Did you mean: azaspirene
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Blood Jun 2005Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine; trade name, Atiprimod) is an orally bioavailable cationic amphiphilic compound that...
Azaspirane (N-N-diethyl-8,8-dipropyl-2-azaspiro [4.5] decane-2-propanamine; trade name, Atiprimod) is an orally bioavailable cationic amphiphilic compound that significantly inhibits production of interleukin 6 (IL-6) and inflammation in rat arthritis and autoimmune animal models. We here characterize the effect of atiprimod on human multiple myeloma (MM) cells. Azaspirane significantly inhibited growth and induced caspase-mediated apoptosis in drug-sensitive and drug-resistant MM cell lines, as well as patient MM cells. IL-6, insulin-like growth factor 1 (IGF-1), or adherence of MM cells to bone marrow stromal cells (BMSCs) did not protect against atiprimod-induced apoptosis. Both conventional (dexamethasone, doxorubicin, melphalan) and novel (arsenic trioxide) agents augment apoptosis induced by atiprimod. Azaspirane inhibits signal transducer activator of transcription 3 (STAT3) and a PI3-K (phosphatidylinositol 3-kinase) target (Akt), but not extracellular signal-regulated kinase 1 and 2 (ERK1/2), inhibits phosphorylation triggered by IL-6, and also inhibits inhibitorkappaBalpha (IkappaBalpha) and nuclear factor kappaB (NFkappaB) p65 phosphorylation triggered by tumor necrosis factor alpha (TNF-alpha). Of importance, azaspirane inhibits both IL-6 and vascular endothelial growth factor (VEGF) secretion in BMSCs triggered by MM cell binding and also inhibits angiogenesis on human umbilical vein cells (HUVECs). Finally, azaspirane demonstrates in vivo antitumor activity against human MM cell growth in severe combined immunodeficient (SCID) mice. These results, therefore, show that azaspirane both induces MM cell apoptosis and inhibits cytokine secretion in the BM milieu, providing the framework for clinical trials to improve patient outcome in MM.
Topics: Animals; Antineoplastic Agents; Apoptosis; Bone Marrow; Cell Communication; Cell Proliferation; Drug Synergism; Endothelium, Vascular; Humans; Interleukin-6; Mice; Mice, SCID; Multiple Myeloma; Neovascularization, Physiologic; Signal Transduction; Spiro Compounds; Stromal Cells; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A
PubMed: 15705788
DOI: 10.1182/blood-2004-09-3794 -
Organic Letters Oct 2006[reaction: see text] An efficient approach to the azaspirane core of FR 901483 is described employing lithiated methoxyallene as a crucial C3 building block and a...
[reaction: see text] An efficient approach to the azaspirane core of FR 901483 is described employing lithiated methoxyallene as a crucial C3 building block and a suitably protected enantiopure ketimine as the second component. The resulting dihydropyrrole derivative was smoothly converted into a spiro keto aldehyde which under acidic conditions provided a novel azanorbornane derivative 15. Under basic reaction conditions, the desired 5-azatricyclo[6.3.1.0(1,5)]dodecane skeleton 16 was generated. The ratio of diastereomers strongly depends on the reaction conditions employed with l-proline in DMSO providing the highest selectivity in favor of one azaspirane product.
Topics: Catalysis; Molecular Structure; Organophosphorus Compounds; Spiro Compounds
PubMed: 17020297
DOI: 10.1021/ol061538y -
International Journal of Oncology Sep 2016Persistent activation of signal transducer and activator of transcription 3 (STAT3) is associated with the progression of a range of tumors. In this report, we present...
An azaspirane derivative suppresses growth and induces apoptosis of ER-positive and ER-negative breast cancer cells through the modulation of JAK2/STAT3 signaling pathway.
Persistent activation of signal transducer and activator of transcription 3 (STAT3) is associated with the progression of a range of tumors. In this report, we present the anticancer activity of 2-(1-(4-(2-cyanophenyl)1-benzyl‑1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5)undecane (CIMO) against breast cancer cells. We observed that CIMO suppresses the proliferation of both estrogen receptor-negative (ER-) (BT-549, MDA-MB‑231) and estrogen receptor-positive (ER+) (MCF-7, and BT-474) breast cancer (BC) cells with IC50 of 3.05, 3.41, 4.12 and 4.19 µM, respectively, and without significantly affecting the viability of normal cells. CIMO was observed to mediate its anti-proliferative effect in ER- BC cells by inhibiting the phosphorylation of JAK2 and STAT3 proteins. Quantitative PCR analysis demonstrated that CIMO decreases the relative mRNA expression of genes that are involved in cell cycle progression (CCND1) and cell survival (BCL2, BCL-xL, BAD, CASP 3/7/9, and TP53). In addition, CIMO was observed to arrest BC cells at G0/G1 phase and of the cell cycle. Furthermore, CIMO suppressed BC cell migration and invasion with concordant regulation of genes involved in epithelial to mesechymal transition (CDH1, CDH2, OCLN and VIM). Thus, we report the utility of a synthetic azaspirane which targets the JAK-STAT pathway in ER- BC.
