677 research outputs found
Agents Antitumorales que interaccionan con el surco menor del'ADN y inibitors de la Tubulina
No full textMinor groove binders are one of the most widely studied class of agents characterized by a high level of sequence specificity and they are still an interesting class of DNA ligands which demonstrate to possess several biological activities.
It is important to underlie that in order to be effective as an anticancer agent, a minor groove binder should covalently and irreversibly bind the DNA with a long permanence of DNA lesion. This presentation will focus on cytotoxics structurally derivates from main minor groove binders such as distamycin A (1) , anthramycin (2) and CC-1065 (3). In particular will be underline the synthesis and biological activity of molecular hybrids deriving among the combination of the distamycin A and naturally occurring alkylating agents (1).
A series of 2-(3’,4’,5’-trimethoxybenzoyl)-3-amino-5-aryl/heteroaryl thiophene derivatives and its corresponding isomers, with a 2-amino-3-(3’,4’,5’-trimethoxybenzoyl)-5-phenyl thiophene core, were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization and their effects on the cell cycle. The SAR was elucidated with various substitutions on the aryl moiety at the 5-position of the thienyl ring (2)
DNA Minor Groove Binders: the sulphur analog of duocarmicycin SA and CC-1065
No full textMinor groove binders are one of the most widely studied class of agents characterized by a high level of sequence specificity and they are still an interesting class of DNA ligands which demonstrate to possess several biological activities.
It is important to underlie that in order to be effective as an anticancer agent, a minor groove binder should covalently and irreversibly bind the DNA with a long permanence of DNA lesion. This presentation will focus on cytotoxics structurally related from main minor groove binders such as distamycin A (1) , anthramycin (2) and CC-1065 (3). In particular, it will be underline the synthesis and biological activity of molecular hybrids deriving among the combination of the distamycin A and naturally occurring alkylating agents.
In the lecture will be presented also the synthesis and the exceptional biological potency of a sulphur analog of Duocarmycin SA and CC-1065
New Modulators of A3 and A2B Adenosine Receptors
No full textAdenosine, an endogenous modulator of a wide range of biological functions in the nervous, cardiovascular, renal, and immune systems, interacts with at least four cell surface receptor subtypes classified as A1, A2A, A2B and A3.1 Clarification of the role of adenosine and its receptors in cancer development may hold great promise for the chemotherapeutic treatment of patients affected by malignancies.2
Different classes of compounds with non-xanthine structures have been reported to be A3 adenosine receptor antagonists.3 The pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine nucleus has been largely investigated by our group. Our interests were focused on the effects of substitution of the phenyl ring of the arylcarbamoyl moiety at N5 position and of substituents at C9 and/or at N7-N8 pyrazole nitrogens. These studies allowed us to obtain a large variety of compounds which showed affinities in the nanomolar range to human A2A or A3 adenosine receptors with high degree of selectivity.3
Compounds presenting an additional fused ring on the xanthine nucleus have been reported to exhibit antagonistic activity with various levels of affinity and selectivity towards the four adenosine receptors subtypes.4 We evaluated the effect of the introduction of a benzyl and a propyl at the 1 and 3 positions, respectively, in a new series of 7-aryl/alkyl-1H,6H-pyrrolo[2,1-f]purine-2,4-diones and 7-aryl/alkyl-1H,8H-imidazo[2,1-f]purine-2,4-diones,5 among which, very potent and selective A3 receptors antagonists have been identified. In particular 1-benzyl-7-methyl-3-propyl-1H,8H-imidazo[2,1-f]purine-2,4-dione, shows a subnanomolar affinity with a noteworthy selectivity versus the other adenosine receptors subtypes (Ki (hA3) = 0.8 nM, Ki (hA1/hA3) = 3163, Ki (hA2A/hA3) > 6250, IC50 (hA2B)/Ki (hA3) = 2570).
