Rita Morigi - Academia.edu (original) (raw)
Papers by Rita Morigi
Proceedings of the National Academy of Sciences, 2018
Significance In the past decades, several compounds have been developed specifically targeting G ... more Significance In the past decades, several compounds have been developed specifically targeting G quadruplexes (G4s), as these noncanonical DNA structures are considered promising targets of effective anticancer drugs. However, despite the high number of known ligands, none showed efficacy in cancer patients. We have investigated the interplay of G4s with R loops, another noncanonical DNA structure, and the findings reveal a mechanism of genome instability and cell killing by G4 ligands, particularly effective in cancer cells deficient of BRCA2 activity. This knowledge establishes a mechanistic model of G4 ligand activity in cancer cells that can open new lines of investigation aiming at developing clinically effective G4 ligands.
![Research paper thumbnail of Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents](https://attachments.academia-assets.com/78575675/thumbnails/1.jpg)
](European journal of medicinal chemistry, 2019
A small library of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones has been synthesized and ... more A small library of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones has been synthesized and screened according to protocols available at the National Cancer Institute (NCI). Some derivatives were potent antiproliferative agents, showing GI50 values in the nanomolar range. Remarkably, when most active compounds against leukemia cells were tested in human peripheral blood lymphocytes from healthy donors, were 100-200 times less cytotoxic. Some compounds, selected by the Biological Evaluation Committee of NCI, were examined to determine tubulin assembly inhibition. Furthermore, flow cytometric studies performed on HeLa, HT-29, and A549 cells, showed that compounds 14 and 25 caused a block in the G2/M phase. Interestingly, these derivatives induced apoptosis through the mitochondrial death pathway, causing in parallel significant activation of both caspase-3 and -9, PARP cleavage and down-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1. Finally, compound 25 was also teste...
Molecules
A series of new Knoevenagel adducts, bearing two indolinone systems, has been synthesized and eva... more A series of new Knoevenagel adducts, bearing two indolinone systems, has been synthesized and evaluated on 60 human cancer cell lines according to protocols available at the National Cancer Institute (Bethesda, MD, USA). Some derivatives proved to be potent antiproliferative agents, showing GI50 values in the submicromolar range. Compound 5b emerged as the most active and was further studied in Jurkat cells in order to determine the effects on cell-cycle phases and the kind of cell death induced. Finally, oxidative stress and DNA damage induced by compound 5b were also analyzed.
Molecules
Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen recept... more Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen receptor beta (ERβ) expression has been suggested to act as a tumor suppressor in epithelial ovarian cancer by reducing both tumor growth and metastasis. ERβ expression abnormalities represent a critical step in the development and progression of ovarian cancer: for these reasons, its re-expression by genetic engineering, as well as the use of targeted ERβ therapies, still constitute an important therapeutic approach. 3-{[2-chloro-1-(4-chlorobenzyl)-5-methoxy-6-methyl-1H-indol-3-yl]methylene}-5-hydroxy-6-methyl-1,3-dihydro-2H-indol-2-one, referred to here as compound 3, has been shown to have cytostatic as well cytotoxic effects on various hormone-dependent cancer cell lines. However, the mechanism of its anti-carcinogenic activity is not well understood. Here, we offer a possible explanation of such an effect in the human ovarian cancer cell line IGROV1. Chromatin binding protein assay and li...
![Research paper thumbnail of Imidazo[2,1b ] Thiazole: Introduction, Current and Perspective](https://attachments.academia-assets.com/78575668/thumbnails/1.jpg)
](Bioenergetics: Open Access, 2017
![Research paper thumbnail of Synthesis of 3-(Imidazo[2,1-b]thiazol-6-yl)-2H-chromen-2-one Derivatives and Study of Their Antiviral Activity against Parvovirus B19](https://attachments.academia-assets.com/78575667/thumbnails/1.jpg)
](Molecules
Parvovirus B19 (B19V) is a human pathogenic virus associated with a wide range of clinical condit... more Parvovirus B19 (B19V) is a human pathogenic virus associated with a wide range of clinical conditions. Currently, there are no recognized antiviral drugs for B19V treatment; therefore, efforts in the search for compounds inhibiting B19V replication are now being pursued. Coumarins (chromen-2-ones) are considered a privileged structure for designing novel orally bioavailable and non-peptidic antiviral agents. To further contribute to the development of new drugs against B19V, our research was focused on the synthesis, characterization and evaluation of antiviral activity of some new 3-(imidazo[2,1-b]thiazol-6-yl)-2H-chromen-2-one derivatives. The effects of the synthesized compounds on cell viability and viral replication were investigated by employing two relevant cellular systems, the myeloblastoid cell line UT7/EpoS1 and primary erythroid progenitor cells (EPCs). Some of the tested compounds showed inhibitory activity both on cell viability and on viral replication, depending on t...
