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Giampiero Spalluto

Publications and source records attributed to Giampiero Spalluto.

29 records · Page 2Linked to original sources
PubMed2004

Synthesis and biological evaluation of new phenidone analogues as potential dual cyclooxygenase (COX-1 and COX-2) and human lipoxygenase (5-LOX) inhibitors.

A new series of potential human 5-LOX inhibitors structurally related to the 1-phenyl-3-pyrazolidinone (phenidone, 2) has been synthesized and the activity against COX-1, COX-2, and human 5-LOX enzymes has been evaluated. In contrast with literature data, we observed that phenidone resulted to be inactive against human 5-LOX, while retains its activity against cyclooxygenases in a micromolar range. The present results suggest that the substitution of the amino function at the 4-position is detrimental in terms of activity toward COX-1 and COX-2, while the presence of a double bond at the 4,5-position does not alter the biological profile against COX. The absence of activity vs. human 5-LOX strongly suggests a re-consideration of phenidone and its analogs as 5-LOX inhibitors in humans.

Cyclooxygenase Inhibitors↗
PubMed2003

Synthesis and anti-HIV properties of new water-soluble bis-functionalized[60]fullerene derivatives.

A new series of bis-functionalized fullerene C(60) derivatives bearing two or more solubilizing chains have been evaluated for their activity against HIV-1 and HIV-2 strains. Some of the compounds show activity against HIV-1 type in the low micromolar range. The effect of the positions of the addends on the C(60) nucleus has been investigated, indicating that only trans-2 isomers possess promising activity. The presence of a quaternary pyrrolidinium nitrogen is essential to increase solubility.

Anti-HIV Agents↗
PubMed2003

Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as adenosine receptor antagonists. Influence of the N5 substituent on the affinity at the human A 3 and A 2B adenosine receptor subtypes: a molecular modeling investigation.

A new series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines bearing various substituents at both the N5-pyrimidinyl and N8-pyrazolyl positions have been synthesized, and their binding affinities at the four human adenosine receptor subtypes (hA(1), hA(2A), hA(2B), and hA(3)) have been evaluated. All the described compounds contain arylacetyl moieties at the N5 position and arylalkyl substituents at the N8 position. Surprisingly, all the compounds present their most potent affinities at the hA(2B) adenosine receptor with a range of selectivities against the other subtypes. When bulky groups are present simultaneously at the N5 and N8 positions (e.g., compound 9), the best selectivity for the hA(2B) receptor was observed (K(i)(hA(1)) = 1100 nM; K(i)(hA(2A)) = 800 nM; K(i)(hA(2B)) = 20 nM; K(i)(hA(3)) = 300 nM, K(i)(hA(1)/A(2B)) = 55, K(i)(hA(2A)/A(2B)) = 40, K(i)(hA(3)/hA(2B)) = 15). To understand the molecular significance of these results, we compared the putative TM (transmembrane) binding motif of compound 9 on both hA(2B) and hA(3) receptors. From our docking studies, compound 9 fits neatly inside the TM region of the hA(2B) receptor but not in the corresponding hA(3) region, illustrating significant differences between the two subtypes. The study herein presented permits an understanding of why the bioisosteric replacement of an -NH, present in previously reported hA(3) receptor antagonists, with a -CH(2) group at the N5 position induces such large differences in hA(2B)/hA(3) affinity. In the molecular structure of the hA(3) receptor, two residues, Ser243 (TM6) and Ser271 (TM7), create a hydrophilic region, which seems to permit a better accommodation of the phenylurea series into this putative hA(3) binding site than the phenylacetyl series.

Adenosine-5'-(N-ethylcarboxamide)↗
PubMed2003

Medicinal chemistry of A2A adenosine receptor antagonists.

