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Biomedical Chromatography : BMC Nov 2006The lipophilicity of a library of N-phenylamino-2-azaspiro[4.4]nonane- and [4.5]decane-1,3-dione derivatives has been determined by reversed-phase thin-layer...
The lipophilicity of a library of N-phenylamino-2-azaspiro[4.4]nonane- and [4.5]decane-1,3-dione derivatives has been determined by reversed-phase thin-layer chromatography with n-propanol-Tris buffer (pH 7.4) mixtures as mobile phases. Examination of chromatographic behaviour revealed a linear correlation between R(M) values and the concentration of n-propanol in the mobile phase. The partition coefficients (logP) were also calculated by use of the PrologP module of the Pallas computer program. Comparison of R(M0) values and calculated (logP(PALLAS)) data revealed the correlation expressed by the equation: logP(PALLAS) = 0.9995 R(M0) + 1.3451 (n = 28; r = 0.8971; F = 107.13; p < 0.05). The role of the lipophilicity in the anticonvulsant activity of a set of compounds examined is discussed: the active anticonvulsants were less lipophilic than inactive ones.
Topics: Animals; Anticonvulsants; Chromatography, Thin Layer; Lipids; Mice; Rats; Spiro Compounds
PubMed: 16799923
DOI: 10.1002/bmc.682 -
The Journal of Organic Chemistry Feb 2005A formal total synthesis of the immunosuppressant FR901483 has been accomplished. The key step in the synthesis utilizes a tandem cationic aza-Cope rearrangement/Mannich...
A formal total synthesis of the immunosuppressant FR901483 has been accomplished. The key step in the synthesis utilizes a tandem cationic aza-Cope rearrangement/Mannich cyclization reaction for accessing the unprecedented bridging tricyclic azaspirane substructure of this compound. The tandem reaction proceeds through a bridgehead iminium ion, a functionality that has rarely been explored in the context of natural product syntheses. Improved stereoselectivity was observed in an aldol reaction when using a Boc-protected amino aldehyde and zinc chloride as an additive. A stereoselective epimerization of the aldehyde-containing stereocenter was achieved with l-phenylalanine upon completion of the Mannich cyclization. Finally, this synthesis is the only one to date that controls the stereochemistry of the oxygen-bearing stereocenters. All other synthetic routes required late stage adjustments to at least one of these stereocenters.
Topics: Aza Compounds; Cations; Cyclization; Immunosuppressive Agents; Organophosphorus Compounds; Stereoisomerism
PubMed: 15675848
DOI: 10.1021/jo0483567 -
Molecular Cancer Therapeutics Jan 2007Atiprimod is a novel anticancer and antiangiogenic drug candidate which is currently being evaluated in patients with liver carcinoid and multiple myeloma. In this...
Deactivation of Akt and STAT3 signaling promotes apoptosis, inhibits proliferation, and enhances the sensitivity of hepatocellular carcinoma cells to an anticancer agent, Atiprimod.
Atiprimod is a novel anticancer and antiangiogenic drug candidate which is currently being evaluated in patients with liver carcinoid and multiple myeloma. In this study, we report that atiprimod selectively inhibited proliferation and induced apoptosis in HCC cells that expressed either hepatitis B virus (HBV) or hepatitis C virus, through deactivation of protein kinase B (Akt) and signal transducers and activators of transcription 3 (STAT3) signaling. In HepG2 AD38 cells, which express HBV genome under the control of a tetracycline-off promoter, both Akt and STAT3 were constitutively activated in response to HBV expression. However, this constitutive activation was not sensitive to lamivudine, a drug that inhibits HBV replication without affecting its gene expression, suggesting that HBV replication per se might not be responsible for the activation. Interestingly, the electrophoretic mobility of p-STAT3 protein bands on immunoblot was slower when AD38 cells were cultured in the absence of tetracycline, suggesting a differential phosphorylation in response to HBV expression. In HCC cells, interleukin 6 stimulates the phosphorylation of STAT3 both at serine 727 and at tyrosine 705 positions. The interleukin 6-stimulated activation of STAT3 and Akt was inhibited not only by atiprimod but also by LY294002, a phosphoinositide-3-kinase-specific inhibitor, and by NS398, a cyclooxygenase-2-selective inhibitor. The combination of these compounds did not produce any additive effect, implying that the mechanisms by which HBV activates Akt and STAT3 might also involve phosphoinositide-3-kinase and cyclooxygenase-2. Collectively, these results suggest that atiprimod could be useful as a multifunctional drug candidate for the treatment of HCC in humans.
Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Cyclooxygenase 2; Enzyme Activation; Gene Expression Regulation, Viral; Hepacivirus; Hepatitis B virus; Humans; Interleukin-6; Liver Neoplasms; Models, Biological; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor; Signal Transduction; Spiro Compounds; Virus Replication
PubMed: 17237271
DOI: 10.1158/1535-7163.MCT-06-0561 -
Journal of Neuropathology and... May 1987Spirogermanium (SG) is an azaspirane compound that incorporates the element germanium into a heterocyclic ring structure. It is currently being tested in phase II...
Spirogermanium (SG) is an azaspirane compound that incorporates the element germanium into a heterocyclic ring structure. It is currently being tested in phase II clinical trials as an anti-neoplastic agent and, in experimental animals, has suppressed adjuvant arthritis. In this study, SG suppressed experimental autoimmune encephalomyelitis in the Lewis rat. Suppression was a dose-dependent phenomenon and doses of 28 mg/kg and 40 mg/kg given intraperitoneally five through 14 days postinoculation gave significant protection. Perivascular inflammation in the central nervous system was also suppressed in animals receiving effective doses. Although these doses were well tolerated, cytoplasmic lamellar-bodies were found in the central nervous system of all SG-treated animals. Also, animals treated with SG developed diarrhea and weight loss, although histologic study of the gastrointestinal tract revealed no lesions.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Immunosuppressive Agents; Lymph Nodes; Lymphocyte Activation; Organometallic Compounds; Rats; Rats, Inbred Lew; Spinal Cord; Spiro Compounds; Spleen
PubMed: 3494106
DOI: 10.1097/00005072-198705000-00002 -
Leukemia Dec 2007Atiprimod (Atip) is a novel oral agent with anti-inflammatory properties. Although its in vitro activity and effects on signaling in multiple myeloma (MM) have been...
Atiprimod (Atip) is a novel oral agent with anti-inflammatory properties. Although its in vitro activity and effects on signaling in multiple myeloma (MM) have been previously reported, here we investigated its molecular and in vivo effects in MM. Gene expression analysis of MM cells identified downregulation of genes involved in adhesion, cell-signaling, cell cycle and bone morphogenetic protein (BMP) pathways and upregulation of genes implicated in apoptosis and bone development, following Atip treatment. The pathway analysis identified integrin, TGF-beta and FGF signaling as well as Wnt/beta-catenin, IGF1 and cell-cycle regulation networks as being most modulated by Atip treatment. We further evaluated its in vivo activity in three mouse models. The subcutaneous model confirmed its in vivo activity and established its dose; the SCID-hu model using INA-6 cells, confirmed its ability to overcome the protective effects of BM milieu; and the SCID-hu model using primary MM cells reconfirmed its activity in a model closest to human disease. Finally, we observed reduced number of osteoclasts and modulation of genes related to BMP pathways. Taken together, these data demonstrate the in vitro and in vivo antitumor activity of Atip, delineate potential molecular targets triggered by this agent, and provide a preclinical rational for its clinical evaluation in MM.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Bone Resorption; Cell Adhesion; Cell Cycle; Cell Line, Tumor; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Metabolic Networks and Pathways; Mice; Mice, Nude; Mice, SCID; Multiple Myeloma; Neoplasm Proteins; Osteogenesis; Signal Transduction; Spiro Compounds; Xenograft Model Antitumor Assays
PubMed: 17882285
DOI: 10.1038/sj.leu.2404912 -
Leukemia Research Mar 2012The proteasome inhibitor bortezomib (BTZ) is known to be chemotherapeutic in relapsed or refractory mantle cell lymphoma (MCL). Atiprimod (ATI), a novel cationic...
