Publications by authors named "Romeo Romagnoli"

147 Publications

Concise synthesis and biological evaluation of 2-Aryl-3-Anilinobenzo[b]thiophene derivatives as potent apoptosis-inducing agents.

Bioorg Chem 2021 Apr 20;112:104919. Epub 2021 Apr 20.

Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, 44121 Ferrara, Italy.

Many clinically used agents active in cancer chemotherapy exert their activity through the induction of cell death (apoptosis) by targeting microtubules, altering protein function or inhibiting DNA synthesis. The benzo[b]thiophene scaffold holds a pivotal place as a pharmacophore for the development of anticancer agents, and, in addition, this scaffold has many pharmacological activities. We have developed a flexible method for the construction of a new series of 2-aryl-3-(3,4,5-trimethoxyanilino)-6-methoxybenzo[b]thiophenes as potent antiproliferative agents, giving access to a wide range of substitution patterns at the 2-position of the 6-methoxybenzo[b]thiophene common intermediate. In the present study, all the synthesized compounds retained the 3-(3,4,5-trimethoxyanilino)-6-methoxybenzo[b]thiophene moiety, and the structure-activity relationship was examined by modification of the aryl group at its 2-position with electron-withdrawing (F) or electron-releasing (alkyl and alkoxy) groups. We found that small substituents, such as fluorine or methyl, could be placed in the para-position of the 2-phenyl ring, and these modifications only slightly reduced antiproliferative activity relative to the unsubstituted 2-phenyl analogue. Compounds 3a and 3b, bearing the phenyl and para-fluorophenyl at the 2-position of the 6-methoxybenzo[b]thiophene nucleus, respectively, exhibited the greatest antiproliferative activity among the tested compounds. The treatment of both Caco2 (not metastatic) and HCT-116 (metastatic) colon carcinoma cells with 3a or 3b triggered a significant induction of apoptosis as demonstrated by the increased expression of cleaved-poly(ADP-ribose) polymerase (PARP), receptor-interacting protein (RIP) and caspase-3 proteins. The same effect was not observed with non-transformed colon 841 CoN cells. A potential additional effect during mitosis for 3a in metastatic cells and for 3b in non-metastatic cells was also observed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2021.104919DOI Listing
April 2021

A facile synthesis of diaryl pyrroles led to the discovery of potent colchicine site antimitotic agents.

Eur J Med Chem 2021 Mar 29;214:113229. Epub 2021 Jan 29.

Istituto di Ricerca Pediatrica (IRP), Corso Stati Uniti 4, 35128, Padova, Italy. Electronic address:

Three different series of cis-restricted analogues of combretastatin A-4 (CA-4), corresponding to thirty-nine molecules that contained a pyrrole nucleus interposed between the two aryl rings, were prepared by a palladium-mediated coupling approach and evaluated for their antiproliferative activity against six human cancer cell lines. In the two series of 1,2-diaryl pyrrole derivatives, results suggested that the presence of the 3',4',5'-trimethoxyphenyl moiety at the N-1 position of the pyrrole ring was more favorable for antiproliferative activity. In the series of 3,4-diarylpyrrole analogues, three compounds (11i-k) exhibited maximal antiproliferative activity, showing excellent antiproliferative activity against the CA-4 resistant HT-29 cells. Inhibition of tubulin polymerization of selected 1,2 pyrrole derivatives (9a, 9c, 9o and 10a) was similar to that observed with CA-4, while the isomeric 3,4-pyrrole analogues 11i-k were generally from 1.5- to 2-fold more active than CA-4. Compounds 11j and 11k were the only compounds that showed activity as inhibitors of colchicine binding comparable to that CA-4. Compound 11j had biological properties consistent with its intracellular target being tubulin. This compound was able to block the cell cycle in metaphase and to induce significant apoptosis at a concentration of 25 nM, following the mitochondrial pathway, with low toxicity for normal cells. More importantly, compound 11j exerted activity in vivo superior to that of CA-4P, being able to significantly reduce tumor growth in a syngeneic murine tumor model even at the lower dose tested (5.0 mg/kg).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2021.113229DOI Listing
March 2021

Thioridazine requires calcium influx to induce MLL-AF6-rearranged AML cell death.

Blood Adv 2020 09;4(18):4417-4429

Haematology-Oncology Clinic and Laboratory, Department of Woman and Child Health, and.

In pediatric acute myeloid leukemia (AML), intensive chemotherapy and allogeneic hematopoietic stem cell transplantation are the cornerstones of treatment in high-risk cases, with severe late effects and a still high risk of disease recurrence as the main drawbacks. The identification of targeted, more effective, safer drugs is thus desirable. We performed a high-throughput drug-screening assay of 1280 compounds and identified thioridazine (TDZ), a drug that was highly selective for the t(6;11)(q27;q23) MLL-AF6 (6;11)AML rearrangement, which mediates a dramatically poor (below 20%) survival rate. TDZ induced cell death and irreversible progress toward the loss of leukemia cell clonogenic capacity in vitro. Thus, we explored its mechanism of action and found a profound cytoskeletal remodeling of blast cells that led to Ca2+ influx, triggering apoptosis through mitochondrial depolarization, confirming that this latter phenomenon occurs selectively in t(6;11)AML, for which AF6 does not work as a cytoskeletal regulator, because it is sequestered into the nucleus by the fusion gene. We confirmed TDZ-mediated t(6;11)AML toxicity in vivo and enhanced the drug's safety by developing novel TDZ analogues that exerted the same effect on leukemia reduction, but with lowered neuroleptic effects in vivo. Overall, these results refine the MLL-AF6 AML leukemogenic mechanism and suggest that the benefits of targeting it be corroborated in further clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020002001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509857PMC
September 2020

The Detrimental Action of Adenosine on Glutamate-Induced Cytotoxicity in PC12 Cells Can Be Shifted towards a Neuroprotective Role through AAR Positive Allosteric Modulation.

