The Experts below are selected from a list of 264 Experts worldwide ranked by ideXlab platform
Vincent C. Manganiello - One of the best experts on this subject based on the ideXlab platform.
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Phosphodiesterase type 3A (PDE3A), but not type 3B (PDE3B), contributes to the adverse cardiac remodeling induced by pressure overload
Journal of molecular and cellular cardiology, 2019Co-Authors: Nazari Polidovitch, Faiyaz Ahmad, Sibao Yang, Huan Sun, Robert Lakin, Xiaodong Gao, Patrick C. Turnbull, Carmelina Chiarello, Christopher G. R. Perry, Vincent C. ManganielloAbstract:Abstract Phosphodiesterase type 3 (PDE3) Inhibitors block the cAMP hydrolyzing activity of both PDE3 isoforms, PDE3A and PDE3B, which have distinct roles in the heart. Although PDE3 Inhibitors improve cardiac function in heart disease patients, they also increase mortality. Nevertheless, PDE3 Inhibitors can provide benefit to non-ischemic heart disease patients and are used extensively to treat heart failure in dogs. Since the isoform-dependence of the complex cardiac actions of PDE3 inhibition in diseased hearts remains unknown, we assessed the effects of PDE3 Inhibitors as well as gene ablation of PDE3A or PDEB in mice following the induction of non-ischemic heart disease by pressure-overload with transverse-aortic constriction (TAC). As expected, after 6 weeks of TAC, mice exhibited left ventricular contractile dysfunction, dilation, hypertrophy and interstitial fibrosis, in association with increased macrophage numbers, activation of p38 MAPK and elevated PDE3 activity. Chronic PDE3 inhibition with milrinone (MIL), at doses that did not affect either cardiac contractility or arterial blood pressure, profoundly attenuated the adverse ventricular remodeling, reduced macrophage number and diminished p38-MAPK activation induced by TAC. Surprisingly, whole-body ablation of PDE3A, but not PDE3B, provided similar protection against TAC-induced adverse ventricular remodeling, and the addition of MIL to mice lacking PDE3A provided no further protection. Our results support the conclusion that PDE3A plays an important role in adverse cardiac remodeling induced by chronic pressure overload in mice, although the underlying biochemical mechanisms remain to be fully elucidated. The implications of this conclusion on the clinical use of PDE3 Inhibitors are discussed.
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Cyclic Nucleotide Phosphodiesterases
Encyclopedia of Biological Chemistry, 2013Co-Authors: Vincent C. Manganiello, J. Fontana, Eva Degerman, Faiyaz AhmadAbstract:Class I cyclic nucleotide phosphodiesterases (PDEs) comprise the 11 structurally related, highly regulated, and functionally distinct mammalian PDE gene families (PDEs 1–11). By catalyzing hydrolysis of cyclic adenosine monophosphate and cyclic guanosine monophosphate, these enzymes regulate the intracellular concentrations, and, consequently, the biological effects of these important intracellular second messengers. PDEs exhibit a common structural organization, with a conserved catalytic domain in the C-terminal regions. The subcellular localization of PDEs and their interactions with molecular scaffolds and regulatory partners occasion their assembly into specialized macromolecular complexes within discrete functional microdomains, thus allowing for precise and spatial/temporal control and compartmentation of cyclic nucleotide-mediated signal transduction. The PDE superfamily is a target for drug discovery, with PDE5 Inhibitors used for erectile dysfunction and pulmonary hypertension, PDE3 Inhibitors for peripheral arterial disease and acute decompensated heart failure.
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From PDE3B to the regulation of energy homeostasis.
Current opinion in pharmacology, 2011Co-Authors: Eva Degerman, Faiyaz Ahmad, Lena Stenson, Youn Wook Chung, Emilia Guirguis, Bilal Omar, Vincent C. ManganielloAbstract:The incidence of obesity in the developed world is increasing at an alarming rate. Concurrent with the increase in the incidence of obesity is an increase in the incidence of type 2 diabetes. Cyclic AMP (cAMP) and cGMP are key second messengers in all cells; for example, when it comes to processes of relevance for the regulation of energy metabolism, cAMP is a key mediator in the regulation of lipolysis, glycogenolysis, gluconeogenesis and pancreatic β cell insulin secretion. PDE3B, one of several enzymes which hydrolyze cAMP and cGMP, is expressed in cells of importance for the regulation of energy homeostasis, including adipocytes, hepatocytes, hypothalamic cells and β cells. It has been shown, using PDE3 Inhibitors and gene targeting approaches in cells and animals, that altered levels of PDE3B result in a number of changes in the regulation of glucose and lipid metabolism and in overall energy homeostasis. This article highlights the complexity involved in the regulation of PDE3B by hormones, and in the regulation of downstream metabolic effects by PDE3B in several interacting tissues.