Medicinal chemistry (Shariqah (United Arab Emirates)), 2018
Fused five-membered heterocyclic rings containing bridgehead nitrogen atom are particularly versa... more Fused five-membered heterocyclic rings containing bridgehead nitrogen atom are particularly versatile in the field of medicinal chemistry because of their different biological activities. Among them, the imidazo[2,1-b]thiazole is an attractive fused heterocyclic core that has been extensively studied. The aim of the current study was to study the therapeutic applications of imidazo[2,1- b]thiazole derivatives as antimicrobial agents for the treatment of genitourinary infections. A traditional synthetic methodology was involved to obtain a small series of imidazothiazole derivatives. Herein, we report the antimicrobial activity of the imidazo[2,1-b]thiazole or imidazo[2,1- b]thiazolidine derivatives against selected fungi, Gram-positive and Gram-negative bacteria. Moreover, experiments were carried out to investigate the interference towards the endogenous microbiota. The most interesting of the series are the thiocyano derivatives (19, 23) showing a good profile for the treatment of...
Journal of pharmaceutical and biomedical analysis, Jan 5, 2017
1,4-Anthraquinone (ANQ) is proposed as a novel pre-column reagent for high performance liquid chr... more 1,4-Anthraquinone (ANQ) is proposed as a novel pre-column reagent for high performance liquid chromatography (HPLC) determination of N-acetylcysteine (NAC) and captopril (CAP) in pharmaceutical formulations. The derivatization reactions were carried out at room temperature: NAC at pH 8 for 1min, while CAP at pH 7.5 for 20min. Both reactions reached completeness at a reagent to thiol molar ratio of about 2.5. The synthesised derivatives were characterized by (1)H NMR and IR. The chromatographic separations were performed on a C18 Phenomenex Synergi Fusion 4μm (250mm×4.6mm I.D.) stainless steel column with detection at λ=300nm. The mobile phase consisted of methanol/triethylammonium (TEA) phosphate buffer (pH 3; 0.05mol/L) 75:25 (v/v) at a flow-rate of 0.4mL/min for NAC and 88:12 (v/v), at a flow-rate of 0.6mL/min for CAP. The validation parameters (linearity, sensitivity, accuracy, precision, specificity and stability) were highly satisfactory. Linear response was observed (determina...
Current Medicinal Chemistry, 2016
Despite in recent years a substantial progress has been made in the treatment of pulmonary hypert... more Despite in recent years a substantial progress has been made in the treatment of pulmonary hypertension, it is still a severe disease characterized by poor prognosis, and the search for new drugs remains a priority. Current remedies address mainly the vasoconstrictor/vasodilator imbalance in the pulmonary circulation, while the causes of the disease are only moderately affected. Recently, the role of receptor and non receptor kinases in pulmonary hypertension has emerged and these targets were extensively considered for the development of new therapeutic strategies. This review discusses the patents on small-molecules targeting kinases involved in the proliferation/apoptosis imbalance, typically present in pulmonary hypertension. Bibliographic research for the inventions was carried out using Espacenet and SciFinder databases, "pulmonary hypertension and kinases" as research query and the range from 2010 to 2015. Only patents published in English were considered. A qualitative analysis of the contents of each patent was made to examine the reported compounds, the studies performed and the resulting conclusions. The review includes about thirty applications. Moreover, in order to illustrate the patho-phisiology of the disease and the mechanisms of the targets, about forty additional papers were reported. Considering that imatinib, a PDGF receptor inhibitor, entered the clinical trials for the treatment of pulmonary hypertension, the first patents were devoted to inhibitors of tyrosine kinase receptors, such as PDGFR and c-Kit. Subsequently, in addition to kinase receptors, the role of other pathways involved in pulmonary hypertension have emerged, and some research groups have focused their attention also on non-receptor kinases. Fifteen patents on this topic reported these new targets and new derivatives. However, in most of inventions, although the pulmonary hypertension is among the treatable diseases, the compounds were subjected only to antiproliferative assays and not to specific tests on animal models. The studies reported in this review confirm the continuous research efforts aimed to identify new targets and new drugs for the treatment of pulmonary hypertension. Several inhibitors of kinase were described. These compounds could inhibit mainly important branching processes and pathological growth of blood vessels, thereby might increase the lifespan of patients.
