Synthesis and structure-activity relationships of novel benzofuran farnesyltransferase inhibitors

Kamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd., 200-Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 03/2009; 19(6):1753-7. DOI: 10.1016/j.bmcl.2009.01.074
Source: PubMed


A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC(50)=1.1nM) and antitumor activity in human cancer xenografts in mice.

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    • ". Farnesyltransferase inhibitors [ref. [47]]. "
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    ABSTRACT: In nature's collection of biologically active heterocycles, benzofuran derivatives constitute a major group. The broad spectrum of pharmacological activity in individual benzofurans indicates that this series of compounds is of an undoubted interest. Benzofuran and its derivatives have attracted medicinal chemists and pharmacologists due to their pronounced biological activities and their potential applications as pharmacological agents. Due to the wide range of biological activities of benzofurans, their structure activity relationships have generated interest among medicinal chemists, and this has culminated in the discovery of several lead molecules in numerous disease conditions. The outstanding development of benzofuran derivatives in diverse diseases in very short span of time proves its magnitude for medicinal chemistry research. The present review is endeavour to highlight the progress in the various pharmacological activities of benzofuran derivatives in the current literature with an update of recent research findings on this nucleus.
    European Journal of Medicinal Chemistry 11/2014; 97(1). DOI:10.1016/j.ejmech.2014.11.039 · 3.45 Impact Factor
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    • "CoMFA and CoMSIA [121] [122] [130] [131] 3 Abbott-initiated imidazole-containing compounds Docking, CoMFA and CoMSIA [85] [121] [122] [131] [132] 4 Structurally different compounds (ether and 2-amino- nicotinonitrile derivatives) 3D-QSAR, MFA [14] [133] [134] 5 Non-thiol CAAX peptidommetic inhibitors Genetic neural network [135] [138] [139] 6 Structurally diverse compounds (imidazole and other nucleus) Pharmacophore analysis [85] [121] [122] [132] [133] [140] 7 Piperidine derivatives QSAR-MLRA [21] [141] 8 Benzofuran derivatives QSAR-MLRA [142] [143] 9 SCH 226734, R115777, SCH 66336, BMS 214662, L-778123 and U49 MD, DFT, virtual screening. ADMET [144] [145] [146] [147] 10 Piperidine substituted trihalobenzocyclohepta pyridine analogues MLRA [148] [149] [150] [151] 11 Cinnamaldehyde analogues 3D-QSAR-PLS [152] [153] 12 2,3-Bis-benzylidenesuccinaldehyde derivatives CoMFA and CoMSIA [154] 13 Large, diverse data set Neural network & MLRA [149] 14 1-(4-Pyridylacetyl)-4-(8-chloro-5,6-dihydro-11H- benzo[5] [6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine deriva- tives Pharmacophore model [157] [158] [159] [160] [161] 15 Benzo[f]perhydroisoindole Response surface modelling QSAR [162] 16 2,5-Diaminobenzophenone CoMFA and CoMSIA [163] 17 Imidazole containing 2,3,4,5-tetrahydro-1H- benzo[c][1] [2]diazepines QSAR-MLRA [164] 18 Imidazole containing 2,3,4,5-tetrahydro-1H- benzo[c][1] [2]diazepines QSAR-MLRA, ANN, SVM [165] 19 Aryl thiophene derivatives QSAR-MLRA [166] [167] 20 6-Cyano-1-(3-methyl-3H-imidazol-4-yl methyl)-3-substituted- 1,2,3,4-tetrahydroquinoline derivatives QSAR-MLRA [17] [49] [168] [169] 21 Cinnamic acid derivatives CoMFA and CoMSIA [2] [43] [132] [170] [171] [172] [173] [174] [175] 22 2,5-Diaminobenzophenone MIA-QSAR [176] 23 1,2,3,4-Tetrahydroquinoline and benzonitrile analogs Multivariate image analysis QSAR [17] [129] [177] approaches appear to be particularly rewarding in terms of both cost and time benefits [123] [124] [125] [126] [127]. "

    Current Medicinal Chemistry 09/2013; · 3.85 Impact Factor
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    • "However, a study in which modifications were made to the core structure of tipifarnib to generate novel benzofuran FTIs showed that the antiproliferative properties of the tipifarnib analogs were not exclusively related to their affinity for farnesyltransferase (Asoh et al., 2009). Some compounds with high FTI activity exhibited little antiproliferative effects, suggesting that FTI activity is not sufficient to inhibit cancer cell growth (Asoh et al., 2009). Thus, the molecular mechanisms by which tipifarnib triggers cell death still remain elusive and have not been unequivocally associated with farnesyltransferase inhibition. "
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    ABSTRACT: A major contributing factor to the high mortality rate associated with acute myeloid leukemia and multiple myeloma is the development of resistance to chemotherapy. We have shown that the combination of tipifarnib, a nonpeptidomimetic farnesyltransferase inhibitor (FTI), with bortezomib, a proteosome inhibitor, promotes synergistic death and overcomes de novo drug resistance in acute myeloid leukemia cell lines. Experiments were undertaken to identify the molecular mechanisms by which tipifarnib produces cell death in acute myeloid leukemia and multiple myeloma cell lines (U937 and 8226, respectively). Tipifarnib, but not other FTIs tested [N-[4-[2(R)-amino-3-mercaptopropyl]amino-2-phenylbenzoyl]methionine methyl ester trifluoroacetate salt (FTI-277) and 2'-methyl-5-((((1-trityl-1H-imidazol-4-yl)methyl)amino)methyl)-[1,1'-biphenyl]-2-carboxylic acid (FTI-2153), promotes elevations in intracellular free-calcium concentrations ([Ca(2+)](i)) in both cell lines. These elevations in [Ca(2+)](i) were accompanied by highly dynamic plasmalemmal blebbing and frequently resulted in membrane lysis. The tipifarnib-induced elevations in [Ca(2+)](i) were not blocked by thapsigargin or ruthenium red, but were inhibited by application of Ca(2+)-free extracellular solution and by the Ca(2+) channel blockers Gd(3+) and La(3+). Conversely, 2-aminoethoxydiphenyl borate (2-APB) potentiated the tipifarnib-evoked [Ca(2+)](i) overload. Preventing Ca(2+) influx diminished tipifarnib-evoked cell death, whereas 2-APB potentiated this effect, demonstrating a link between tipifarnib-induced Ca(2+) influx and apoptosis. These data suggest that tipifarnib exerts its effects by acting on a membrane channel with pharmacological properties consistent with store-operated channels containing the Orai3 subunit. It is noteworthy that Orai3 transcripts were found to be expressed at lower levels in tipifarnib-resistant 8226/R5 cells. Our results indicate tipifarnib causes cell death via a novel mechanism involving activation of a plasma membrane Ca(2+) channel and intracellular Ca(2+) overload.
    Journal of Pharmacology and Experimental Therapeutics 03/2011; 337(3):636-43. DOI:10.1124/jpet.110.172809 · 3.97 Impact Factor
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