Cells 2020 05 18;9(5). Epub 2020 May 18.

Department of Morphology, Surgery and Experimental Medicine, Pharmacology Section, University of Ferrara, 44121 Ferrara, Italy.

Glutamate cytotoxicity is implicated in neuronal death in different neurological disorders including stroke, traumatic brain injury, and neurodegenerative diseases. Adenosine is a nucleoside that plays an important role in modulating neuronal activity and its receptors have been identified as promising therapeutic targets for glutamate cytotoxicity. The purpose of this study is to elucidate the role of adenosine and its receptors on glutamate-induced injury in PC12 cells and to verify the protective effect of the novel A adenosine receptor positive allosteric modulator, TRR469. Flow cytometry experiments to detect apoptosis revealed that adenosine has a dual role in glutamate cytotoxicity, with A and A adenosine receptor (AR) activation exacerbating and A AR activation improving glutamate-induced cell injury. The overall effect of endogenous adenosine in PC12 cells resulted in a facilitating action on glutamate cytotoxicity, as demonstrated by the use of adenosine deaminase and selective antagonists. However, enhancing the action of endogenous adenosine on AARs by TRR469 completely abrogated glutamate-mediated cell death, caspase 3/7 activation, ROS production, and mitochondrial membrane potential loss. Our results indicate a novel potential therapeutic strategy against glutamate cytotoxicity based on the positive allosteric modulation of AARs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells9051242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290574PMC
May 2020

Design, synthesis, in vitro and in vivo biological evaluation of 2-amino-3-aroylbenzo[b]furan derivatives as highly potent tubulin polymerization inhibitors.

Eur J Med Chem 2020 Aug 12;200:112448. Epub 2020 May 12.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131, Padova, Italy. Electronic address:

A new class of inhibitors of tubulin polymerization based on the 2-amino-3-(3',4',5'-trimethoxybenzoyl)benzo[b]furan molecular scaffold was synthesized and evaluated for in vivo and in vitro biological activity. These derivatives were synthesized with different electron-releasing or electron-withdrawing substituents at one of the C-4 through C-7 positions. Methoxy substitution and location on the benzene part of the benzo[b]furan ring played an important role in affecting antiproliferative activity, with the greatest activity occurring with the methoxy group at the C-6 position, the least with the substituent at C-4. The same effect was also observed with ethoxy, methyl or bromine at the C-6 position of the benzo[b]furan skeleton, with the 6-ethoxy-2-amino-3-(3',4',5'-trimethoxybenzoyl)benzo[b]furan derivative 4f as the most promising compound of the series. This compound showed remarkable antiproliferative activity (IC: 5 pM) against the Daoy medulloblastoma cell line, and 4f was nearly devoid of toxicity on healthy human lymphocytes and astrocytes. The potent antiproliferative activity of 4f was derived from its inhibition of tubulin polymerization by binding to the colchicine site. The compound was also examined for in vivo activity, showing higher potency at 15 mg/kg compared with the reference compound combretastatin A-4 phosphate at 30 mg/kg against a syngeneic murine mammary tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2020.112448DOI Listing
August 2020

Synthesis and Biological Evaluation of 2-Substituted Benzyl-/Phenylethylamino-4-amino-5-aroylthiazoles as Apoptosis-Inducing Anticancer Agents.

Molecules 2020 May 6;25(9). Epub 2020 May 6.

Dipartimento di Scienze Chimiche e Farmaceutiche, University of Ferrara, Via L. Borsari 46, 44121 Ferrara, Italy.

Induction of apoptosis is a common chemotherapeutic mechanism to kill cancer cells The thiazole system has been reported over the past decades as a building block for the preparation of anticancer agents. A novel series of 2-arylalkylamino-4-amino-5-(3',4',5'-trimethoxybenzoyl)-thiazole derivatives designed as dual inhibitors of tubulin and cyclin-dependent kinases (CDKs) were synthesized and evaluated for their antiproliferative activity in vitro against two cancer cell lines and, for selected highly active compounds, for interactions with tubulin and cyclin-dependent kinases and for cell cycle and apoptosis effects. Structure-activity relationships were elucidated for various substituents at the 2-position of the thiazole skeleton. Among the synthesized compounds, the most active analogues were found to be the -chlorobenzylamino derivative as well as the -chloro and -methoxyphenethylamino analogues and , respectively, which inhibited the growth of U-937 and SK-MEL-1 cancer cell lines with IC values ranging from 5.7 to 12.2 μM. On U-937 cells, the tested compounds and induced apoptosis in a time and concentration dependent manner. These two latter molecules did not affect tubulin polymerization (IC > 20 μM) nor CDK activity at a single concentration of 10 μM, suggesting alternative targets than tubulin and CDK for the compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules25092177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248693PMC
May 2020

Synthesis and Biological Evaluation of New Antitubulin Agents Containing 2-(3',4',5'-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3-]pyridine Scaffold.

Molecules 2020 Apr 7;25(7). Epub 2020 Apr 7.

Dipartimento di Scienze della Vita e Biotecnologie, Università di Ferrara, 44121 Ferrara, Italy.