Journal of Medicinal Chemistry, 2016
Expert Opinion on Therapeutic Patents, 2015
2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done ... more 2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done on this bicyclic structure by academic and company researchers to synthesize compounds directed to a plethora of molecular targets in order to discover new drug leads. This review presents up-to-date information in the field of cancer therapy research based on this small building block. The present review gives an account of the recent patent literature (2008-2014) describing the discovery of 2-indolinone derivatives with selected therapeutic activities. In this period, a large amount of patents were published on this topic. We have limited the analysis to 37 patents on 2-indolinone derivatives having potential clinical application as chemotherapeutic agents. In this review, the therapeutic applications of 2-indolinone derivatives for the treatment of cancer reported in international patents have been discussed. 2-Indolinone is the scaffold of the compounds considered from a medicinal chemistry perspective. Many of them have been developed and marketed for therapeutic use. In cancer chemotherapy, progress has been made in designing selective 2-indolinone derivatives. Some of them show preclinical efficacy. However, 2-indolinone has not exhausted all of its potential in the development of new compounds for clinical applications and remains a great tool for future research.
Anticancer research
The paper reports the cytotoxic activity of pyridylmethylene-2-indolinones previously described a... more The paper reports the cytotoxic activity of pyridylmethylene-2-indolinones previously described as cardiotonics and the synthesis of three analogs of the most potent cytotoxic agent. Some of these compounds could be useful, when associated with anthracyclines, to reduce the cardiotoxicity of these potent antitumor drugs.
A newly synthesized indole-derivative is able to induce cytostatic and cytotoxic effects in the c... more A newly synthesized indole-derivative is able to induce cytostatic and cytotoxic effects in the colon cancer cells HT29, effecting apoptosis by activation of an intrinsic pathway. Magnesium is involved in both cell growth and apoptosis even though its role in the latter process is not well defined.The aims of this work were: firstly, to verify if magnesium content is related to the proliferative rate in HT29 cells; secondly, to assess the involvement of the cation in mitochondriamediated apoptosis triggered by the new antiproliferative molecule.The effects of the indole-derivative in treated cells included cell-cycle arrest in the G2/M phase, and apoptotic death confirmed by release of cytochrome c from the mitochondrial compartment. Moreover, we demonstrated that the basal content of magnesium in HT29 cells inversely correlates with cell saturation density. In addition, a decrease in both free and intracellular total magnesium concentration was observed along with the induced apoptosis. Taken together, these data suggest that magnesium participates in the complex signaling network of cell proliferation and apoptosis.
![Research paper thumbnail of Diethyl 4-(6-Chloroimidazo[2,1-b]thiazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and Ethyl 4-(6-Chloroimidazo[2,1-b]thiazol-5-yl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate](https://attachments.academia-assets.com/73281674/thumbnails/1.jpg)
](Molbank, 2012
Diethyl 4-(6-chloroimidazo[2,1-b]thiazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate... more Diethyl 4-(6-chloroimidazo[2,1-b]thiazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and ethyl 4-(6-chloroimidazo[2,1-b]thiazol-5-yl)-6-methyl-2-oxo-1,2,3,4tetrahydropyrimidine-5-carboxylate were obtained simultaneously by the Biginelli reaction using a green protocol and curtailing reaction time.
