The Experts below are selected from a list of 1023 Experts worldwide ranked by ideXlab platform
Peggy J. K. D. Schreur - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites.
Journal of Medicinal Chemistry, 1997Co-Authors: Richard F. Heier, Lester A Dolak, J. N. Duncan, M. F. Lipton, M. A. Mauragis, Nanette F. Nichols, Deborah K. Hyslop, I J Martin, Montford F. Piercey, Peggy J. K. D. SchreurAbstract:The Imidazoquinoline (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one [(R)-6]; intermediate metabolites, where N-demethylation to the Imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient...
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Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites.
Journal of medicinal chemistry, 1997Co-Authors: Richard F. Heier, Lester A Dolak, J. N. Duncan, M. F. Lipton, M. A. Mauragis, Nanette F. Nichols, Deborah K. Hyslop, I J Martin, Montford F. Piercey, Peggy J. K. D. SchreurAbstract:The Imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H) -one [(R)-6], intermediate metabolites, where N-demethylation to the Imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3-6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.
Sunil A David - One of the best experts on this subject based on the ideXlab platform.
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Structure-activity relationships in Toll-like receptor 7 agonistic 1H-imidazo[4,5-c]pyridines.
Organic and Biomolecular Chemistry, 2013Co-Authors: Breanna M. Crall, Alec R. Hermanson, Subbalakshmi S Malladi, Rajalakshmi Balakrishna, Sunil A DavidAbstract:Engagement of TLR7 in plasmacytoid dendritic cells leads to the induction of IFN-α/β which plays essential functions in the control of adaptive immunity. We had previously examined structure–activity relationships (SAR) in TLR7/8-agonistic Imidazoquinolines with a focus on substituents at the N1, C2, N3 and N4 positions, and we now report SAR on 1H-imidazo[4,5-c]pyridines. 1-Benzyl-2-butyl-1H-imidazo[4,5-c]pyridin-4-amine was found to be a pure TLR7-agonist with negligible activity on TLR8. Increase in potency was observed in N6-substituted analogues, especially in those compounds with electron-rich substituents. Direct aryl–aryl connections at C6 abrogated activity, but TLR7 agonism was reinstated in 6-benzyl and 6-phenethyl analogues. Consistent with the pure TLR7-agonistic behavior, prominent IFN-α induction in human PBMCs was observed with minimal proinflammatory cytokine induction. A benzologue of Imidazoquinoline was also synthesized which showed substantial improvements in potency over the parent imidazopyridine. Distinct differences in N6-substituted analogues were observed with respect to IFN-α induction in human PBMCs on the one hand, and CD69 upregulation in lymphocytic subsets, on the other.
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Synthesis of trimeric Imidazoquinoline dendrimer 3.
2013Co-Authors: Nikunj M Shukla, Cole A Mutz, Deepak B. Salunke, Subbalakshmi S Malladi, Rajalakshmi Balakrishna, Sunil A DavidAbstract:Synthesis of trimeric Imidazoquinoline dendrimer 3.
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Synthesis of Click reaction derived Imidazoquinoline dendrimer 8.
2013Co-Authors: Nikunj M Shukla, Cole A Mutz, Deepak B. Salunke, Subbalakshmi S Malladi, Rajalakshmi Balakrishna, Sunil A DavidAbstract:Synthesis of Click reaction derived Imidazoquinoline dendrimer 8.
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Anti-bovine α-lactalbumin-specific IgG titers.
2013Co-Authors: Nikunj M Shukla, Cole A Mutz, Deepak B. Salunke, Subbalakshmi S Malladi, Rajalakshmi Balakrishna, Sunil A DavidAbstract:Top: Anti-bovine α-lactalbumin-specific IgG titers in rabbits adjuvanted with 4, 8, a TLR7-specific Imidazoquinoline (1-benzyl-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine; reported as Compound 31 in Ref. 9), and unadjuvanted controls (n = 3 per cohort). Ratios of immune/pre-immune titers yielding absorbance values of 1.0 are shown for the individual samples. Each symbol corresponds to the titer of a single animal. Bottom: Chaotropic ELISA showing apparent titers as a function of chaotrope (NaSCN) concentration. Means and SD are shown.