Two novel series of compounds based on the 4,5,6,7-tetrahydrothieno[2,3-]pyridine and 4,5,6,7-tetrahydrobenzo[]thiophene molecular skeleton, characterized by the presence of a 3',4',5'-trimethoxyanilino moiety and a cyano or an alkoxycarbonyl group at its 2- or 3-position, respectively, were designed, synthesized, and evaluated for antiproliferative activity on a panel of cancer cell lines and for selected highly active compounds, inhibition of tubulin polymerization, and cell cycle effects. We have identified the 2-(3',4',5'-trimethoxyanilino)-3-cyano-6-methoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-]pyridine derivative and its 6-ethoxycarbonyl homologue as new antiproliferative agents that inhibit cancer cell growth with IC values ranging from 1.1 to 4.7 μM against a panel of three cancer cell lines. Their interaction with tubulin at micromolar levels leads to the accumulation of cells in the G2/M phase of the cell cycle and to an apoptotic cell death. The cell apoptosis study found that compounds and were very effective in the induction of apoptosis in a dose-dependent manner. These two derivatives did not induce cell death in normal human peripheral blood mononuclear cells, suggesting that they may be selective against cancer cells. Molecular docking studies confirmed that the inhibitory activity of these molecules on tubulin polymerization derived from binding to the colchicine site.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules25071690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181277PMC
April 2020

Design, synthesis and biological evaluation of 2-alkoxycarbonyl-3-anilinoindoles as a new class of potent inhibitors of tubulin polymerization.

Bioorg Chem 2020 04 18;97:103665. Epub 2020 Feb 18.

Rega Institute for Medical Research, KU Leuven, Laboratory of Virology and Chemotherapy, Leuven, Belgium.

A new class of inhibitors of tubulin polymerization based on the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)indole molecular skeleton was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization and cell cycle effects. The results presented show that the methoxy substitution and location on the indole nucleus plays an important role in inhibition of cell growth, and the most favorable position for the substituent was at C-6. In addition, a small-size ester function (methoxy/ethoxycarbonyl) at the 2-position of the indole core was desirable. Also, analogues that were alkylated with methyl, ethyl or n-propyl groups or had a benzyl moiety on the N-1 indolic nitrogen retained activity equivalent to those observed in the parent N-1H analogues. The most promising compounds of the series were 2-methoxycarbonyl-3-(3',4'.5'-trimethoxyanilino)-5-methoxyindole 3f and 1-methyl-2-methoxycarbonyl-3-(3',4'.5'-trimethoxyanilino)-6-methoxy-indole 3w, both of which target tubulin at the colchicine site with antitubulin activities comparable to that of the reference compound combretastatin A-4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2020.103665DOI Listing
April 2020

Design, synthesis and biological evaluation of novel vicinal diaryl-substituted 1H-Pyrazole analogues of combretastatin A-4 as highly potent tubulin polymerization inhibitors.

Eur J Med Chem 2019 Nov 1;181:111577. Epub 2019 Aug 1.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131, Padova, Italy; Istituto di Ricerca Pediatrica (IRP), Corso Stati Uniti 4, 35128, Padova, Italy. Electronic address:

A series of 3-(3',4',5'-trimethoxyphenyl)-4-substituted 1H-pyrazole and their related 3-aryl-4-(3',4',5'-trimethoxyphenyl)-1-H-pyrazole regioisomeric derivatives, prepared as cis-rigidified combretastatin A-4 (CA-4) analogues, were synthesized and evaluated for their in vitro antiproliferative against six different cancer cell lines and, for selected highly active compounds, inhibitory effects on tubulin polymerization, cell cycle effects and in vivo potency. We retained the 3',4',5'-trimethoxyphenyl moiety as ring A throughout the present investigation, and a structure-activity relationship (SAR) information was obtained by adding electron-withdrawing (OCF, CF) or electron-releasing (alkyl and alkoxy) groups on the second aryl ring, corresponding to the B-ring of CA-4, either at the 3- or 4-position of the pyrazole nucleus. In addition, the B-ring was replaced with a benzo[b]thien-2-yl moiety. For many of the compounds, their activity was greater than, or comparable with, that of CA-4. Maximal activity was observed with the two regioisomeric derivatives characterized by the presence of a 4-ethoxyphenyl and a 3',4',5'-trimethoxyphenyl group at the C-3 and C-4 positions, and vice versa, of the 1H-pyrazole ring. The data showed that the 3',4',5'-trimethoxyphenyl moiety can be moved from the 3- to the 4-position of the 1H-pyrazole ring without significantly affecting antiproliferative activity. The most active derivatives bound to the colchicine site of tubulin and inhibited tubulin polymerization at submicromolar concentrations. In vivo experiments, on an orthotopic murine mammary tumor, revealed that 4c inhibited tumor growth even at low concentrations (5 mg/kg) compared to CA-4P (30 mg/kg).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2019.111577DOI Listing
November 2019

Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2- d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors.

J Med Chem 2019 02 18;62(3):1274-1290. Epub 2019 Jan 18.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia , Università di Padova , 35131 Padova , Italy.

The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3',4',5'-trimethoxyanilino)thieno[3,2- d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3',4',5'-trimethoxyanilino)-6-( p-tolyl)thieno[3,2- d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC value of 0.71 μM, and 6g inhibited EGFR activity with an IC value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.8b01391DOI Listing
February 2019

Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3',4',5'-trimethoxyphenyl)-3-(2'-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach.

J Enzyme Inhib Med Chem 2018 Dec;33(1):1225-1238

d Department of Biochemistry and Molecular Biology, Research Institute in Biomedical and Health Sciences (IUIBS) , University of Las Palmas de Gran Canaria (ULPGC) , Spain.

Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3',4',5'-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3',4',5'-trimethoxyphenyl)-2-propen-1-one framework. The structure-activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC: 18 μM). This derivative also displayed cytotoxic properties (IC values ∼1 μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3',4',5'-trimethoxyphenyl scaffold.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14756366.2018.1493473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116705PMC
December 2018

3-Aryl/Heteroaryl-5-amino-1-(3',4',5'-trimethoxybenzoyl)-1,2,4-triazoles as antimicrotubule agents. Design, synthesis, antiproliferative activity and inhibition of tubulin polymerization.

Bioorg Chem 2018 10 30;80:361-374. Epub 2018 Jun 30.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy. Electronic address:

Many natural and synthetic substances are known to interfere with the dynamic assembly of tubulin, preventing the formation of microtubules. In our search for potent and selective antitumor agents, a novel series of 1-(3',4',5'-trimethoxybenzoyl)-5-amino-1,2,4-triazoles were synthesized. The compounds had different heterocycles, including thiophene, furan or the three isomeric pyridines, and they possessed a phenyl ring bearing electron-releasing or electron-withdrawing substituents at the 3-position of the 5-amino-1,2,4-triazole system. Most of the twenty-two tested compounds showed moderate to potent antiproliferative activities against a panel of solid tumor and leukemic cell lines, with four (5j, 5k, 5o and 5p) showing strong antiproliferative activity (IC < 1 μM) against selected cancer cells. Among them, several molecules preferentially inhibited the proliferation of leukemic cell lines, showing IC values 2-100-fold lower for Jurkat and RS4;11 cells than those for the three lines derived from solid tumors (HeLa, HT-29 and MCF-7 cells). Compound 5k strongly inhibited tubulin assembly, with an IC value of 0.66 μM, half that obtained in simultaneous experiments with CA-4 (IC = 1.3 μM).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2018.06.037DOI Listing
October 2018

Synthesis and biological evaluation of alpha-bromoacryloylamido indolyl pyridinyl propenones as potent apoptotic inducers in human leukaemia cells.

J Enzyme Inhib Med Chem 2018 Dec;33(1):727-742

c Departamento de Bioquímica y Biología Molecular , Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de las Palmas de Gran Canaria , Spain.

The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. To investigate the influence of the position of the pyridine nitrogen on biological activity, two different series of α-bromoacryloylamido indolyl pyridinyl propenones 3a-h and 4a-d were designed and synthesized by a pharmacophore hybridization approach and evaluated for their antiproliferative activity against a panel of six human cancer cell lines. These hybrid molecules were prepared to combine the α-bromoacryloyl moiety with two series of indole-inspired chalcone analogues, possessing an indole derivative and a 3- or 4-pyridine ring, respectively, linked on either side of 2-propen-1-one system. The structure-activity relationship was also investigated by the insertion of alkyl or benzyl moieties at the N-1 position of the indole nucleus. We found that most of the newly synthesized displayed high antiproliferative activity against U-937, MOLT-3, K-562, and NALM-6 leukaemia cell lines, with one-digit to double-digit nanomolar IC values. The antiproliferative activities of 3-pyridinyl derivatives 3f-h revealed that N-benzyl indole analogues generally exhibited lower activity compared to N-H or N-alkyl derivatives 3a-b and 3c-e, respectively. Moreover, cellular mechanism studies elucidated that compound 4a induced apoptosis along with a decrease of mitochondrial membrane potential and activated caspase-3 in a concentration-dependent manner.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14756366.2018.1450749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009983PMC
December 2018

2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition.

Eur J Med Chem 2018 Jan;143:683-698

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia Pediatrica, Università di Padova, 35131 Padova, Italy. Electronic address:

Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a, 4c, 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC values ranging from 0.13 to 0.84 μM against four different cancer cell lines. Three agents (4a, 4c and 4i) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c, containing the 2'-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IC value of 140 nM, inhibited tubulin polymerization with an IC value of 1.2 μM, similar to that of CA-4 (IC: 1.1 μM), and induced apoptosis in HeLa cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2017.11.096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791907PMC
January 2018

A Adenosine Receptors as Modulators of Inflammation: From Medicinal Chemistry to Therapy.

Med Res Rev 2018 07 6;38(4):1031-1072. Epub 2017 Jul 6.

Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121, Ferrara, Italy.

The A adenosine receptor (A AR) subtype is a novel, promising therapeutic target for inflammatory diseases, such as rheumatoid arthritis (RA) and psoriasis, as well as liver cancer. A AR is coupled to inhibition of adenylyl cyclase and regulation of mitogen-activated protein kinase (MAPK) pathways, leading to modulation of transcription. Furthermore, A AR affects functions of almost all immune cells and the proliferation of cancer cells. Numerous A AR agonists, partial agonists, antagonists, and allosteric modulators have been reported, and their structure-activity relationships (SARs) have been studied culminating in the development of potent and selective molecules with drug-like characteristics. The efficacy of nucleoside agonists may be suppressed to produce antagonists, by structural modification of the ribose moiety. Diverse classes of heterocycles have been discovered as selective A AR blockers, although with large species differences. Thus, as a result of intense basic research efforts, the outlook for development of A AR modulators for human therapeutics is encouraging. Two prototypical selective agonists, N6-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA; CF101) and 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; CF102), have progressed to advanced clinical trials. They were found safe and well tolerated in all preclinical and human clinical studies and showed promising results, particularly in psoriasis and RA, where the A AR is both a promising therapeutic target and a biologically predictive marker, suggesting a personalized medicine approach. Targeting the A AR may pave the way for safe and efficacious treatments for patient populations affected by inflammatory diseases, cancer, and other conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/med.21456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756520PMC
July 2018

Effects of Pimozide Derivatives on pSTAT5 in K562 Cells.