Anti-cancer drug design
The synthesis of 3-(5-imidazo]2,1-blthiazolylmethylene)-2-indolinones, analogs of compounds recen... more The synthesis of 3-(5-imidazo]2,1-blthiazolylmethylene)-2-indolinones, analogs of compounds recently published, is described. The EIZ isomerism was studied by means of nuclear Overhauser effect experiments and X-ray crystallography. All the compounds were tested as potential antitumor agents. They were also tested as potential inhibitors of cyclin-dependent kinase 1 (CDK1), in order to determine if the antitumor activity was related to this mechanism of action. The results showed that under certain substitution conditions (5-methoxy group for the indole benzene ring and 2-methyl group for the imidazothiazole system), an interesting antitumor activity was found for some compounds. From the analysis of the antitumor data, 3-1(2,6-dimethylimidazo[2,1-bJ-thiazol-5-yl)methylenel-5-methoxy-2-indolinone was the most active of the whole series.
Cancer is a disease of remarkable importance in the world today and is projected to become the pr... more Cancer is a disease of remarkable importance in the world today and is projected to become the primary cause of death within the coming years, therefore the design and development of new antitumor agents is one of the most pressing research areas in medicinal chemistry. Considering the importance of thiazole ring as scaffold present in a wide range of therapeutic agents, the medicinal chemists have been encouraged to synthesize a large number of novel antitumors bearing this heterocycle, which furnish extensive synthetic possibilities due to the presence of several reaction sites. The present review describes the patents from 2008 to present concerning new thiazole compounds useful for the development of new drug molecules. It has been divided according to the molecular target and describes the pathways involved in the biological activities and the structure of the most potent compounds, together with the screening results.
![Research paper thumbnail of Imidazo[2,1 -b]thiazolylmethylene- and indolylmethylene-2-indolinones: a new class of cyclin-dependent kinase inhibitors Design, synthesis, and CDK1/cyclin B inhibition](https://attachments.academia-assets.com/41167401/thumbnails/1.jpg)
](Anti-cancer drug design
Compounds containing a 2-indolinone moiety linked to imidazothiazole and indole fragments were st... more Compounds containing a 2-indolinone moiety linked to imidazothiazole and indole fragments were studied as cyclin-dependent kinase inhibitors. The activity of all the new derivatives was tested in vitro against CDK1/cyclinB and the selectivity towards two other kinases was determined for the most promising compounds. The binding mode of one representative compound was investigated by means of a three-dimensional model of the inhibitor-CDK1 complex. The work allowed us to identify (2-chloroindolyl)methylene-2-indolinone as a new lead of a class of CDK1/cyclinB inhibitors, whose potency can be improved by the introduction of suitable variations on the basic molecular skeleton.
Proceedings of the National Academy of Sciences, 2018
Significance In the past decades, several compounds have been developed specifically targeting G ... more Significance In the past decades, several compounds have been developed specifically targeting G quadruplexes (G4s), as these noncanonical DNA structures are considered promising targets of effective anticancer drugs. However, despite the high number of known ligands, none showed efficacy in cancer patients. We have investigated the interplay of G4s with R loops, another noncanonical DNA structure, and the findings reveal a mechanism of genome instability and cell killing by G4 ligands, particularly effective in cancer cells deficient of BRCA2 activity. This knowledge establishes a mechanistic model of G4 ligand activity in cancer cells that can open new lines of investigation aiming at developing clinically effective G4 ligands.
European journal of medicinal chemistry, 2019
A small library of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones has been synthesized and ... more A small library of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones has been synthesized and screened according to protocols available at the National Cancer Institute (NCI). Some derivatives were potent antiproliferative agents, showing GI50 values in the nanomolar range. Remarkably, when most active compounds against leukemia cells were tested in human peripheral blood lymphocytes from healthy donors, were 100-200 times less cytotoxic. Some compounds, selected by the Biological Evaluation Committee of NCI, were examined to determine tubulin assembly inhibition. Furthermore, flow cytometric studies performed on HeLa, HT-29, and A549 cells, showed that compounds 14 and 25 caused a block in the G2/M phase. Interestingly, these derivatives induced apoptosis through the mitochondrial death pathway, causing in parallel significant activation of both caspase-3 and -9, PARP cleavage and down-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1. Finally, compound 25 was also teste...