Topics: Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cyclin D1; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Janus Kinase 2; MCF-7 Cells; Phosphorylation; STAT3 Transcription Factor; Signal Transduction; Spiro Compounds
PubMed: 27500741
DOI: 10.3892/ijo.2016.3615 -
Journal of the American Society of... Apr 1993The azaspirane SKF 105685 (N,N-dimethyl-8, 8-dipropyl-2-azaspiro (4.5) decane-2-propanamine dihydrochloride) has been shown to attenuate or reverse the course of...
The azaspirane SKF 105685 (N,N-dimethyl-8, 8-dipropyl-2-azaspiro (4.5) decane-2-propanamine dihydrochloride) has been shown to attenuate or reverse the course of immunologic disease in several animal models, possibly through the induction of nonspecific suppressor activity. To investigate its effects on immune-mediated renal disease, SKF 105685 was administered by gavage to rats with kidney allografts. Six days after transplantation, GFR (inulin clearance, 1.46 +/- 0.27 versus 0.41 +/- 0.15 mL/min per kg; P < 0.005) and RPF (p-aminohippurate clearance, 5.48 +/- 0.98 versus 1.99 +/- 0.72 mL/min per kg; P < 0.01) were significantly higher in SKF 105685-treated rats compared with vehicle-treated control rats. In addition, mononuclear inflammatory cell infiltrates were significantly reduced in SKF 105685-treated animals compared with controls. Treatment also reduced renal production of thromboxane B2 (81 +/- 22 versus 424 +/- 76 pg/min per mg of protein; P < 0.0005), prostaglandin E2 (612 +/- 165 versus 2,059 +/- 351 pg/min per mg of protein; P < 0.005), and 6-keto prostaglandin F1 alpha (217 +/- 56 versus 943 +/- 186 pg/min per mg of protein; P < 0.005), but interleukin-1 beta mRNA levels within kidney allografts were not affected by treatment. Thus, the azaspirane SKF 105685 is a novel immunosuppressive agent that substantially ameliorates renal allograft rejection in the rat. Although the mechanism of action is unknown, the beneficial effects of SKF 105685 in rejection may relate to its ability to induce suppressor activity and/or its effects on eicosanoid production.
Topics: Animals; Arthritis, Experimental; Drug Evaluation, Preclinical; Eicosanoids; Graft Rejection; Immunosuppressive Agents; Inflammation; Interleukin-1; Kidney Transplantation; Male; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Rats, Inbred Strains; Renal Circulation; Spiro Compounds; Transplantation, Homologous
PubMed: 8318684
DOI: 10.1681/ASN.V3101680 -
The Journal of Biological Chemistry Dec 2014Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates genes involved in cell growth, proliferation, and survival, and given...
Development of a novel azaspirane that targets the Janus kinase-signal transducer and activator of transcription (STAT) pathway in hepatocellular carcinoma in vitro and in vivo.
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates genes involved in cell growth, proliferation, and survival, and given its association with many types of cancers, it has recently emerged as a promising target for therapy. In this work, we present the synthesis of N-substituted azaspirane derivatives and their biological evaluation against hepatocellular carcinoma (HCC) cells (IC50 = 7.3 μm), thereby identifying 2-(1-(4-(2-cyanophenyl)1-benzyl-1H-indol-3-yl)-5-(4-methoxy-phenyl)-1-oxa-3-azaspiro(5,5) undecane (CIMO) as a potent inhibitor of the JAK-STAT pathway with selectivity over normal LO2 cells (IC50 > 100 μm). The lead compound, CIMO, suppresses proliferation of HCC cells and achieves this effect by reducing both constitutive and inducible phosphorylation of JAK1, JAK2, and STAT3. Interestingly, CIMO displayed inhibition of Tyr-705 phosphorylation, which is required for nuclear translocation of STAT3, but it has no effect on Ser-727 phosphorylation. CIMO accumulates cancer cells in the sub-G1 phase and decreases STAT3 in the nucleus and thereby causes down-regulation of genes regulated via STAT3. Suppression of STAT3 phosphorylation by CIMO and knockdown of STAT3 mRNA using siRNA transfection displayed a similar effect on the viability of HCC cells. Furthermore, CIMO significantly decreased the tumor development in an orthotopic HCC mouse model through the modulation of phospho-STAT3, Ki-67, and cleaved caspase-3 in tumor tissues. Thus, CIMO represents a chemically novel and biologically in vitro and in vivo validated compound, which targets the JAK-STAT pathway as a potential cancer treatment.
Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Caspase 3; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Hepatocytes; Humans; Janus Kinase 2; Liver Neoplasms; Mice; Mice, Nude; Phosphorylation; RNA, Messenger; RNA, Small Interfering; STAT3 Transcription Factor; Signal Transduction; Spiro Compounds; Tumor Burden; Xenograft Model Antitumor Assays
PubMed: 25320076
DOI: 10.1074/jbc.M114.601104 -
Journal of the American Chemical Society Aug 2001A solution to the long-standing problem presented by the oxidative cyclization of a phenolic 3-arylpropionamide to a spirolactam has been developed in this laboratory...
A solution to the long-standing problem presented by the oxidative cyclization of a phenolic 3-arylpropionamide to a spirolactam has been developed in this laboratory via oxazoline chemistry. This research was motivated by our interest in some novel tricyclic azaspirane natural products formally derived from tyrosine, such as FR901483 and TAN1251C. In this paper, we disclose full details of the total synthesis of these substances.
Topics: Aza Compounds; Immunosuppressive Agents; Organophosphorus Compounds; Spiro Compounds
PubMed: 11480973
DOI: 10.1021/ja016030z -
Current Cancer Drug Targets Feb 2007Constitutive activation of the Signal Transducers and Activators of Transcription 3 (Stat3) meditated signaling pathway is very important for cell growth and survival.... (Review)
Review
Constitutive activation of the Signal Transducers and Activators of Transcription 3 (Stat3) meditated signaling pathway is very important for cell growth and survival. Compelling evidence from mechanistic studies with antisense, RNA interference (RNAi), peptides, and small molecular inhibitors indicate that blocking Stat3 signaling can lead to successful suppression of tumor cell growth and apoptosis. Thus, Stat3 is an attractive molecular target for the development of novel cancer therapeutics. In this article, we present the first comprehensive review focusing on small molecule inhibitors that effectively block the Stat3 signaling pathway. These inhibitors, from a structural point of view, are divided into five classes of compounds. They include (1) natural products and derivatives, such as curcumin, resveratrol and others, (2) tyrphostins, (3) platinum-containing complexes, (4) peptidomimetics, and (5) azaspiranes. Some compounds may have multiple targets including Stat3 protein, therefore these compounds need further optimization and validation. The purpose of this review is to provide a resource for researchers interested in Stat3 targeted small molecules which will be beneficial for database development and template design for future drug development.
Topics: Animals; Antineoplastic Agents; Curcumin; Flavonoids; Humans; Piperidines; Resveratrol; STAT3 Transcription Factor; Signal Transduction; Stilbenes; Triterpenes
PubMed: 17305481
DOI: 10.2174/156800907780006922 -
Journal of Autoimmunity Feb 1993Immunomodulatory azaspirane compounds have immunosuppressive activity in animal models of autoimmune disease such as adjuvant-induced arthritis and experimental...
Immunomodulatory azaspirane compounds have immunosuppressive activity in animal models of autoimmune disease such as adjuvant-induced arthritis and experimental autoimmune encephalomyelitis. The mechanism of action of azaspiranes appears to be the induction of antigen non-specific (natural) suppressor cell activity. In this study, we tested the azaspirane, SK&F 106610 in an animal model of autoimmune (type 1) diabetes, the BB rat. Oral administration of SK&F 106610 (15 mg/kg/day) to diabetes-prone BB rats, from age 30 days, significantly decreased diabetes incidence at 100 days from 80% (24 of 30 control rats) to 32% (10 of 31 drug-treated rats, P < 0.001). Protection from diabetes by SK&F 106610 was accompanied by decreased lymphocytic infiltration of the pancreatic islets (insulitis). No changes occurred in splenic T cell, B cell or macrophage subsets, or in proliferative responses to the mitogens lipopolysaccharide and concanavalin A (Con-A). Cell mixing experiments in vitro, however, revealed increased antigen non-specific suppressor activity (suppression of splenic lymphoproliferative response to Con-A) in spleens of SK&F 106610-treated rats. The suppressor cell activity was enriched in a low density fraction of splenic cells relatively depleted of T cells, B cells, macrophages and natural killer cells. These results indicate that the azaspirane compound, SK&F 106610 can prevent insulitis and autoimmune diabetes in BB rats and that these actions may be related to the activation of non-specific (natural) suppressor cells.