The proteasome inhibitor bortezomib (BTZ) is known to be chemotherapeutic in relapsed or refractory mantle cell lymphoma (MCL). Atiprimod (ATI), a novel cationic amphophilic compound, has been tested in clinical trials in multiple myeloma (MM). We sought to evaluate the effect of an ATI-BTZ combination on MCL and to elucidate its therapeutic mechanisms. The ATI and BTZ combination significantly inhibited growth and induced apoptosis of both cultured MCL cell lines and freshly isolated tumor cells from patients with refractory or relapsed MCL. However, the combination yielded lower cytotoxicity in normal peripheral blood mononuclear cells (PBMC). Furthermore, ATI and BTZ induced apoptosis via two different signaling pathways. More significantly, ATI and BTZ markedly delayed tumor growth and prolonged survival in MCL-bearing NOD-SCID mice. Our results demonstrate that ATI and BTZ confer significant therapeutic effects in MCL in vitro and in vivo and should therefore be investigated in a clinical trial in patients with relapsed or refractory MCL.
Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Inducing Factor; Blotting, Western; Boronic Acids; Bortezomib; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; In Vitro Techniques; Leukocytes, Mononuclear; Lymphoma, Mantle-Cell; Male; Mice; Mice, Inbred NOD; Mice, SCID; Pyrazines; Spiro Compounds; Survival Rate
PubMed: 22000823
DOI: 10.1016/j.leukres.2011.09.014 -
Toxicology and Applied Pharmacology Aug 1999Azaspiranes are cationic amphiphilic compounds that are active in a number of models of autoimmune disease and transplantation. Repeated administration of cationic...
Azaspiranes are cationic amphiphilic compounds that are active in a number of models of autoimmune disease and transplantation. Repeated administration of cationic amphiphiles induces phospholipid accumulation in a variety of species. The present study was conducted to explore the mechanism of phospholipid accumulation in rats caused by treatment with the novel azaspirane, SK&F 106615 (atiprimod). Atiprimod inhibited the activities of partially purified phospholipases A(2) and C, but not D, in a noncompetitive manner in vitro. Treatment of rats for 28 days with 10 mg/kg/day of atiprimod increased the contents of arachidonate-containing molecular species within plasmalogen subclasses of hepatic phosphatidylcholine and phosphatidylethanolamine. In contrast, diacyl-linked species were not affected, indicating a selective effect upon an hepatic plasmalogen-selective phospholipase A(2). Taken together, the data suggest that the beneficial effects of atiprimod in autoimmune diseases may involve inhibition of phospholipase A(2) and C activities. Further, the data suggest that atiprimod is a selective inhibitor of plasmalogen-selective phospholipase A(2) in vivo.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Binding, Competitive; In Vitro Techniques; Macrophages, Alveolar; Male; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipases; Phospholipids; Rats; Rats, Sprague-Dawley; Spiro Compounds
PubMed: 10448120
DOI: 10.1006/taap.1999.8732 -
Leukemia Research Jan 2007In studies of multiple myeloma cells, atiprimod was shown to block Stat3 activation and inhibited colony-forming cell proliferation. We hypothesized that atiprimod may...
In studies of multiple myeloma cells, atiprimod was shown to block Stat3 activation and inhibited colony-forming cell proliferation. We hypothesized that atiprimod may also inhibit activation of intracellular signaling pathways in AML cells resulting in apoptosis and growth inhibition. We demonstrate that atiprimod inhibited clonogenic growth of AML cell lines and fresh AML marrow cells whereas it did not significantly affect growth of normal hematopoietic progenitors from marrow samples of healthy controls. Atiprimod decreased phosphorylation of Stat3 and Stat5, and protein levels of Jak2, whereas gene expression of Jak2 was not affected. Atiprimod further induced apoptosis by cleavage of caspase 3 and PARP. In summary, our data suggest that atiprimod has a significant antiproliferative and proapoptotic effect on AML cells. This effect may be facilitated by inhibition of the Jak-Stat signaling pathway. Further evaluation of atiprimod in clinical trials of AML should be considered.
Topics: Acute Disease; Blast Crisis; Cell Division; Cell Line, Tumor; DNA Primers; Enzyme Inhibitors; Humans; Janus Kinase 2; Leukemia, Myeloid; Phosphorylation; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; STAT5 Transcription Factor; Spiro Compounds
PubMed: 16828865
DOI: 10.1016/j.leukres.2006.05.027 -
International Journal of... Feb 1993SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-propanamine+ ++ dihydrochloride) is a novel azaspirane with beneficial activity in animal models of...
SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-propanamine+ ++ dihydrochloride) is a novel azaspirane with beneficial activity in animal models of autoimmune disease such as adjuvant-induced arthritis and experimental encephalomyelitis in the Lewis rat and lupus-like disease in the MRL mouse. The activity of SK&F 105685 in these models is associated with the induction of non-specific suppressor cell (SC) activity as defined by the ability of cells from drug-treated animals to inhibit the proliferative response of lymphocytes from control animals to concanavalin A. To evaluate the immunotoxicologic potential of SK&F 105685, the effect on immune function of one month of dosing with 1 mg/kg/day of SK&F 105685 was examined in the dog. Differential blood cell counts and ex vivo immune function assays were performed using blood collected before dosing on days 1 (baseline), 15 and 29, of the study. Immune function assays were performed on spleen cells on day 30. Under the conditions of the study, SK&F 105685 displayed pharmacological activity as demonstrated by the induction of splenic SC activity. The drug did not affect the total number or relative percentages of the various white blood cell types present in peripheral blood and did not cause generalized immunosuppression. The ability of peripheral blood lymphocytes or spleen cells to produce IL-2 or proliferate in response to mitogenic stimulation was not affected by drug treatment. SK&F 105685 also failed to affect the candidacidal activity of polymorphonuclear leucocytes and spleen cells indicating that it is unlikely to compromise nonspecific resistance to infection. SK&F 105685 however, was able to inhibit the generation of a specific in vitro antibody response to sheep red blood cells (SRBC) by splenocytes from treated animals. Inhibition of the anti-SRBC antibody response was also observed upon addition of the drug to normal spleen cells. Addition of the drug at different time points during the culture period indicated that SK&F 105685 was interfering with an event(s) occurring during the first 72 h of culture. Taken together, these results suggest that, in a therapeutic setting, SK&F 105685 is unlikely to compromise the immune status of the host as it can down-regulate a specific immune response without causing generalized immunosuppression.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antibody Formation; Candida albicans; Cytotoxicity, Immunologic; Dogs; Erythrocytes; Immunity; In Vitro Techniques; Interleukin-2; Lymphocyte Activation; Male; Sheep; Spiro Compounds; T-Lymphocytes, Regulatory
PubMed: 8468115
DOI: 10.1016/0192-0561(93)90087-f -
Journal of Medicinal Chemistry Nov 1990Spirogermanium (1; 8,8-diethyl-N,N-dimethyl-2-aza-8- germaspiro[4.5]decane-2-propanamine dihydrochloride) is a potent cytotoxic agent in vitro which has demonstrated... (Comparative Study)
Comparative Study
Spirogermanium (1; 8,8-diethyl-N,N-dimethyl-2-aza-8- germaspiro[4.5]decane-2-propanamine dihydrochloride) is a potent cytotoxic agent in vitro which has demonstrated limited activity in experimental animal tumor models. Subsequently, it has been reported that spirogermanium has antiarthritic and suppressor cell-inducing activity. We have synthesized a series of substituted 8-hetero-2-azaspiro[4.5]decane and 9-hetero-3-azaspiro[5.5]undecane analogues of spirogermanium to identify the heteroatom requirements for in vivo antiarthritic and suppressor cell-inducing activity. This structure-activity relationship study has identified that appropriately substituted silicon and carbon analogues of spirogermanium retain both antiarthritic and immunosuppressive activity, with the 8,8-dipropyl (carbon) analogue being among the most active. Following the identification of N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine++ + dihydrochloride (9) as a more active analogue than spirogermanium, a series of 8,8-dipropyl analogues with various amine substituents were synthesized. A number of these analogues had activity similar to that of 9. A correlation between activity in the adjuvant arthritic rat and the ability to induce suppressor cells (r = 0.894, p less than 0.001) suggests an association between the two pharmacologic effects. While the precise biochemical mechanism(s) for the pharmacological activity is unclear, these data suggest that compounds within this series, e.g., N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine++ + dihydrochloride, may provide effective therapy in diseases of autoimmune origin and/or the prevention of rejection in tissue transplantation.
Topics: Animals; Arthritis, Experimental; Aza Compounds; Chemical Phenomena; Chemistry; Immunosuppressive Agents; Male; Molecular Structure; Organometallic Compounds; Rats; Rats, Inbred Lew; Spiro Compounds; Structure-Activity Relationship; T-Lymphocytes, Regulatory
PubMed: 2146392
DOI: 10.1021/jm00173a010