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Potent Adjuvanticity of a Pure TLR7-Agonistic Imidazoquinoline Dendrimer
PLOS ONE, 2012Co-Authors: Nikunj M Shukla, Cole A Mutz, Deepak B. Salunke, Subbalakshmi S Malladi, Rajalakshmi Balakrishna, Sunil A DavidAbstract:Engagement of toll-like receptors (TLRs) serve to link innate immune responses with adaptive immunity and can be exploited as powerful vaccine adjuvants for eliciting both primary and anamnestic immune responses. TLR7 agonists are highly immunostimulatory without inducing dominant proinflammatory cytokine responses. We synthesized a dendrimeric molecule bearing six units of a potent TLR7/TLR8 dual-agonistic Imidazoquinoline to explore if multimerization of TLR7/8 would result in altered activity profiles. A complete loss of TLR8-stimulatory activity with selective retention of the TLR7-agonistic activity was observed in the dendrimer. This was reflected by a complete absence of TLR8-driven proinflammatory cytokine and interferon (IFN)-γ induction in human PBMCs, with preservation of TLR7-driven IFN-α induction. The dendrimer was found to be superior to the Imidazoquinoline monomer in inducing high titers of high-affinity antibodies to bovine α-lactalbumin. Additionally, epitope mapping experiments showed that the dendrimer induced immunoreactivity to more contiguous peptide epitopes along the amino acid sequence of the model antigen.
Richard F. Heier - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites.
Journal of Medicinal Chemistry, 1997Co-Authors: Richard F. Heier, Lester A Dolak, J. N. Duncan, M. F. Lipton, M. A. Mauragis, Nanette F. Nichols, Deborah K. Hyslop, I J Martin, Montford F. Piercey, Peggy J. K. D. SchreurAbstract:The Imidazoquinoline (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one [(R)-6]; intermediate metabolites, where N-demethylation to the Imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient...
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Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites.
Journal of medicinal chemistry, 1997Co-Authors: Richard F. Heier, Lester A Dolak, J. N. Duncan, M. F. Lipton, M. A. Mauragis, Nanette F. Nichols, Deborah K. Hyslop, I J Martin, Montford F. Piercey, Peggy J. K. D. SchreurAbstract:The Imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H) -one [(R)-6], intermediate metabolites, where N-demethylation to the Imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3-6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.
Douglas S Scherr - One of the best experts on this subject based on the ideXlab platform.
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Toll-Like Receptor 7 Agonist Therapy with Imidazoquinoline Enhances Cancer Cell Death and Increases Lymphocytic Infiltration and Proinflammatory Cytokine Production in Established Tumors of a Renal Cell Carcinoma Mouse Model
Journal of Oncology, 2012Co-Authors: Eric Kauffman, Michael J. Schwartz, Douglas S ScherrAbstract:Imidazoquinolines are synthetic toll-like receptor 7 and 8 agonists and potent dendritic cell activators with established anticancer activity. Here we test the hypothesis that Imidazoquinoline has in vivo efficacy within established renal cell carcinoma (RCC) tumors. Immunocompetent mice bearing syngeneic RCC xenografts were treated with Imidazoquinoline or placebo at two separate time points. Harvested tumors were assayed by TUNEL/caspase-3/Ki67 immunostains to evaluate cell death/apoptosis/proliferation, and CD3/B220/CD45 immunostains to evaluate T-cell lymphocyte/B-cell lymphocyte/pan-leukocyte tumor infiltration. ELISA measurement of tumor and serum levels of proinflammatory cytokines, IL-6 and MCP-1, was performed. A single Imidazoquinoline dose significantly decreased RCC tumor growth by 50% and repeat dosing compounded the effect, without observed weight loss or other toxicity. Tumor immunostaining revealed significant increases in cell death and apoptosis without changes in cell proliferation, supporting induction of apoptosis as the primary mechanism of tumor growth suppression. Imidazoquinoline treatment also significantly enhanced peritumoral aggregation and intratumoral infiltration by T-cell lymphocytes, while increasing intratumoral (but not serum) levels of proinflammatory cytokines. In conclusion, Imidazoquinoline treatment enhances T-cell lymphocyte infiltration and proinflammatory cytokine production within established mouse RCC tumors, while suppressing tumor growth via induction of cancer cell apoptosis. These findings support a therapeutic role for Imidazoquinoline in RCC.
