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Biomedical subjects

B Cacciari

Publications and source records attributed to B Cacciari.

33 records · Page 2Linked to original sources
PubMed1998

Heterocyclic analogs of DNA minor groove alkylating agents.

It is generally accepted that neoplastic transformation is related to genes alteration or oncogene activation. In particular, DNA minor groove binding drugs have been extensively studied through the years in order to influence the regulation of gene expression by means of specific interactions with DNA bases moieties. Pyrrolo[2,1-c],[1,4].benzodiazepines (PBDs), CC-1065 and distamycins are three classes of minor groove binders which showed interesting cytotoxicity profiles, refined through already reviewed processes of SAR studies. Among the modifications to the three families of antitumor compounds, heterocyclic substitutions have been extensively applied by many groups in order to either modify the reactivity profile or introduce extra interactions within the minor groove, thus changing the binding site or modulating the binding sequence. The updated material related to these modifications has been rationalised and ordered to offer an overview of the argument.

Alkylating Agents↗
PubMed1997

Synthesis, cytotoxicity, antitumor activity and sequence selective binding of two pyrazole analogs structurally related to the antitumor agents U-71,184 and adozelesin.

Two pyrazole analogs structurally related to the antitumor agents adozelesin and U-71,184 respectively were synthesized. By using a polymerase chain reaction approach, both compounds show selective binding to A + T rich sequences exactly as reference compound U-71,184. In in vitro assays, against L1210 cell lines, both derivatives showed cytotoxicity in the pM range, values comparable with the natural target compound (+)-CC-1065. The most active compound showed very high antitumor activity in mice implanted with L1210 cells (ILS% 363).

Animals↗
PubMed1997

Synthesis, cytotoxicity and antitumor activity of some new simplified pyrazole analogs of the antitumor agent CC-1065. Effect of an hydrophobic group on antitumor activity.

Three simplified pyrazole analogs (7-9) of the antitumor agents CC-1065, were synthesized. In in vitro assays, against L1210 cell lines all derivatives showed a cytotoxicity in a pM range, values close to the natural target compound (+)-CC-1065. In in vivo tests, against disseminate L1210 leukemia cells, synthesized compounds showed a good potency (O.D. 300 micrograms/Kg) but no activity. These observations further validate the effect of the hydrophilic and/or hydrophobic characteristics of the substituents present on the molecules, confirming the relevance of this phenomena on in vivo activity. In fact in this case the increase of hydrophobic characteristics of the molecules produce the loss of activity, probably due to a worse bioavailability of the drugs in animals.

Animals↗
PubMed1997

Synthesis, solvolytic stability and cytotoxicity of a modified derivative of CPzI, a pyrazole analog of the alkylation subunit of the antitumor agent CC-1065: effect of the nitrogen substitution on the functional reactivity.

The synthesis and the comparative preliminary biological evaluation of a new pyrazole analog (16) of the CC-1065 alkylating unit (CPI) are described. This new derivative showed low cytotoxicity against L1210 murine leukemia (IC50 3064 nM) with respect to reference compound, but contrarily to literature data, was found to be more stable to solvolysis than the natural derivative (+/-)-N-Boc-CPI (pH 3, t1/2 = 212 h vs. 37 h). The results of such investigation showed that alkylation of the pyrazole nitrogen caused a loss of cytotoxic activity in vitro against tumor cells. This experimental observation allowed us to confirm the importance of free N-H for the anticellular activity.

Alkylation↗
PubMed1996

Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives: potent and selective A(2A) adenosine antagonists.

A series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives (10a-o,q,r), bearing alkyl and aralkyl chains on positions 7 and 8, were synthesized in the attempt to obtain potent and selective antagonists for the A(2A) adenosine receptor subtype. The compounds were tested in binding and functional assays to evaluate their potency for the A(2A) compared with the A1 adenosine receptor subtype. In binding studies in rat brain membranes, most of the compounds showed affinity for A(2A) receptors in the low nanomolar range with a different degree of A(2A) versus A1 selectivity. Comparison of N(7) (10a-d,h-o)- and N(8) (10e-g)-substituted pyrazolo derivatives indicates that N(7) substitution decreases the A1 affinity with the concomitant increase of A(2A) selectivity. Specifically, the introduction of a 3-phenylpropyl group at pyrazolo nitrogen in position 7 (101) increased significantly the A(2A) selectivity, being 210-fold, while the A(2A) receptor affinity remained high (Ki=2.4 nM). With regards to the affinity for A(2A) receptors, also the compound 10n, bearing in the 7-position a beta-morpholin-4-ylethyl group, deserves attention (Ki=5.6 nM) even though the A2A selectivity (84-fold) was not as high as that of 101. Conversely, the compound 10m (N(7)-4-phenylbutyl derivative) showed a remarkable selectivity (A1/a(2A) ratio = 129) associated with lower A(2A) affinity (Ki = 21 nM). In functional studies, most of the compounds examined reversed 5'-(N-ethylcarbamoyl) adenosine-induced inhibition of rabbit platelet aggregation inhibition which is a biological response mediated by the A2A receptor subtype. The compounds are potent and selective A2A antagonists which can be useful to elucidate the pathophysiological role of this adenosine receptor subtype. These compounds deserve to be further developed to assess their potential for treatment of neurodegenerative disorders such as Parkinson's disease.