Molecules
A series of new Knoevenagel adducts, bearing two indolinone systems, has been synthesized and eva... more A series of new Knoevenagel adducts, bearing two indolinone systems, has been synthesized and evaluated on 60 human cancer cell lines according to protocols available at the National Cancer Institute (Bethesda, MD, USA). Some derivatives proved to be potent antiproliferative agents, showing GI50 values in the submicromolar range. Compound 5b emerged as the most active and was further studied in Jurkat cells in order to determine the effects on cell-cycle phases and the kind of cell death induced. Finally, oxidative stress and DNA damage induced by compound 5b were also analyzed.
Molecules
Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen recept... more Ovarian cancer remains the leading cause of mortality among gynecological tumors. Estrogen receptor beta (ERβ) expression has been suggested to act as a tumor suppressor in epithelial ovarian cancer by reducing both tumor growth and metastasis. ERβ expression abnormalities represent a critical step in the development and progression of ovarian cancer: for these reasons, its re-expression by genetic engineering, as well as the use of targeted ERβ therapies, still constitute an important therapeutic approach. 3-{[2-chloro-1-(4-chlorobenzyl)-5-methoxy-6-methyl-1H-indol-3-yl]methylene}-5-hydroxy-6-methyl-1,3-dihydro-2H-indol-2-one, referred to here as compound 3, has been shown to have cytostatic as well cytotoxic effects on various hormone-dependent cancer cell lines. However, the mechanism of its anti-carcinogenic activity is not well understood. Here, we offer a possible explanation of such an effect in the human ovarian cancer cell line IGROV1. Chromatin binding protein assay and li...
Bioenergetics: Open Access, 2017
Molecules
Parvovirus B19 (B19V) is a human pathogenic virus associated with a wide range of clinical condit... more Parvovirus B19 (B19V) is a human pathogenic virus associated with a wide range of clinical conditions. Currently, there are no recognized antiviral drugs for B19V treatment; therefore, efforts in the search for compounds inhibiting B19V replication are now being pursued. Coumarins (chromen-2-ones) are considered a privileged structure for designing novel orally bioavailable and non-peptidic antiviral agents. To further contribute to the development of new drugs against B19V, our research was focused on the synthesis, characterization and evaluation of antiviral activity of some new 3-(imidazo[2,1-b]thiazol-6-yl)-2H-chromen-2-one derivatives. The effects of the synthesized compounds on cell viability and viral replication were investigated by employing two relevant cellular systems, the myeloblastoid cell line UT7/EpoS1 and primary erythroid progenitor cells (EPCs). Some of the tested compounds showed inhibitory activity both on cell viability and on viral replication, depending on t...
Medicinal chemistry (Shariqah (United Arab Emirates)), 2018
Fused five-membered heterocyclic rings containing bridgehead nitrogen atom are particularly versa... more Fused five-membered heterocyclic rings containing bridgehead nitrogen atom are particularly versatile in the field of medicinal chemistry because of their different biological activities. Among them, the imidazo[2,1-b]thiazole is an attractive fused heterocyclic core that has been extensively studied. The aim of the current study was to study the therapeutic applications of imidazo[2,1- b]thiazole derivatives as antimicrobial agents for the treatment of genitourinary infections. A traditional synthetic methodology was involved to obtain a small series of imidazothiazole derivatives. Herein, we report the antimicrobial activity of the imidazo[2,1-b]thiazole or imidazo[2,1- b]thiazolidine derivatives against selected fungi, Gram-positive and Gram-negative bacteria. Moreover, experiments were carried out to investigate the interference towards the endogenous microbiota. The most interesting of the series are the thiocyano derivatives (19, 23) showing a good profile for the treatment of...