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Expression and regulation of cyclic nucleotide phosphodiesterases in human and rat pancreatic islets
PloS one, 2010Co-Authors: Emilia Heimann, Vincent C. Manganiello, Helena A. Jones, Svante Resjö, Lena Stenson, Eva DegermanAbstract:As shown by transgenic mouse models and by using phosphodiesterase 3 (PDE3) Inhibitors, PDE3B has an important role in the regulation of insulin secretion in pancreatic β-cells. However, very little is known about the regulation of the enzyme. Here, we show that PDE3B is activated in response to high glucose, insulin and cAMP elevation in rat pancreatic islets and INS-1 (832/13) cells. Activation by glucose was not affected by the presence of diazoxide. PDE3B activation was coupled to an increase as well as a decrease in total phosphorylation of the enzyme. In addition to PDE3B, several other PDEs were detected in human pancreatic islets: PDE1, PDE3, PDE4C, PDE7A, PDE8A and PDE10A. We conclude that PDE3B is activated in response to agents relevant for β-cell function and that activation is linked to increased as well as decreased phosphorylation of the enzyme. Moreover, we conclude that several PDEs are present in human pancreatic islets.
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Re-discovering PDE3 Inhibitors--new opportunities for a long neglected target.
Current topics in medicinal chemistry, 2007Co-Authors: Philip E. Thompson, Vincent C. Manganiello, Eva DegermanAbstract:The PDE3 enzymes or "low Km cGMP-inhibited phosphodiesterases" have long been established as important mediators of cellular physiology, and synthetic PDE3 Inhibitors have been critical to the delineation of the enzymes' roles. Yet despite decades of progress on the biology of these enzymes, the medicinal chemistry landscape relating to PDE3 Inhibitors has remained essentially unchanged since the mid 1990's. Up until then the field was at the cutting edge of drug design; without the tools of molecular and structural biology, molecules of high potency were being achieved using logical pharmacophore models and lead modification. Yet virtually all the impetus went out of this area on the back of failures at the clinic and PDE3 as a therapeutic target largely fell out of favour. A decade later and with the "new" technologies of structural and molecular biology breathing new life into PDE3 research in general, PDE3 Inhibitors are sought for target validation in an array of therapeutic applications. In this review, we examine the current state of PDE3 research; firstly we summarize the structural and functional properties of PDE3 enzymes with particular attention to the heterogeneity within this class of enzymes which differ markedly in expression, localisation and means of regulation across various tissue types. It is the structural and functional complexity of the PDE3 enzymes that underpins the re-emergence of PDE3s roles as targets for drug design. We then look at past clinical evaluation of PDE3 Inhibitors that occurred without that information and which may have had a significant bearing on the outcome of those drug discovery efforts. Finally we look at current approaches to the design of PDE3 Inhibitors which utilize that historic data but also incorporate new inputs from structural biology and combinatorial chemistry.
Eva Degerman - One of the best experts on this subject based on the ideXlab platform.
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Cyclic Nucleotide Phosphodiesterases
Encyclopedia of Biological Chemistry, 2013Co-Authors: Vincent C. Manganiello, J. Fontana, Eva Degerman, Faiyaz AhmadAbstract:Class I cyclic nucleotide phosphodiesterases (PDEs) comprise the 11 structurally related, highly regulated, and functionally distinct mammalian PDE gene families (PDEs 1–11). By catalyzing hydrolysis of cyclic adenosine monophosphate and cyclic guanosine monophosphate, these enzymes regulate the intracellular concentrations, and, consequently, the biological effects of these important intracellular second messengers. PDEs exhibit a common structural organization, with a conserved catalytic domain in the C-terminal regions. The subcellular localization of PDEs and their interactions with molecular scaffolds and regulatory partners occasion their assembly into specialized macromolecular complexes within discrete functional microdomains, thus allowing for precise and spatial/temporal control and compartmentation of cyclic nucleotide-mediated signal transduction. The PDE superfamily is a target for drug discovery, with PDE5 Inhibitors used for erectile dysfunction and pulmonary hypertension, PDE3 Inhibitors for peripheral arterial disease and acute decompensated heart failure.