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Established Tumors of a Renal Cell Carcinoma Mouse Model
2011Co-Authors: Eric C. Kauffman, Michael J. Schwartz, Huixian Liu, Douglas S ScherrAbstract:License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Imidazoquinolines are synthetic toll-like receptor 7 and 8 agonists and potent dendritic cell activators with established anticancer activity. Here we test the hypothesis that Imidazoquinoline has in vivo efficacy within established renal cell carcinoma (RCC) tumors. Immunocompetent mice bearing syngeneic RCC xenografts were treated with Imidazoquinoline or placebo at two separate time points. Harvested tumors were assayed by TUNEL/caspase-3/Ki67 immunostains to evaluate cell death/apoptosis/proliferation, and CD3/B220/CD45 immunostains to evaluate T-cell lymphocyte/B-cell lymphocyte/pan-leukocyte tumor infiltration. ELISA measurement of tumor and serum levels of proinflammatory cytokines, IL-6 and MCP-1, was performed. A single Imidazoquinoline dose significantly decreased RCC tumor growth by 50 % and repeat dosing compounded the effect, without observed weight loss or other toxicity. Tumor immunostaining revealed significant increases in cell death and apoptosis without changes in cell proliferation, supporting induction of apoptosis as the primary mechanism of tumor growth suppression. Imidazoquinoline treatment also significantly enhanced peritumoral aggregation and intratumoral infiltration by T-cell lymphocytes, while increasing intratumoral (but not serum) levels of proinflammatory cytokines. In conclusion
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Antitumor effects of an Imidazoquinoline in renal cell carcinoma.
Urology, 2009Co-Authors: Michael J. Schwartz, Hideki Kawamoto, David H Hwang, Douglas S ScherrAbstract:Objectives To evaluate the effects of Imidazoquinolines in renal cell carcinoma (RCC). Methods In vitro experiments were carried out using mouse (RENCA) and human (CAKI-1, CAKI-2, and A-498) RCC cell lines. Toll-like receptor-7 (TLR7) expression was assessed by Western blot. We determined the ability of Imidazoquinolines to induce apoptosis and inhibit cell viability in vitro. For in vivo experiments, RENCA cells were injected into the tail vein of syngeneic mice. One week after injection, mice were given oral Imidazoquinoline or placebo for 14 days. Mice were then sacrificed, and lungs were inspected for tumor nodules. Immunohistochemical staining was used to assess apoptosis in vivo. Results Toll-like receptor-7 was expressed in all cell lines tested, with RENCA cells showing the highest level of expression. Imidazoquinolines inhibited in vitro cell viability of RENCA, CAKI-2, and A-498 cell lines in a time-dependent manner. Viability of CAKI-1 was not inhibited significantly. Apoptosis induction was pronounced in RENCA cells treated with Imidazoquinoline. Compared with placebo, oral Imidazoquinoline significantly reduced the number of pulmonary metastasis and increased cell death in vivo. Conclusions Imidazoquinolines inhibit cell viability and cause deoxyribonucleic acid fragmentation leading to apoptosis in RCC cell lines, potentially working through the TLR7 expressed by RCC cell lines. Preliminary data from a mouse model of metastatic RCC also suggest antitumor effects and induction of apoptosis in vivo.
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Tumour growth inhibition by an Imidazoquinoline is associated with c-Myc down-regulation in urothelial cell carcinoma.
BJUI, 2008Co-Authors: Michael J. Schwartz, David H Hwang, Douglas S ScherrAbstract:OBJECTIVE To detect and characterize the potential role of c-Myc in the inhibition of proliferation and induction of cell death of urothelial cell carcinoma by Imidazoquinolines, Toll-like receptor-7 (TLR7) agonists, that are thought to exert their immunogenic effects through the MyD88/NF-κB pathway. MATERIALS AND METHODS Human (T24) and murine (MBT-2) bladder cancer cell lines were cultured in normal culture medium or medium supplemented with Imidazoquinoline. The effects of Imidazoquinoline on gene expression, transcription and tumorigenesis were then evaluated. Effects of Imidazoquinoline on in vivo bladder tumour growth and gene expression were investigated using a mouse model of orthotopic bladder cancer. RESULTS There was a dose-dependent decrease in c-Myc expression in bladder cancer cells treated with Imidazoquinoline; the transcriptional activity of c-Myc was also significantly reduced. Furthermore, the in vitro proliferation and tumorigenesis of MBT-2 cells were suppressed in a dose-dependent manner. For in vivo experiments, a third of mice with bladder cancer treated with intravesical Imidazoquinoline showed evidence of residual bladder tumour, vs all the placebo-treated mice. In vivo expression of c-Myc, cyclin D2 and proliferating cell nuclear antigen in the bladder tumour tissue were also down-regulated. CONCLUSIONS Imidazoquinolines can inhibit c-Myc expression and directly affect cell growth and tumorigenesis of bladder cancer cells, independent of an immune response. These direct effects might be synergistic with previously described immunogenic actions of Imidazoquinolines. Our findings could broaden the potential application of Imidazoquinoline therapy beyond dermatological malignancies, and further clinical studies are warranted.