Journal of pharmaceutical and biomedical analysis, Jan 5, 2017
1,4-Anthraquinone (ANQ) is proposed as a novel pre-column reagent for high performance liquid chr... more 1,4-Anthraquinone (ANQ) is proposed as a novel pre-column reagent for high performance liquid chromatography (HPLC) determination of N-acetylcysteine (NAC) and captopril (CAP) in pharmaceutical formulations. The derivatization reactions were carried out at room temperature: NAC at pH 8 for 1min, while CAP at pH 7.5 for 20min. Both reactions reached completeness at a reagent to thiol molar ratio of about 2.5. The synthesised derivatives were characterized by (1)H NMR and IR. The chromatographic separations were performed on a C18 Phenomenex Synergi Fusion 4μm (250mm×4.6mm I.D.) stainless steel column with detection at λ=300nm. The mobile phase consisted of methanol/triethylammonium (TEA) phosphate buffer (pH 3; 0.05mol/L) 75:25 (v/v) at a flow-rate of 0.4mL/min for NAC and 88:12 (v/v), at a flow-rate of 0.6mL/min for CAP. The validation parameters (linearity, sensitivity, accuracy, precision, specificity and stability) were highly satisfactory. Linear response was observed (determina...
Current Medicinal Chemistry, 2016
Despite in recent years a substantial progress has been made in the treatment of pulmonary hypert... more Despite in recent years a substantial progress has been made in the treatment of pulmonary hypertension, it is still a severe disease characterized by poor prognosis, and the search for new drugs remains a priority. Current remedies address mainly the vasoconstrictor/vasodilator imbalance in the pulmonary circulation, while the causes of the disease are only moderately affected. Recently, the role of receptor and non receptor kinases in pulmonary hypertension has emerged and these targets were extensively considered for the development of new therapeutic strategies. This review discusses the patents on small-molecules targeting kinases involved in the proliferation/apoptosis imbalance, typically present in pulmonary hypertension. Bibliographic research for the inventions was carried out using Espacenet and SciFinder databases, "pulmonary hypertension and kinases" as research query and the range from 2010 to 2015. Only patents published in English were considered. A qualitative analysis of the contents of each patent was made to examine the reported compounds, the studies performed and the resulting conclusions. The review includes about thirty applications. Moreover, in order to illustrate the patho-phisiology of the disease and the mechanisms of the targets, about forty additional papers were reported. Considering that imatinib, a PDGF receptor inhibitor, entered the clinical trials for the treatment of pulmonary hypertension, the first patents were devoted to inhibitors of tyrosine kinase receptors, such as PDGFR and c-Kit. Subsequently, in addition to kinase receptors, the role of other pathways involved in pulmonary hypertension have emerged, and some research groups have focused their attention also on non-receptor kinases. Fifteen patents on this topic reported these new targets and new derivatives. However, in most of inventions, although the pulmonary hypertension is among the treatable diseases, the compounds were subjected only to antiproliferative assays and not to specific tests on animal models. The studies reported in this review confirm the continuous research efforts aimed to identify new targets and new drugs for the treatment of pulmonary hypertension. Several inhibitors of kinase were described. These compounds could inhibit mainly important branching processes and pathological growth of blood vessels, thereby might increase the lifespan of patients.
Journal of Medicinal Chemistry, 2016
Expert Opinion on Therapeutic Patents, 2015
2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done ... more 2-Indolinone is a well-known aromatic heterocyclic organic compound. A lot of work has been done on this bicyclic structure by academic and company researchers to synthesize compounds directed to a plethora of molecular targets in order to discover new drug leads. This review presents up-to-date information in the field of cancer therapy research based on this small building block. The present review gives an account of the recent patent literature (2008-2014) describing the discovery of 2-indolinone derivatives with selected therapeutic activities. In this period, a large amount of patents were published on this topic. We have limited the analysis to 37 patents on 2-indolinone derivatives having potential clinical application as chemotherapeutic agents. In this review, the therapeutic applications of 2-indolinone derivatives for the treatment of cancer reported in international patents have been discussed. 2-Indolinone is the scaffold of the compounds considered from a medicinal chemistry perspective. Many of them have been developed and marketed for therapeutic use. In cancer chemotherapy, progress has been made in designing selective 2-indolinone derivatives. Some of them show preclinical efficacy. However, 2-indolinone has not exhausted all of its potential in the development of new compounds for clinical applications and remains a great tool for future research.