ChemMedChem 2017 08 19;12(15):1183-1190. Epub 2017 Jul 19.

Dipartimento di Scienze per la Promozione della Salute e Materno Infantile, Centro Interdipartimentale di Ricerca in Oncologia Clinica, Università di Palermo, via del Vespro 129, 902127, Palermo, Italy.

STAT5 is a transcription factor, a member of the STAT family of signaling proteins. STAT5 is involved in many types of cancer, including chronic myelogenous leukemia (CML), in which this protein is found constitutively activated as a consequence of BCR-ABL expression. The neuroleptic drug pimozide was recently reported to act as an inhibitor of STAT5 phosphorylation and is capable of inducing apoptosis in CML cells in vitro. Our research group has synthesized simple derivatives of pimozide with cytotoxic activity and that are able to decrease the levels of phosphorylated STAT5. In this work we continued the search for novel STAT5 inhibitors, synthesizing compounds in which the benzoimidazolinone ring of pimozide is either maintained or modified, in order to obtain further structure-activity relationship information for this class of STAT5 inhibitors. Two compounds of the series showed potent cytotoxic activity against BCR-ABL-positive and pSTAT5-overexpressing K562 cells and were able to markedly decrease the levels of phosphorylated STAT5.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cmdc.201700234DOI Listing
August 2017

Design, synthesis and biological evaluation of 3-substituted-2-oxindole hybrid derivatives as novel anticancer agents.

Eur J Med Chem 2017 Jul 13;134:258-270. Epub 2017 Apr 13.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy. Electronic address:

The 2-oxindole nucleus is the central core to develop new anticancer agents and its substitution at the 3-position can effect antitumor activity. Utilizing a pharmacophore hybridization approach, a novel series of antiproliferative agents was obtained by the modification of the structure of 3-substituted-2-oxindole pharmacophore by the attachment of the α-bromoacryloyl moiety, acting as a Michael acceptor, at the 5-position of 2-oxindole framework. The impact of the substituent at the 3-position of 2-oxindole core on the potency and selectivity against a panel of seven different cancer cell lines was examined. We found that these hybrid molecules displayed potent antiproliferative activity against a panel of four cancer cell lines, with one-to double digit nanomolar 50% inhibitory concentrations (IC). A distinctive selective antiproliferative activity was obtained towards CCRF-CEM and RS4; 11 leukemic cell lines. In order to study the possible mechanism of action, we observed that the two most active compounds namely 3(E) and 6(Z) strongly induce apoptosis that follow the mitochondrial pathway. Interestingly a decrease of intracellular reduced glutathione content (GSH) and reactive oxygen species (ROS) production was detected in treated cells compared with controls suggesting that these effects may be involved in their mechanism of action.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2017.03.089DOI Listing
July 2017

Synthesis and Biological Evaluation of 2-Methyl-4,5-Disubstituted Oxazoles as a Novel Class of Highly Potent Antitubulin Agents.

Sci Rep 2017 04 13;7:46356. Epub 2017 Apr 13.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.

Antimitotic agents that interfere with microtubule formation are one of the major classes of cytotoxic drugs for cancer treatment. Multiple 2-methyl-4-(3',4',5'-trimethoxyphenyl)-5-substituted oxazoles and their related 4-substituted-5-(3',4',5'-trimethoxyphenyl) regioisomeric derivatives designed as cis-constrained combretastatin A-4 (CA-4) analogues were synthesized and evaluated for their antiproliferative activity in vitro against a panel of cancer cell lines and, for selected highly active compounds, interaction with tubulin, cell cycle effects and in vivo potency. Both these series of compounds were characterized by the presence of a common 3',4',5'-trimethoxyphenyl ring at either the C-4 or C-5 position of the 2-methyloxazole ring. Compounds 4g and 4i, bearing a m-fluoro-p-methoxyphenyl or p-ethoxyphenyl moiety at the 5-position of 2-methyloxazole nucleus, respectively, exhibited the greatest antiproliferative activity, with IC values of 0.35-4.6 nM (4g) and 0.5-20.2 nM (4i), which are similar to those obtained with CA-4. These compounds bound to the colchicine site of tubulin and inhibited tubulin polymerization at submicromolar concentrations. Furthermore, 4i strongly induced apoptosis that follows the mitochondrial pathway. In vivo, 4i in a mouse syngeneic model demonstrated high antitumor activity which significantly reduced the tumor mass at doses ten times lower than that required for CA-4P, suggesting that 4i warrants further evaluation as a potential anticancer drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep46356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390315PMC
April 2017

Pronounced anti-proliferative activity and tumor cell selectivity of 5-alkyl-2-amino-3-methylcarboxylate thiophenes.

Eur J Med Chem 2017 May 23;132:219-235. Epub 2017 Mar 23.