Due to the clearly demonstrated receptor-receptor interaction between adenosine A(2A) and dopamine D(2) receptors in the basal ganglia, the discovery and development of potent and selective A(2A)adenosine receptor antagonists became, in the last ten years, an attractive field of research to discovery new drugs for the treatment of neurodegenerative disorders, such as Parkinsons disease. Different compounds have been deeply investigated as A(2A) adenosine receptor antagonists, which could be classified in two great families: xanthine derivatives and nitrogen poliheterocyclic systems. These studies led to the discovery of some highly potent and selective A(2A) adenosine receptor antagonists such as ZM241385, SCH58261 and some xanthine derivatives (KW6002), which have been used as pharmacological tools for studying this receptor subtype. However, those compounds showed some problems that do not permit their use in clinical studies, such as poor water solubility (SCH58261, and xanthine derivatives) or good affinity for A(2B) adenosine receptor subtype (ZM241385). In the last few years great efforts have been made to overcome these problems, trying to optimize not only the pharmacological profile but also the pharmacokinetic character of this class of compounds. The aim of this report is to briefly summarize the recent progress made in this attractive field of research.

Drug Design↗
PubMed2002

Synthesis, biological properties, and molecular modeling investigation of the first potent, selective, and water-soluble human A(3) adenosine receptor antagonist.

A new, highly potent, selective, and water-soluble antagonist of the hA(3) adenosine receptor was synthesized and tested in binding and functional assays. Compound 4 (5-[[(4-pyridyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine hydrochloride) displayed high water solubility (15 mM) and the highest affinity (K(i) = 0.01 nM) and selectivity for the hA(3) versus A(1), A(2A), and A(2B) receptors (>10000-fold) ever reported. A Schild analysis of the antagonism by 4 of agonist-induced inhibition of cAMP production in CHO cells expressing the hA(3) receptor indicated a K(B) value of 0.20 nM.

Animals↗
PubMed2002

Synthesis, biological activity, and molecular modeling investigation of new pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as human A(3) adenosine receptor antagonists.

A new series of pyrazolotriazolopyrimidines bearing different substitutions on the phenylcarbamoyl moieties at the N5 position, being highly potent and selective human A(3) adenosine receptor antagonists, is described. The compounds represent an extension and an improvement of our previous work on this class of compounds (J. Med. Chem. 1999, 42, 4473-4478; J. Med. Chem. 2000, 43, 4768-4780). All the synthesized compounds showed A(3) adenosine receptor affinity in the subnanomolar range and high levels of selectivity in radioligand binding assays at the human A(1), A(2A), A(2B), and A(3) adenosine receptors. In particular, the effect of the substitution and its position on the phenyl ring have been studied. From binding data, it is evident that the unsubstituted derivatives on the phenyl ring (e.g., compound 59, hA(3) = 0.16 nM, hA(1)/hA(3) = 3713, hA(2A)/hA(3) = 2381, hA(2B)/hA(3) = 1388) showed the best profile in terms of affinity and selectivity at the human A(3) adenosine receptors. The introduction of a sulfonic acid moiety at the para position on the phenyl ring was attempted in order to design water soluble derivatives. However, this substitution led to a dramatic decrease of affinity at all four adenosine receptor subtypes. A computer-generated model of the human A(3) receptor was built and analyzed to better interpret these results, demonstrating that steric control, in particular at the para position on the phenyl ring, plays a fundamental role in the receptor interaction. Some of the synthesized compounds proved to be full antagonists in a specific functional model, where the inhibition of cAMP-generation by IB-MECA was measured in membranes of CHO cells stably transfected with the human A(3) receptor with IC(50) values in the nanomolar range, with a statistically significative linear relationship with the binding data.

Animals↗
PubMed2002

7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as A2A adenosine receptor antagonists: a study on the importance of modifications at the side chain on the activity and solubility.