Topics: Administration, Oral; Animals; Autoimmune Diseases; Diabetes Mellitus, Type 1; Female; Immunophenotyping; Immunosuppressive Agents; Islets of Langerhans; Lymphocyte Activation; Lymphocyte Subsets; Male; Piperidines; Rats; Rats, Inbred BB; Spiro Compounds; Spleen; T-Lymphocytes, Regulatory
PubMed: 8457285
DOI: 10.1006/jaut.1993.1004 -
IDrugs : the Investigational Drugs... Mar 2000Atiprimod is a macrophage-targeting oral cytokine inhibitor which is being developed by AnorMED as a potential treatment for rheumatoid arthritis and other autoimmune...
Atiprimod is a macrophage-targeting oral cytokine inhibitor which is being developed by AnorMED as a potential treatment for rheumatoid arthritis and other autoimmune diseases. Phase I trials have been successfully completed and phase II multicenter trials have been approved by the FDA [303260]. The compound was discovered in a joint research and development program with SmithKline and French (now SmithKline Beecham, SB) but following acceptance of the phase II protocol by the FDA, SB decided not to proceed with further development of atiprimod as a result of an internal restructuring program [350042]. All rights to atiprimod and other azaspiranes developed in this program have reverted to AnorMED, which is seeking corporate partners for further development of the compound [303260,337657]. The compound was originally disclosed in European patent, EP-00310321, entitled 'Preparation of N-aminoalkyl-2-azaspiro[4.5]decanes and analogs as immunosuppresants', while a cost-effective, efficacious pilot plant synthesis has also been described [298722].
PubMed: 16103943
DOI: No ID Found -
Experimental Hematology Aug 1991The immunomodulatory azaspirane SK&F 105685 has immunosuppressive activity in animal models of autoimmune disease such as adjuvant-induced arthritis and experimental...
Administration of an immunomodulatory azaspirane, SK&F 105685, or human recombinant interleukin 1 stimulates myelopoiesis and enhances survival from lethal irradiation in C57Bl/6 mice.
The immunomodulatory azaspirane SK&F 105685 has immunosuppressive activity in animal models of autoimmune disease such as adjuvant-induced arthritis and experimental autoimmune encephalomyelitis. The mechanism of SK&F 105685 appears to be the induction of nonspecific suppressor cell (SC) activity. SC appear to be "null cells," that is, cells that lack specific cell surface markers of mature B cells, T cells, natural killer (NK) cells, or macrophages. Because we hypothesized that the induction of SC was associated with enhanced hematopoiesis, we sought to determine the hematopoietic potential of SK&F 105685. Recombinant interleukin 1 alpha (rIL-1) was included as a positive control for hematopoietic stimulation in our studies. We demonstrate here that administration of SK&F 105685 increases the number of granulocyte-macrophage colony-forming units (CFU-GM) within the bone marrow 24 h after injection in a dose-dependent manner. In addition, the percentage of CFU-GM in S-phase of the cell cycle was significantly increased, as was colony-stimulating activity (CSA) present in the serum of treated animals. In our experiments IL-1 did not increase marrow CFU-GM; however, splenic CFU-GM, the proportion of CFU-GM in S-phase of the cell cycle, and serum CSA were all increased 24 h after a single treatment. Administration of SK&F 105685 24 h prior to lethal irradiation resulted in a dose-related increase in the number of surviving mice. These results demonstrate that SK&F 105685 and rIL-1 stimulate myelopoiesis in vivo and suggest a mechanism by which prophylactic treatment with these agents protects mice from otherwise lethal irradiation.
Topics: Adjuvants, Immunologic; Animals; Bone Marrow; Bone Marrow Cells; Colony-Stimulating Factors; Female; Gamma Rays; Granulocytes; Hematopoiesis; Hematopoietic Stem Cells; Interleukin-1; Macrophages; Mice; Mice, Inbred C57BL; Recombinant Proteins; S Phase; Spiro Compounds; Spleen
PubMed: 1893948
DOI: No ID Found