KU Leuven, Rega Institute for Medical Research, Herestraat 49, Postbus 1043, B-3000 Leuven, Belgium. Electronic address:

5-(2-(4-Methoxyphenyl)ethyl)-2-amino-3-methylcarboxylate thiophene (TR560) is the prototype drug of a recently discovered novel class of tumor-selective compounds that preferentially inhibit the proliferation of specific tumor cell types (e.g. leukemia/lymphoma). Here, we further increased tumor selectivity by simplification of the molecule through replacing the 4-methoxyphenyl moiety by an alkyl chain. Several 2-amino-3-methylcarboxylate thiophene derivatives containing at C-5 an alkyl group consisting of at least 6 (hexyl) to 9 (nonyl) carbon units showed pronounced anti-proliferative activity in the mid-nanomolar range with 500- to 1000-fold tumor cell selectivity. The compounds preferentially inhibited the proliferation of T-lymphoma CEM and Molt/4, prostate PC-3, kidney Caki-1 and hepatoma Huh-7 tumor cells, but were virtually inactive against other tumor cell lines including B-lymphoma Raji and cervix carcinoma HeLa cells. The novel prototype drug 3j (containing a 5-heptyl chain) elicited a cytotoxic, rather than cytostatic activity, already after 4 h of exposure. The unusual tumor selectivity could not be explained by a differential uptake (or efflux) of the drug by sensitive versus resistant tumor cells. Exposure of a fluorescent derivative of 3j revealed pronounced uptake of the drug in the cytoplasm, no visible appearance in the nucleus, and a predominant localization in the endoplasmic reticulum. These observations may be helpful to narrow down the intracellular localization and identification of the molecular target of the 5-substituted thiophene derivatives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2017.03.044DOI Listing
May 2017

Positive allosteric modulation of A adenosine receptors as a novel and promising therapeutic strategy for anxiety.

Neuropharmacology 2016 12 14;111:283-292. Epub 2016 Sep 14.

Department of Medical Sciences, Pharmacology Section, University of Ferrara, Via Fossato di Mortara 17/19, 44121 Ferrara, Italy. Electronic address:

Activation of A adenosine receptors (ARs) has been associated with anxiolytic-like effects in different behavioral tests, but development of AAR agonists for therapeutic use has been hampered, most likely due to the presence of side effects. With the aim to identify a safer approach for the treatment of anxiety, we investigated, in mice, the anxiolytic-like properties of a novel AAR positive allosteric modulator, TRR469. Acute administration of TRR469 (0.3-3 mg/kg) resulted in robust anxiolytic-like effects in the elevated plus maze, the dark/light box, the open field and the marble burying tests. The magnitude of the anxiolytic action of TRR469 was comparable to that obtained with benzodiazepine diazepam (1 mg/kg). The use of the AAR antagonist DPCPX (3 mg/kg) suggested that the effects of TRR469 were mediated by this receptor subtype. In contrast to diazepam, the novel positive allosteric modulator did not potentiate the sedative effect of ethanol (3.5 g/kg) evaluated by the loss of righting reflex. While diazepam produced motor coordination impairment in the rotarod test, this effect being enhanced by the presence of ethanol (1.5 g/kg), TRR469 did not elicit locomotor disturbances either when administered alone or in the presence of ethanol. In vitro, TRR469 was able to increase the number of AAR recognizable by the agonist radioligand [H]-CCPA in mouse brain regions involved in emotional processes. TRR469 markedly increased the affinity of the agonist CCPA, suggesting the capability, in vivo, to increase the affinity of endogenous adenosine. Taken together, these findings indicate that the positive allosteric modulation of AAR may represent a promising approach for the treatment of anxiety-related disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuropharm.2016.09.015DOI Listing
December 2016

The Novel Antitubulin Agent TR-764 Strongly Reduces Tumor Vasculature and Inhibits HIF-1α Activation.

Sci Rep 2016 06 13;6:27886. Epub 2016 Jun 13.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia pediatrica, Università di Padova, 35128 Padova, Italy.

Tubulin binding agents (TBAs) are commonly used in cancer therapy as antimitotics. It has been described that TBAs, like combretastatin A-4 (CA-4), present also antivascular activity and among its derivatives we identified TR-764 as a new inhibitor of tubulin polymerization, based on the 2-(alkoxycarbonyl)-3-(3',4',5'-trimethoxyanilino)benzo[b]thiophene molecular skeleton. The antiangiogenic activity of TR-764 (1-10 nM) was tested in vitro on human umbilical endothelial cells (HUVECs), and in vivo, on the chick embryo chorioallantoic membrane (CAM) and two murine tumor models. TR-764 binding to tubulin triggers cytoskeleton rearrangement without affecting cell cycle and viability. It leads to capillary tube disruption, increased cell permeability, and cell motility reduction. Moreover it disrupts adherens junctions and focal adhesions, through mechanisms involving VE-cadherin/β-catenin and FAK/Src. Importantly, TR-764 is active in hypoxic conditions significantly reducing HIF-1α. In vivo TR-764 (1-100 pmol/egg) remarkably blocks the bFGF proangiogenic activity on CAM and shows a stronger reduction of tumor mass and microvascular density both in murine syngeneic and xenograft tumor models, compared to the lead compound CA-4P. Altogether, our results indicate that TR-764 is a novel TBA with strong potential as both antivascular and antitumor molecule that could improve the common anticancer therapies, by overcoming hypoxia-induced resistance mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep27886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904223PMC
June 2016

Vascular disrupting activity of combretastatin analogues.