It was demonstrated in the early 1990s that adenosine exerts many physiological functions through the interaction with four different receptors, named A1, A2A, A2B, and A3. In the past few years, our group has been involved in the development of A2A antagonists, which led to the synthesis of SCH 58261 (1), the first potent and selective adenosine A2A antagonist, which has been widely used as a reference compound. In this paper, we present an extended series of pyrazolotriazolopyrimidines synthesized with the aim to investigate the influence of the substitutions on the pyrazole ring. The choice of the substituents was based on their capability to improve water solubility while retaining high affinity and selectivity at the human A2A adenosine receptor subtype. In this series, some structural characteristics that are important for activity, i.e., tricyclic structure, free amino group at 5-position, furan ring, and substituent at 7-position on the pyrazole moiety, have been maintained. We focused our attention on the nature of the phenyl ring substituent to improve water solubility. Following this strategy, we developed new compounds with good affinity and selectivity for A2A adenosine receptors, such as 8d (K(i) 0.12 nM; hA1/hA2A ratio = 1025; R(m) = 2.8), 8h (K(i) 0.22; hA1/hA2A ratio = 9818; R(m) = 3.4), 8i (K(i) 0.18 nM; hA1/hA2A ratio = 994; R(m) = 2.8), 8k (K(i) 0.13 nM; hA1/hA2A ratio = 4430; R(m) = 3.6), and 14b (K(i) 0.19 nM; hA1/hA2A ratio = 2273; R(m) = 2.7). All the new synthesized compounds have no significant interaction with either A2B or A3 receptor subtypes. This new series of compounds deeply enlightens some structural requirements to display high affinity and selectivity for the A2A adenosine receptor subtype, although our goal of identifying new compounds with increased water solubility was not completely achieved. On this basis, other strategies will be devised to improve this class of compounds with a profile that appears to be promising for treatment of neurodegenerative disorders, such as Parkinson's disease.

Binding, Competitive↗
PubMed2002

Synthesis, biological activity and molecular modeling studies of 1,2,3,4-tetrahydroisoquinoline derivatives as conformationally constrained analogues of KN62, a potent antagonist of the P2X7-receptor containing a tyrosine moiety.

A new series of ring constrained analogues of the P2X7 receptor antagonist KN62 (1-[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4- phenylpiperazine, CAS 127191-97-3) containing the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid core with S configuration in position 3 was synthesised and their antagonist activities were tested on human macrophage cells. While KN62 is a potent antagonist of the P2X7 receptor, these novel compounds are weak antagonists of the purinergic P2X7 receptor and only one compound (5) showed appreciable activity as P2X7 antagonist, which was 30 times weaker than that reported for KN62. Along with compound 5, the derivatives 11 and 25 were the most active inhibitors in this synthesised series. A molecular modeling study confirmed that an extended rather than folded conformation seems to be crucial for the antagonistic activity at the P2X7 receptor.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2002

Pyrazolo-triazolo-pyrimidine derivatives as adenosine receptor antagonists: a possible template for adenosine receptor subtypes?

Adenosine, a widely distributed modulator, regulates many physiological functions through specific cell membrane G-protein-coupled receptors classified as A(1), A(2A), A(2B) and A(3). An intense medicinal chemistry effort made over the last 20 years has led to a variety of selective adenosine receptor agonists and antagonists. In particular, the pyrazolo-triazolo-pyrimidine nucleus has been strongly investigated in the last years by our group. All the modifications performed and a tentative of structure-activity-relationship is reported. In fact, the combination of different substitutions at the N(7), N(8) and N(5) positions afford compounds which showed good affinity and selectivity for the different adenosine receptor subtypes. The data herein summarized, permit to speculate on the use of this nucleus as possible template for the adenosine receptor subtypes.

Animals↗
PubMedDate not supplied

Fullerene derivatives: an attractive tool for biological applications.

The fullerene family, and especially C60, has very appealing photo-, electro-chemical and physical properties, which can be exploited in many and different biological fields. Fullerene is able to fit inside the hydrophobic cavity of HIV proteases, inhibiting the access of substrates to the catalytic site of the enzyme. It can be used as radical scavenger; in fact some water-soluble derivatives are able to reduce ROS concentrations. At the same time, if exposed to light, fullerene can produce singlet oxygen in high quantum yields. This action, together with the direct electron transfer from excited state of fullerene and DNA bases, can be used to cleave DNA. In this review we report the most recent aspects of fullerene biological applications.

Animals↗