Colotta et al. directed much effort toward the study of adenosine receptor antagonists investigating the 2-arylpyrazolo[3,4-c]-quinoline nucleus.6 In light of the reported activity profile, we decided to synthesize the structural isomers, 2-arylpyrazolo[4,3-c]quinolines,7 some of which showed high A3 receptor affinity and complete selectivity (2-p-tolyl-2,5-dihydro-pyrazolo[4,3-c]quinolin-4-one; KihA1, KihA2A, EC50hA2B>1000 nM, KihA3= 9 nM).
In the search for improved selective A2B antagonists for the treatment of asthma,8 we synthesized a variety of new 1,3-dipropyl-8-heterocyclic-substituted xanthines.9 We introduced several heterocycles, such as pyrazole, isoxazole, pyridine and pyridazine at the 8-position of the xanthine nucleus. We have also investigated different spacers (substituted acetamide, oxyacetamide and urea moieties) on the heterocycle introduced. Some of the synthesized C8-substituted xanthines showed high affinity at A2B receptor subtype and very good selectivity (N-benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]-acetamide; hA2B = 5.5 nM, hA1, hA2A, hA3 > 1000)
DNA Minor Groove Binders and Tubuline Inhibitors as Antitumor Agents
No full textMinor groove binders are one of the most widely studied class of agents characterized by a high level of sequence specificity and they are still an interesting class of DNA ligands which demonstrate to possess several biological activities.
It is important to underlie that in order to be effective as an anticancer agent, a minor groove binder should covalently and irreversibly bind the DNA with a long permanence of DNA lesion. This presentation will focus on cytotoxics structurally derivates from main minor groove binders such as distamycin A (1) , anthramycin (2) and CC-1065 (3). In particular will be underline the synthesis and biological activity of molecular hybrids deriving among the combination of the distamycin A and naturally occurring alkylating agents (1).
A series of 2-(3’,4’,5’-trimethoxybenzoyl)-3-amino-5-aryl/heteroaryl thiophene derivatives and its corresponding isomers, with a 2-amino-3-(3’,4’,5’-trimethoxybenzoyl)-5-phenyl thiophene core, were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization and their effects on the cell cycle. The SAR was elucidated with various substitutions on the aryl moiety at the 5-position of the thienyl ring (2)
Sixth International symposium on adenosine and adenine nucleotides: new frontiers in the third millennium
No full textEditoria
Synthetic Approaches Towards the Marine Alkyl Purines
No full textAgelasines, asmarines and related compds. are natural products with a hybrid terpene-purine structure isolated from numerous genera of sponges (Agela sp, Raspailia sp). Nuttingins and malonganenones are tetraprenylated purine alkaloids from gordonian (Eplexura sp, Leptogorgia sp). Some of these alkaloids displayed broad spectrum activity including cytotoxic activity against several cancer cells. The review summarizes the synthesis of mono- or bi-cyclic diterpenoids usually having a 9-methyladenine moiety
Binding of the radioligand [3H]-SCH 58261, a new non-xanthine A2A adenosine receptor antagonist, to rat striatal membranes
No full textThe present study describes the binding to rat striatal A2A adenosine receptors of the new potent and selective antagonist radioligand, [3H]-5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, [3H]-SCH 58261. [3H]-SCH 58261 specific binding to rat striatal membranes (>90%) was saturable, reversible and dependent upon protein concn. Satn. expts. revealed that [3H]-SCH 58261 labeled a single class of recognition sites with high affinity (Kd = 0.70 nM) and limited capacity (apparent Bmax = 971 fmol mg-1 of protein). The presence of 100 μM GTP in the incubation mixt. did not modify [3H]-SCH 58261 binding parameters. Competition expts. showed that [3H]-SCH 58261 binding is consistent with the labeling of A2A striatal receptors. Adenosine receptor agonists competed with the