Vascul Pharmacol 2016 08 25;83:78-89. Epub 2016 May 25.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy. Electronic address:

Tubulin binding agents (TBAs) are drugs commonly used in cancer therapy as antimitotics. In the last years it has been described that TBAs, like combretastatin A-4 (CA-4), present also vascular disrupting activity and among its derivatives we identified three analogues endowed with potent microtubule depolymerizing activity, higher than that of the lead compound. In this paper we have investigated the anti-vascular activity of these derivatives. We tested the anti-angiogenic effects in human umbilical endothelial cells (HUVEC) and in vivo in chick chorioallantoic membrane assay (CAM), and in a syngeneic tumor mouse model. The three molecules, compound 1: 1-(3,4,5-trimethoxyphenyl)-5-(4-ethoxyphenyl)-1H-1,2,4-triazole; compound 2: (1-(3,4,5-trimethoxyphenyl)-5-(4-ethoxyphenyl)-1H-tetrazole, compound-3 (4-amino-2-p-tolylaminothiazol-5-yl)-(3,4,5-trimethoxyphenyl)-methanone) showed a moderate effect on the growth of HUVEC cells at concentrations below 200nM. At lower concentrations (5-20nM), in particular compound 2, they induced inhibition of capillary tube formation, inhibition of endothelial cell migration and affected endothelial cell morphology as demonstrated by the alteration of the microfilaments network. Moreover, they also increased permeability of HUVEC cells in a time dependent manner. In addition, compounds 1 and 3, as well as the reference compound CA-4, inhibited VEGF-induced phosphorylation of VE-cadherin and in addition compound 3 prevented the VEGF-induced phosphorylation of FAK. In CAM assay, both compounds 2 and 3 efficiently counteracted the strong angiogenic response induced by bFGF, even at the lowest concentration used (1pmol/egg). Moreover in a syngenic mouse model, compounds 1-3 after a single i.p. injection (30mg/kg), showed a stronger reduction of microvascular density. Altogether our results identified these derivatives as potential new vascular disrupting agents candidates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vph.2016.05.006DOI Listing
August 2016

Design and Synthesis of Potent in Vitro and in Vivo Anticancer Agents Based on 1-(3',4',5'-Trimethoxyphenyl)-2-Aryl-1H-Imidazole.

Sci Rep 2016 05 24;6:26602. Epub 2016 May 24.

Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.

A novel series of tubulin polymerization inhibitors, based on the 1-(3',4',5'-trimethoxyphenyl)-2-aryl-1H-imidazole scaffold and designed as cis-restricted combretastatin A-4 analogues, was synthesized with the goal of evaluating the effects of various patterns of substitution on the phenyl at the 2-position of the imidazole ring on biological activity. A chloro and ethoxy group at the meta- and para-positions, respectively, produced the most active compound in the series (4o), with IC50 values of 0.4-3.8 nM against a panel of seven cancer cell lines. Except in HL-60 cells, 4o had greater antiproliferative than CA-4, indicating that the 3'-chloro-4'-ethoxyphenyl moiety was a good surrogate for the CA-4 B-ring. Experiments carried out in a mouse syngenic model demonstrated high antitumor activity of 4o, which significantly reduced the tumor mass at a dose thirty times lower than that required for CA-4P, which was used as a reference compound. Altogether, our findings suggest that 4o is a promising anticancer drug candidate that warrants further preclinical evaluation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep26602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877593PMC
May 2016

Novel iodoacetamido benzoheterocyclic derivatives with potent antileukemic activity are inhibitors of STAT5 phosphorylation.

Eur J Med Chem 2016 Jan 27;108:39-52. Epub 2015 Nov 27.

Centro Interdipartimentale di Ricerca in Oncologia Clinica e Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Malattie Infettive, Università di Palermo, 90125 Palermo, Italy.

Signal Transducer and Activator of Transcription 5 (STAT5) protein, a component of the STAT family of signaling proteins, is considered to be an attractive therapeutic target because of its involvement in the progression of acute myeloid leukemia. In an effort to discover potent molecules able to inhibit the phosphorylation-activation of STAT5, twenty-two compounds were synthesized and evaluated on the basis of our knowledge of the activity of 2-(3',4',5'-trimethoxybenzoyl)-3-iodoacetamido-6-methoxy benzo[b]furan derivative 1 as a potent STAT5 inhibitor. Most of these molecules, structurally related to compound 1, were characterized by the presence of a common 3',4',5'-trimethoxybenzoyl moiety at the 2-position of different benzoheterocycles such as benzo[b]furan, benzo[b]thiophene, indole and N-methylindole. Effects on biological activity of the iodoacetamido group and of different moieties (methyl and methoxy) at the C-3 to C-7 positions were examined. In the series of benzo[b]furan derivatives, moving the iodoacetylamino group from the C-4 to the C-5 or C-6 positions did not significantly affect antiproliferative activity. Compounds 4, 15, 20 and 23 blocked STAT5 signals and induced apoptosis of K562 BCR-ABL positive cells. For compound 23, the trimethoxybenzoyl moiety at the 2-position of the benzo[b]furan core was not essential for potent inhibition of STAT5 activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2015.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724257PMC
January 2016

Current status of A1 adenosine receptor allosteric enhancers.

Future Med Chem 2015 ;7(10):1247-59

Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy.

Adenosine is an ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1, A2A, A2B and A3 adenosine receptors (ARs). Allosteric enhancers to A1ARs may represent novel therapeutic agents because they increase the activity of these receptors by mediating a shift to their active form in the A1AR-G protein ternary complex. In this manner, they are able to amplify the action of endogenous adenosine, which is produced in high concentrations under conditions of metabolic stress. A1AR allosteric enhancers could be used as a justifiable alternative to the exogenous agonists that are characterized by receptor desensitization and downregulation. In this review, an analysis of some of the most interesting allosteric modulators of A1ARs has been reported.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4155/fmc.15.65DOI Listing
January 2016

Design, synthesis and antiproliferative activity of novel heterobivalent hybrids based on imidazo[2,1-b][1,3,4]thiadiazole and imidazo[2,1-b][1,3]thiazole scaffolds.