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From PDE3B to the regulation of energy homeostasis.
Current opinion in pharmacology, 2011Co-Authors: Eva Degerman, Faiyaz Ahmad, Lena Stenson, Youn Wook Chung, Emilia Guirguis, Bilal Omar, Vincent C. ManganielloAbstract:The incidence of obesity in the developed world is increasing at an alarming rate. Concurrent with the increase in the incidence of obesity is an increase in the incidence of type 2 diabetes. Cyclic AMP (cAMP) and cGMP are key second messengers in all cells; for example, when it comes to processes of relevance for the regulation of energy metabolism, cAMP is a key mediator in the regulation of lipolysis, glycogenolysis, gluconeogenesis and pancreatic β cell insulin secretion. PDE3B, one of several enzymes which hydrolyze cAMP and cGMP, is expressed in cells of importance for the regulation of energy homeostasis, including adipocytes, hepatocytes, hypothalamic cells and β cells. It has been shown, using PDE3 Inhibitors and gene targeting approaches in cells and animals, that altered levels of PDE3B result in a number of changes in the regulation of glucose and lipid metabolism and in overall energy homeostasis. This article highlights the complexity involved in the regulation of PDE3B by hormones, and in the regulation of downstream metabolic effects by PDE3B in several interacting tissues.
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Expression and regulation of cyclic nucleotide phosphodiesterases in human and rat pancreatic islets
PloS one, 2010Co-Authors: Emilia Heimann, Vincent C. Manganiello, Helena A. Jones, Svante Resjö, Lena Stenson, Eva DegermanAbstract:As shown by transgenic mouse models and by using phosphodiesterase 3 (PDE3) Inhibitors, PDE3B has an important role in the regulation of insulin secretion in pancreatic β-cells. However, very little is known about the regulation of the enzyme. Here, we show that PDE3B is activated in response to high glucose, insulin and cAMP elevation in rat pancreatic islets and INS-1 (832/13) cells. Activation by glucose was not affected by the presence of diazoxide. PDE3B activation was coupled to an increase as well as a decrease in total phosphorylation of the enzyme. In addition to PDE3B, several other PDEs were detected in human pancreatic islets: PDE1, PDE3, PDE4C, PDE7A, PDE8A and PDE10A. We conclude that PDE3B is activated in response to agents relevant for β-cell function and that activation is linked to increased as well as decreased phosphorylation of the enzyme. Moreover, we conclude that several PDEs are present in human pancreatic islets.
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Re-discovering PDE3 Inhibitors--new opportunities for a long neglected target.
Current topics in medicinal chemistry, 2007Co-Authors: Philip E. Thompson, Vincent C. Manganiello, Eva DegermanAbstract:The PDE3 enzymes or "low Km cGMP-inhibited phosphodiesterases" have long been established as important mediators of cellular physiology, and synthetic PDE3 Inhibitors have been critical to the delineation of the enzymes' roles. Yet despite decades of progress on the biology of these enzymes, the medicinal chemistry landscape relating to PDE3 Inhibitors has remained essentially unchanged since the mid 1990's. Up until then the field was at the cutting edge of drug design; without the tools of molecular and structural biology, molecules of high potency were being achieved using logical pharmacophore models and lead modification. Yet virtually all the impetus went out of this area on the back of failures at the clinic and PDE3 as a therapeutic target largely fell out of favour. A decade later and with the "new" technologies of structural and molecular biology breathing new life into PDE3 research in general, PDE3 Inhibitors are sought for target validation in an array of therapeutic applications. In this review, we examine the current state of PDE3 research; firstly we summarize the structural and functional properties of PDE3 enzymes with particular attention to the heterogeneity within this class of enzymes which differ markedly in expression, localisation and means of regulation across various tissue types. It is the structural and functional complexity of the PDE3 enzymes that underpins the re-emergence of PDE3s roles as targets for drug design. We then look at past clinical evaluation of PDE3 Inhibitors that occurred without that information and which may have had a significant bearing on the outcome of those drug discovery efforts. Finally we look at current approaches to the design of PDE3 Inhibitors which utilize that historic data but also incorporate new inputs from structural biology and combinatorial chemistry.