Anticancer research
The paper reports the cytotoxic activity of pyridylmethylene-2-indolinones previously described a... more The paper reports the cytotoxic activity of pyridylmethylene-2-indolinones previously described as cardiotonics and the synthesis of three analogs of the most potent cytotoxic agent. Some of these compounds could be useful, when associated with anthracyclines, to reduce the cardiotoxicity of these potent antitumor drugs.
A newly synthesized indole-derivative is able to induce cytostatic and cytotoxic effects in the c... more A newly synthesized indole-derivative is able to induce cytostatic and cytotoxic effects in the colon cancer cells HT29, effecting apoptosis by activation of an intrinsic pathway. Magnesium is involved in both cell growth and apoptosis even though its role in the latter process is not well defined.The aims of this work were: firstly, to verify if magnesium content is related to the proliferative rate in HT29 cells; secondly, to assess the involvement of the cation in mitochondriamediated apoptosis triggered by the new antiproliferative molecule.The effects of the indole-derivative in treated cells included cell-cycle arrest in the G2/M phase, and apoptotic death confirmed by release of cytochrome c from the mitochondrial compartment. Moreover, we demonstrated that the basal content of magnesium in HT29 cells inversely correlates with cell saturation density. In addition, a decrease in both free and intracellular total magnesium concentration was observed along with the induced apoptosis. Taken together, these data suggest that magnesium participates in the complex signaling network of cell proliferation and apoptosis.
Molbank, 2012
Diethyl 4-(6-chloroimidazo[2,1-b]thiazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate... more Diethyl 4-(6-chloroimidazo[2,1-b]thiazol-5-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate and ethyl 4-(6-chloroimidazo[2,1-b]thiazol-5-yl)-6-methyl-2-oxo-1,2,3,4tetrahydropyrimidine-5-carboxylate were obtained simultaneously by the Biginelli reaction using a green protocol and curtailing reaction time.
Anti-cancer drug design
The synthesis of 3-(5-imidazo]2,1-blthiazolylmethylene)-2-indolinones, analogs of compounds recen... more The synthesis of 3-(5-imidazo]2,1-blthiazolylmethylene)-2-indolinones, analogs of compounds recently published, is described. The EIZ isomerism was studied by means of nuclear Overhauser effect experiments and X-ray crystallography. All the compounds were tested as potential antitumor agents. They were also tested as potential inhibitors of cyclin-dependent kinase 1 (CDK1), in order to determine if the antitumor activity was related to this mechanism of action. The results showed that under certain substitution conditions (5-methoxy group for the indole benzene ring and 2-methyl group for the imidazothiazole system), an interesting antitumor activity was found for some compounds. From the analysis of the antitumor data, 3-1(2,6-dimethylimidazo[2,1-bJ-thiazol-5-yl)methylenel-5-methoxy-2-indolinone was the most active of the whole series.
Cancer is a disease of remarkable importance in the world today and is projected to become the pr... more Cancer is a disease of remarkable importance in the world today and is projected to become the primary cause of death within the coming years, therefore the design and development of new antitumor agents is one of the most pressing research areas in medicinal chemistry. Considering the importance of thiazole ring as scaffold present in a wide range of therapeutic agents, the medicinal chemists have been encouraged to synthesize a large number of novel antitumors bearing this heterocycle, which furnish extensive synthetic possibilities due to the presence of several reaction sites. The present review describes the patents from 2008 to present concerning new thiazole compounds useful for the development of new drug molecules. It has been divided according to the molecular target and describes the pathways involved in the biological activities and the structure of the most potent compounds, together with the screening results.
Anti-cancer drug design
Compounds containing a 2-indolinone moiety linked to imidazothiazole and indole fragments were st... more Compounds containing a 2-indolinone moiety linked to imidazothiazole and indole fragments were studied as cyclin-dependent kinase inhibitors. The activity of all the new derivatives was tested in vitro against CDK1/cyclinB and the selectivity towards two other kinases was determined for the most promising compounds. The binding mode of one representative compound was investigated by means of a three-dimensional model of the inhibitor-CDK1 complex. The work allowed us to identify (2-chloroindolyl)methylene-2-indolinone as a new lead of a class of CDK1/cyclinB inhibitors, whose potency can be improved by the introduction of suitable variations on the basic molecular skeleton.