Eur J Med Chem 2015 Aug 25;101:205-17. Epub 2015 Jun 25.

Department of Biochemistry, University of Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria, Spain.

Heterobivalent ligands constituted by two different pharmacophores that bind to different molecular targets or to two distinct sites on the same molecular target could be one of the methods used for the treatment of cancer. In view of the importance of imidazo[1,2-b][1,3]thiazole and imidazo[1,2-b][1,3,4]thiadiazole as privileged structures for the preparation of novel anticancer agents, we decided to explore the synthesis and biological evaluation of molecular conjugates comprising these fused bicyclic systems tethered at their C-6 position by a meta-(α-bromoacryloylamido)phenyl moiety. We found that most of the hybrid compounds displayed high antiproliferative activity toward a wide panel of cancer cell lines, with one-digit micromolar to submicromolar 50% inhibitory concentrations (IC50). We have observed that selected compounds 7d, 7e, 7n and 8c induced apoptosis, which was associated with the release of cytochrome c and cleavage of multiple caspases. Overexpression of the protective mitochondrial protein Bcl-2 did not confer protection to cell death induced by these compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2015.06.042DOI Listing
August 2015

Synthesis and biological evaluation of a new series of 2-amino-3-aroyl thiophene derivatives as agonist allosteric modulators of the A1 adenosine receptor. A position-dependent effect study.

Eur J Med Chem 2015 Aug 24;101:185-204. Epub 2015 Jun 24.

Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università di Ferrara, Ferrara, Italy.

The 2-amino-3-(p-chlorobenzoyl)thiophene scaffold has been widely employed as a pharmacophore for the identification of small molecules acting as allosteric modulators at the adenosine A1 receptor. A new series of 2-amino-3-(p-chlorobenzoyl)-4-benzyl-5-arylthiophene derivatives, characterized by the absence as well as the presence of electron-releasing or electron-withdrawing groups on the phenyl ring at the 4- and 5-positions of the thiophene ring, were identified as positive allosteric enhancers at the adenosine A1 receptor in binding (saturation, competition and dissociation kinetics) and functional assays. To better understand the positional requirements of substituents on the 2-amino-3-(p-chlorobenzoyl)thiophene core, the corresponding regioisomeric 4-aryl-5-benzylthiophene analogues were synthesized and found to possess reduced allosteric enhancer activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2015.06.041DOI Listing
August 2015

One-pot reaction to obtain N,N'-disubstituted guanidines of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold as human A3 adenosine receptor antagonists.

J Med Chem 2015 Jul 17;58(13):5355-60. Epub 2015 Jun 17.

‡Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17, 44121 Ferrara, Italy.

In this paper we describe an extension SAR study of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine nucleus as A3AR antagonist. Our initial aim was to replace the phenylcarbamoyl moiety at the 5 position of PTP nucleus with a thiourea functionality to evaluate the contribution of new structural modification against the A3AR. The synthesized 12-25 were not characterized by the predicted side chain but by a 1,3-disubstituted guanidine and are shown to be interesting A3AR antagonists.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.5b00551DOI Listing
July 2015

Pyrazole phenylcyclohexylcarbamates as inhibitors of human fatty acid amide hydrolases (FAAH).

Eur J Med Chem 2015 Jun 5;97:289-305. Epub 2015 May 5.

Dipartimento di Farmacia, Via Bonanno 6, Università di Pisa, 56126 Pisa, Italy.

Fatty acid amide hydrolase (FAAH) inhibitors have gained attention as potential therapeutic targets in the management of neuropathic pain. Here, we report a series of pyrazole phenylcyclohexylcarbamate derivatives standing on the known carbamoyl FAAH inhibitor URB597. Structural modifications led to the recognition of compound 22 that inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 nM). The most active compounds of this series showed significant selectivity toward monoacylglycerol lipase (MAGL) enzyme. In addition, molecular modeling and reversibility behavior of the new class of FAAH inhibitors are presented in this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2015.04.064DOI Listing
June 2015

Design, synthesis, in vitro, and in vivo anticancer and antiangiogenic activity of novel 3-arylaminobenzofuran derivatives targeting the colchicine site on tubulin.

J Med Chem 2015 Apr 26;58(7):3209-22. Epub 2015 Mar 26.

∞Dipartimento di Salute della Donna e del Bambino, Laboratorio di Oncoematologia, Università di Padova, 35131 Padova, Italy.

A new series of compounds characterized by the presence of a 2-methoxy/ethoxycarbonyl group, combined with either no substituent or a methoxy group at each of the four possible positions of the benzene portion of the 3-(3',4',5'-trimethoxyanilino)benzo[b]furan skeleton, were evaluated for antiproliferative activity against cancer cells in culture and, for selected, highly active compounds, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. The greatest antiproliferative activity occurred with a methoxy group introduced at the C-6 position, the least with this substituent at C-4. Thus far, the most promising compound in this series was 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-6-methoxybenzo[b]furan (3g), which inhibited cancer cell growth at nanomolar concentrations (IC50 values of 0.3-27 nM), bound to the colchicine site of tubulin, induced apoptosis, and showed, both in vitro and in vivo, potent vascular disrupting properties derived from the effect of this compound on vascular endothelial cells. Compound 3g had in vivo antitumor activity in a murine model comparable to the activity obtained with combretastatin A-4 phosphate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.5b00155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4407803PMC
April 2015