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regulation and function of the cyclic nucleotide phosphodiesterase PDE3 gene family
Progress in Nucleic Acid Research and Molecular Biology, 2001Co-Authors: Yasmin Shakur, Eva Degerman, Lena Stenson Holst, Tova Rahn Landstrom, Matthew A Movsesian, Vincent C. ManganielloAbstract:Publisher Summary This chapter discusses some general information about cyclic nucleotide phosphodiesterases (PDEs). It also discusses the PDE3 gene family, emphasizing the molecular biology, structure/function relationships, and cellular regulation and functional roles of PDE3s, as well as physiological/pharmacological actions, therapeutic applications, and potential benefits of PDE3 Inhibitors. The major cause of concern in the use of PDE3 Inhibitors as therapeutic agents is the potential for increased mortality in patients with known heart disease. Although caution is certainly warranted in this context, conclusions should not be indiscriminately applied to all PDE3 Inhibitors. The pharmacological profiles of newer PDE3 Inhibitors differ from those of the PDE3 Inhibitors used in earlier heart failure clinical trials. Although milrinone and cilostazol are similar in potency as Inhibitors of PDE3, milrinone had greater effects than cilostazol on increasing both cyclic adenosine monophosphate (cAMP) and contractility in isolated rabbit cardiomyocytes. The ability to target PDE3 Inhibitors to specific isoforms in specific intracellular compartments and/or specific cells may be critical for improvement in efficacy and safety. The acute benefits and chronic adverse actions of PDE3 Inhibitors in patients, with heart failure, may result from the phosphorylation of different substrates of Protein kinase A (PKA) in different intracellular compartments. Newer PDE3 Inhibitors that target a specific isoform in the appropriate compartment could potentially confer beneficial hemodynamic effects without adverse effects on mortality.
Mohsen Shekouhy - One of the best experts on this subject based on the ideXlab platform.
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The synthesis and biological evaluation of nucleobases/tetrazole hybrid compounds: A new class of phosphodiesterase type 3 (PDE3) Inhibitors
Bioorganic & medicinal chemistry, 2020Co-Authors: Mohsen Shekouhy, Somaye Karimian, Ali Moaddeli, Zeinab Faghih, Yousef Delshad, Ali Khalafi-nezhadAbstract:Spired by the chemical structure of Cilostazol, a selective phosphodiesterase 3A (PDE3A) inhibitor, several novel hybrid compounds of nucleobases (uracil, 6-azauracil, 2-thiuracil, adenine, guanine, theophylline and theobromine) and tetrazole were designed and successfully synthesized and their inhibitory effects on PDE3A as well as their cytotoxicity on HeLa and MCF-7 cancerous cell lines were studied. Obtained results show the linear correlation between the inhibitory effect of synthesized compounds and their cytotoxicity. In some cases, the PDE3A inhibitory effects of synthesized compounds are higher than the Cilostazol. Besides, compared to a standard anticancer drug methotrexate, some of the synthesized compounds showed the higher cytotoxicity against the HeLa and MCF-7 cancerous cell lines.
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the synthesis and biological evaluation of nucleobases tetrazole hybrid compounds a new class of phosphodiesterase type 3 PDE3 Inhibitors
Bioorganic & Medicinal Chemistry, 2020Co-Authors: Mohsen Shekouhy, Somaye Karimian, Ali Moaddeli, Zeinab Faghih, Yousef Delshad, Ali KhalafinezhadAbstract:Spired by the chemical structure of Cilostazol, a selective phosphodiesterase 3A (PDE3A) inhibitor, several novel hybrid compounds of nucleobases (uracil, 6-azauracil, 2-thiuracil, adenine, guanine, theophylline and theobromine) and tetrazole were designed and successfully synthesized and their inhibitory effects on PDE3A as well as their cytotoxicity on HeLa and MCF-7 cancerous cell lines were studied. Obtained results show the linear correlation between the inhibitory effect of synthesized compounds and their cytotoxicity. In some cases, the PDE3A inhibitory effects of synthesized compounds are higher than the Cilostazol. Besides, compared to a standard anticancer drug methotrexate, some of the synthesized compounds showed the higher cytotoxicity against the HeLa and MCF-7 cancerous cell lines.