binding of 0.2 nM [3H]-SCH 58261 with the following order of potency: 2-hexynyl-5'-ethylcarboxamidoadenosine (2HE-NECA)>5'-N-ethylcarboxamidoadenosine (NECA)>2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680)>2-phenylaminoadenosine (CV 1808)>R-N6-phenylisopropyladenosine (R-PIA)>N6-cyclohexyladenosine (CCPA)>S-N6-phenylisopropyladenosine (S-PIA). Adenosine antagonists inhibited [3H]-SCH 58261 binding in the following order: 5-amino-9-chloro-2-(furyl)-[1,2,4]-triazolo[1,5-c]quinazoline (CGS 15943)>5-amino-8-(4-fluorobenzyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (8FB-PTP)=SCH 58261>xanthine amine congener (XAC)=(E,18%-Z,82%)7-methyl-8-(3,4-dimethoxystyryl)-1,3-dipropylxanthine (KF 17837S)>8-cyclopentyl-1,3-dipropylxanthine (DPCPX)≥8-phenyltheophylline (8-PT). The Ki values for adenosine antagonists were similar to those labeled with the A2A agonist [3H]-CGS 21680. Affinities of agonists were generally lower. The A1-selective agonist, R-PIA, was found to be about 9 fold more potent than its stereoisomer, S-PIA, thus showing the stereoselectivity of [3H]-SCH 58261 binding. Except for 8-PT, the adenosine agonists and antagonists examd. inhibited [3H]-SCH 58261 binding with Hill coeffs. not significantly different from unity. The present results indicate that [3H]-SCH 58261 is the first non-xanthine adenosine antagonist radioligand which directly labels A2A striatal receptors. High receptor affinity, good selectivity and very low non-specific binding make [3H]-SCH 58261 an excellent probe for studying the A2A adenosine receptor subtype in mammalian brain
A3 ADENOSINE RECEPTORS MODULATE HYPOXIA-INDUCIBLE FACTOR-1ALPHA EXPRESSION IN HUMAN CANCER CELLS
No full textHypoxia appears to induce a program which shifts the cellular phenotype toward an increase in intracellular adenosine. Hypoxia-inducible factor-1 (HIF-1) is a key regulator of genes crucial to many aspects of cancer biology (1). Since the levels of both HIF-1 and adenosine are elevated within the hypoxic environment of solid tumors, we investigated whether adenosine may regulate HIF-1. In particular, we investigated the effect of A3 receptor antagonists on HIF-1 and vascular endothelial growth factor expression (2-5). The response to adenosine was generated at the cell surface because the inhibition of A3 receptor expression, by using small interfering RNA, abolished nucleoside effects. Furthermore, we characterized the signaling pathways induced by A3 receptors in hypoxia and provide results of how human tumor growth may be influenced through the adenosinergic system (6).
(1) Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003, 3, 721–732.
(2) Merighi, S.; Benini, A.; Mirandola, P.; Gessi, S.; Varani, K.; Simioni, C.; Leung, E.; Maclennan, S.; Baraldi, P.G.; Borea, P.A. Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. Mol Pharmacol. 2007, 72, 395-406.
(3) Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Baraldi, P.G.; Borea PA. Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of bad in glioblastoma cells. Mol Pharmacol. 2007, 72, 162-72.
(4) Merighi, S.; Benini, A.; Mirandola, P.; Gessi, S.; Varani, K.; Leung, E.; Maclennan, S.; Borea, P.A. Adenosine modulates vascular endothelial growth factor expression via hypoxia-inducible factor-1 in human glioblastoma cells. Biochem Pharmacol. 2006, 72, 19-31.
(5) Merighi, S.; Benini, A.; Mirandola, P.; Gessi, S.; Varani, K.; Leung, E.; Maclennan, S.; Baraldi, P.G.; Borea, P.A. A3 adenosine receptors modulate hypoxia-inducible factor-1alpha expression in human A375 melanoma cells. Neoplasia 2005, 7, 894-903.
(6) Merighi S.; Benini A.; Mirandola P.; Gessi S.; Varani K.; Leung E.; Maclennan S.; Borea PA. A3 adenosine receptor activation inhibits cell proliferation via phosphatidylinositol 3-kinase/Akt-dependent inhibition of the extracellular signal-regulated kinase 1/2 phosphorylation in A375 human melanoma cells. J Biol Chem. 2005, 280, 19516-26
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