a promising therapeutic strategy for the treatment of GGCT‐overexpressing tumors. 相似文献
A recombinant Escherichia coli expressing P450pyr monooxygenase of Sphingomonas sp. HXN‐200 was developed as a useful biocatalyst for regio‐ and stereoselective hydroxylations, with no side reaction and easy cell growth. The resting E. coli cells showed an activity of 4.1 U/g cdw and 9.9 U/g cdw for the hydroxylation of N‐benzylpyrrolidin‐2‐one 1 and N‐benzyloxycarbonylpyrrolidine 3 , respectively, being as active as the wide‐type strain. Biohydroxylation of N‐benzylpyrrolidin‐2‐one 1 with the resting cells gave (S)‐N‐benzyl‐4‐hydroxypyrrolidin‐2‐one 2 in >99% ee and 10.8 mM, a 2.6 times increase of product concentration in comparison with the wild‐type strain. Biohydroxylation of N‐tert‐butoxycarbonylpiperidin‐2‐one 5 , N‐benzylpiperidine 7 and N‐tert‐butoxycarbonylazetidine 9 with the E. coli cells afforded the corresponding 4‐hydroxypiperidin‐2‐one 6 , 4‐hydroxypiperidine 8 , and 3‐hydroxyazetidine 10 in 14 mM, 17 mM, and 21 mM, respectively. Moreover, hydroxylation of (−)‐β‐pinene 11 with the recombinant E. coli cells showed excellent regio‐ and stereoselectivity and gave (1R)‐trans‐pinocarveol 12 in 82% yield and 4.1 mM, which is over 200 times higher than that obtained with the best biocatalytic system known thus far. The recombinant strain was also able to hydroxylate other types of substrates with unique selectivity: biohydroxylation of norbornane 13 gave exo‐norbornaeol 14 , with exo/endo selectivity of 95%; tetralin 15 and 6‐methoxytetralin 17 were hydroxylated at the non‐activated 2‐position, for the first time, with regioselectivities of 83–84%. 相似文献
Addition of allyl halides to the organolithium species derived from lithiation of N‐tert‐butoxycarbonylindoline with sec‐butyllithium (sec‐BuLi) and tetramethylethylenediamine (TMEDA) occurs regioselectively by SN2 allylation. In contrast, the organolithium species can be transmetalated to the mixed zinc cuprate that undergoes regioselective SN2′ allylations. Transmetalation to the organozinc chloride allows a Negishi‐type cross‐coupling reaction with aryl bromides using palladium catalysis with triphenylphosphine (PPh3) as ligand. The chemistry was applied to a very short synthesis of 7‐prenylindole and of the alkaloid vasconine. 相似文献