Matthew A Movsesian - One of the best experts on this subject based on the ideXlab platform.
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Novel approaches to targeting PDE3 in cardiovascular disease.
Pharmacology & therapeutics, 2016Co-Authors: Matthew A MovsesianAbstract:Inhibitors of PDE3, a family of dual-specificity cyclic nucleotide phosphodiesterases, are used clinically to increase cardiac contractility by raising intracellular cAMP content in cardiac myocytes and to reduce vascular resistance by increasing intracellular cGMP content in vascular smooth muscle myocytes. When used in the treatment of patients with heart failure, PDE3 Inhibitors are effective in the acute setting but increase sudden cardiac death with long-term administration, possibly reflecting pro-apoptotic and pro-hypertrophic consequences of increased cAMP-mediated signaling in cardiac myocytes. cAMP-mediated signaling in cardiac myocytes is highly compartmentalized, and different phosphodiesterases, by controlling cAMP content in functionally discrete intracellular microcompartments, regulate different cAMP-mediated pathways. Four variants/isoforms of PDE3 (PDE3A1, PDE3A2, PDE3A3, and PDE3B) are expressed in cardiac myocytes, and new experimental results have demonstrated that these isoforms, which are differentially localized intracellularly through unique protein-protein interactions, control different physiologic responses. While the catalytic regions of these isoforms may be too similar to allow the catalytic activity of each isoform to be selectively inhibited, targeting their unique protein-protein interactions may allow desired responses to be elicited without the adverse consequences that limit the usefulness of existing PDE3 Inhibitors.
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PDE3 inhibition in dilated cardiomyopathy.
Current opinion in pharmacology, 2011Co-Authors: Matthew A Movsesian, Omar Wever-pinzon, Fabrice VandeputAbstract:In dilated cardiomyopathy, a condition characterized by chamber enlargement and reduced myocardial contractility, decreases in β-adrenergic receptor density and increases in Gαi and β-adrenergic receptor kinase activities attenuate the stimulation of adenylyl cyclase in response to catecholamines. PDE3 Inhibitors have been used to ‘overcome’ the reduction in cAMP generation by blocking cAMP hydrolysis. These drugs increase contractility in the short-term, but long-term administration leads to an increase in mortality that correlates with an increase in sudden cardiac death. Whether separate mechanisms account for these beneficial and harmful effects, and, if so, whether PDE3 can be targeted so as to increase contractility without increasing mortality are questions that remain unanswered.
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Inhibitors of cyclic nucleotide phosphodiesterase 3 and 5 as therapeutic agents in heart failure.
Expert opinion on investigational drugs, 2006Co-Authors: Josef Stehlik, Matthew A MovsesianAbstract:Cyclic nucleotide phosphodiesterases (PDE) 3 and 5 regulate cAMP and cGMP signalling in cardiac and smooth muscle myocytes. Important advances in the understanding of the roles of these enzymes have recently been made. PDE3 Inhibitors have inotropic and vasodilatory properties, and although they acutely improve haemodynamics in patients with heart failure, they do not improve long-term morbidity and mortality. Although combination therapy with β-adrenergic receptor antagonists or selective inhibition of specific PDE3 isoforms might result in a more favourable long-term outcome, more clinical data are needed to test this proposition. The role of PDE5 Inhibitors in the treatment of cardiac disease is evolving. PDE5 Inhibitors cause pulmonary and systemic vasodilation. How these drugs will compare with other vasodilators in terms of long-term outcomes in patients with heart failure is unknown. Recent studies also suggest that PDE5 Inhibitors may have antihypertropic effects, exerted through increased myocard...
