Pyrazolo-triazolo-pyrimidines as adenosine receptor antagonists: A complete structure–activity profile

In the last 5 years, many efforts have been conducted searching potent and selective human A3 adenosine antagonists. In this field several different classes of compounds, possessing very good affinity (nM range) and with a broad range of selectivity, have been proposed. Recently, our group synthesized a new series of pyrazolo-triazolo-pyrimidines bearing different substitutions at the N5 and N8 positions, which have been described as highly potent and selective human A3 adenosine receptor antagonists. The present review summarizes available data and provides an overview of the structure–activity relationships found for this class of human A3 adenosine receptor antagonists

DNA Minor Groove Binders: the sulphur analog of duocarmicycin SA and CC-1065

Minor 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

Agents Antitumorales que interaccionan con el surco menor del'ADN y inibitors de la Tubulina

Minor 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)

New Modulators of A3 and A2B Adenosine Receptors

Adenosine, 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

Minor 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. 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

Anti-Cancer Agents - Preface

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Anti-cancer agents - Preface

Prefac

Sixth International symposium on adenosine and adenine nucleotides: new frontiers in the third millennium

Editoria