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antitumor effects of Imidazoquinolines in urothelial cell carcinoma of the bladder
The Journal of Urology, 2007Co-Authors: Eric B Smith, Hideki Kawamoto, Michael Schwartz, David H Hwang, Douglas S ScherrAbstract:Purpose: Imidazoquinolines (Toll-like receptor-7 agonists) are a class of synthetic immune modulating agents. Imiquimod, a member of this drug family, is currently used as first line topical therapy for genital condyloma. It recently showed clinical efficacy against several benign and malignant skin lesions, including actinic keratosis and basal cell carcinoma. Working primarily through the stimulation of a proinflammatory immune response, the mechanism of action of imiquimod may be similar to that through which bacillus Calmette-Guerin is thought to act. We hypothesized that Imidazoquinolines have therapeutic potential against bladder cancer. We determined the in vitro and in vivo effects of Imidazoquinolines against bladder cancer cells. Materials and Methods: The human and murine J82, T24, TCC-SUP (American Tissue Culture Collection, Manassas, Virginia) and MBT-2 bladder cancer cell lines were cultured in normal culture medium or medium supplemented with Imidazoquinoline. Effects on cell viability, apoptosis induction and cytokine production were evaluated. In addition, the effects of Imidazoquinoline on in vivo bladder tumor growth were determined via intravesical instillation in an orthotopic bladder tumor model in the mouse. Results: A dose dependent decrease in cell viability was observed in all tumor cell lines treated with Imidazoquinoline. In addition, Imidazoquinoline significantly induced apoptosis and cytokine production. In in vivo experiments most mice treated with Imidazoquinoline showed only an intense inflammatory response with no evidence of tumor, while control mice showed tumor growth. Conclusions: Imidazoquinolines have potent direct activity against bladder cancer cells by decreasing cell viability and inducing apoptosis and cytokine production. In addition, in vivo data suggest antitumor effects in an orthotopic bladder cancer mouse model. Therefore, Imidazoquinolines may have therapeutic potential as a synthetic intravesical agent against bladder cancer.
Nanette F. Nichols - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites.
Journal of Medicinal Chemistry, 1997Co-Authors: Richard F. Heier, Lester A Dolak, J. N. Duncan, M. F. Lipton, M. A. Mauragis, Nanette F. Nichols, Deborah K. Hyslop, I J Martin, Montford F. Piercey, Peggy J. K. D. SchreurAbstract:The Imidazoquinoline (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one [(R)-6]; intermediate metabolites, where N-demethylation to the Imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient...
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Synthesis and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine and its metabolites.
Journal of medicinal chemistry, 1997Co-Authors: Richard F. Heier, Lester A Dolak, J. N. Duncan, M. F. Lipton, M. A. Mauragis, Nanette F. Nichols, Deborah K. Hyslop, I J Martin, Montford F. Piercey, Peggy J. K. D. SchreurAbstract:The Imidazoquinoline (R)-5,6-Dihydro-N,N-dimethyl-4H-imidazo[4,5,1-ij]quinolin-5-amine [(R)-3] is a potent dopamine agonist when tested in animals but surprisingly shows very low affinity in in vitro binding assays. When incubated with mouse or monkey liver S9 microsomes, (R)-3 is metabolized by N-demethylation and oxidation to (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]quinolin-2(1H) -one [(R)-6], intermediate metabolites, where N-demethylation to the Imidazoquinoline (R)-4 and where oxidation to the imidazoquinolinone (R)-5 has taken place, are also observed in these incubates. A cross-species study on the metabolism of (R)-3 in vitro has shown large variations in the extent of metabolism from species to species. Imidazoquinolinones (R)-5 and (R)-6 have comparable activity to (R)-3 in animals and also show good dopaminergic (D2) and serotonergic (5HT1A) activities in binding assays. It is probable that these metabolites account at least in part for the in vivo activity found for (R)-3. Efficient syntheses for compounds 3-6 as single enantiomers from quinoline are presented together with information on the biological activities and metabolic stabilities of these compounds.