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Comparison of the Effects of Cilostazol and Milrinone on cAMP-PDE Activity, Intracellular cAMP and Calcium in the Heart
Cardiovascular Drugs and Therapy, 2002Co-Authors: Yasmin Shakur, Masuhiro Yoshitake, Jun-ichi Kambayashi, Matthew A Movsesian, Miranda Fong, James Hensley, James Cone, Yongge LiuAbstract:We investigated the basis for the difference in the cardiotonic effects of the PDE3 Inhibitors cilostazol and milrinone in the rabbit heart. Cilostazol displayed greater selectivity than milrinone for inhibition of cAMP-PDE activity in microsomal vs cytosolic fractions from rabbit heart. This difference was due to the inhibition of significantly less cytosolic cAMP-PDE activity by cilostazol compared to milrinone. A combination of cilostazol (>15 μM) and the PDE4 selective inhibitor, rolipram (5 μM), inhibited levels of cytosolic cAMP-PDE activity similar to those inhibited by milrinone on its own. This suggested that milrinone inhibited PDE4 in addition to PDE3 activity. In isolated rabbit cardiomyocytes, milrinone (>10 μM) caused greater elevations in intracellular cAMP and calcium than cilostazol. In the presence of rolipram, however, the cAMP and calcium elevating effects of cilostazol and milrinone were similar. Therefore, in rabbit heart, partial inhibition of PDE4 by milrinone contributed to greater increases in cardiomyocyte cAMP and calcium levels than cilostazol. PDE4 activity in failing human heart was lower than in rabbit heart and there was no significant difference in the inhibition of human cytosolic cAMP-PDE by cilostazol and milrinone. Our results suggest that in normal rabbit heart inhibition of PDE4 by milrinone may partly contribute to the greater cardiotonic effect of milrinone when compared to cilostazol. However, the lower level of PDE4 activity in failing human heart suggests that factors other than inhibition of PDE4 by milrinone may contribute to differences in cardiotonic action when compared to cilostazol.
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regulation and function of the cyclic nucleotide phosphodiesterase PDE3 gene family
Progress in Nucleic Acid Research and Molecular Biology, 2001Co-Authors: Yasmin Shakur, Eva Degerman, Lena Stenson Holst, Tova Rahn Landstrom, Matthew A Movsesian, Vincent C. ManganielloAbstract:Publisher Summary This chapter discusses some general information about cyclic nucleotide phosphodiesterases (PDEs). It also discusses the PDE3 gene family, emphasizing the molecular biology, structure/function relationships, and cellular regulation and functional roles of PDE3s, as well as physiological/pharmacological actions, therapeutic applications, and potential benefits of PDE3 Inhibitors. The major cause of concern in the use of PDE3 Inhibitors as therapeutic agents is the potential for increased mortality in patients with known heart disease. Although caution is certainly warranted in this context, conclusions should not be indiscriminately applied to all PDE3 Inhibitors. The pharmacological profiles of newer PDE3 Inhibitors differ from those of the PDE3 Inhibitors used in earlier heart failure clinical trials. Although milrinone and cilostazol are similar in potency as Inhibitors of PDE3, milrinone had greater effects than cilostazol on increasing both cyclic adenosine monophosphate (cAMP) and contractility in isolated rabbit cardiomyocytes. The ability to target PDE3 Inhibitors to specific isoforms in specific intracellular compartments and/or specific cells may be critical for improvement in efficacy and safety. The acute benefits and chronic adverse actions of PDE3 Inhibitors in patients, with heart failure, may result from the phosphorylation of different substrates of Protein kinase A (PKA) in different intracellular compartments. Newer PDE3 Inhibitors that target a specific isoform in the appropriate compartment could potentially confer beneficial hemodynamic effects without adverse effects on mortality.
Ali Khalafi-nezhad - One of the best experts on this subject based on the ideXlab platform.
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The synthesis and biological evaluation of nucleobases/tetrazole hybrid compounds: A new class of phosphodiesterase type 3 (PDE3) Inhibitors
Bioorganic & medicinal chemistry, 2020Co-Authors: Mohsen Shekouhy, Somaye Karimian, Ali Moaddeli, Zeinab Faghih, Yousef Delshad, Ali Khalafi-nezhadAbstract:Spired by the chemical structure of Cilostazol, a selective phosphodiesterase 3A (PDE3A) inhibitor, several novel hybrid compounds of nucleobases (uracil, 6-azauracil, 2-thiuracil, adenine, guanine, theophylline and theobromine) and tetrazole were designed and successfully synthesized and their inhibitory effects on PDE3A as well as their cytotoxicity on HeLa and MCF-7 cancerous cell lines were studied. Obtained results show the linear correlation between the inhibitory effect of synthesized compounds and their cytotoxicity. In some cases, the PDE3A inhibitory effects of synthesized compounds are higher than the Cilostazol. Besides, compared to a standard anticancer drug methotrexate, some of the synthesized compounds showed the higher cytotoxicity against the HeLa and MCF-7 cancerous cell lines.