Animals↗
PubMed1996

Novel N6-(substituted-phenylcarbamoyl)adenosine-5'-uronamides as potent agonists for A3 adenosine receptors.

A series of adenosine-5'-uronamide derivatives bearing N6-phenylurea groups have been synthesized and tested for their affinity at A1 and A2A adenosine receptors in rat brain membranes and at cloned rat A3 receptors from stably transfected CHO cells. Some N6-arylcarbamoyl derivatives, N6-((2-chlorophenyl)carbamoyl)-, N6-((3-chlorophenyl)carbamoyl)-, and N6-((4-methoxyphenyl)carbamoyl)adenosine-5'-ethyluronamide (4l-n), were found to have affinity at A3 receptors in the low nanomolar range (Ki values < 10 nM). In CHO cells stably transfected with the rat A3 receptor, compound 4n was found to be a full agonist in inhibiting adenylate cyclase activity. The present study represents the first example of N6-acyl-substituted adenosine analogs having high affinity at adenosine receptors and, in particular, at the A3 receptor subtype.

Adenylyl Cyclases↗
PubMed1996

1H-pyrazolo[4,3-d]pyrimidine-7(6H)-one and 5H-pyrazolo[4,3-d] 1,2,3-triazin-4(3H)-one derivatives. Synthesis and in vitro biological activity at adenosine A1 and A2a receptors.

The affinity of newly synthesized 1H-pyrazolo[4,3-d] pyrimidine-7 (6H)- one (5a-f) and 5H-pyrazolo[4,3-d]1,2,3,-triazin-4(3H)-one (6a-i) derivatives for A1 and A2a adenosine receptors was investigated in rat cerebral membranes. The compounds showed affinities in the micromolar range for both adenosine A1 and A2a receptors. In particular 5d was the most interesting compound and showed some degree of selectivity for the A1 receptor (Ki values being 2 mumol/l; A1/A2a ratio < 0.021). The present study provides useful information for a better understanding of the structure-activity relationships of antagonists at adenosine receptors.

Adenosine↗
PubMed1996

Synthesis, antiviral and antiproliferative activity of a new class of 5-(alkyl or arylthio)-6-vinyl uracils.

Uracil derivatives bearing substituted or unsubstituted vinyl groups at position C6 and alkyl- or arylthio groups at position C5 were synthesized and tested in vitro for antiviral and antiproliferative activity. None of the compounds were active against HIV-1. However, some of them inhibited the proliferation of leukemia, lymphoma and solid tumor-derived cell lines at micromolar concentrations. The maximum potency of antiproliferative activity correlates with the presence of unsubstituted vinyl groups and alkyl- or arylthio substituents.

Anti-HIV Agents↗
PubMed1994

Synthesis and antitumor activity of a new class of pyrazolo[4,3-e]pyrrolo[1,2-a][1,4]diazepinone analogues of pyrrolo[1,4][2,1-c]benzodiazepines.

A new class of pyrrolo[1,4]benzodiazepine (PBD) analogues featuring a pyrazolo[4,3-e]pyrrolo[1,2-a][1,4]diazepinone ring system has been designed and synthesized. These compounds, 2a-o, are characterized by the substitution of the aromatic A ring, characteristic of the PBDs, with a disubstituted pyrazole ring bearing alkyl and benzyl substituents at N6 or N7 and alkyl or carbomethoxy substituents at C8. Biological evaluation revealed an appreciable in vitro cytotoxic activity for compounds 2a,b,f-i.

Animals↗
PubMed1993

Synthesis and cardiodepressant activity of dialkyl 1,4-dihydro-2,6-dimethyl-4-(pentatomic-heteroaryl)-3,5-pyridine-dicarbo xylates. 2.

A new series of 1,4-dihydropyridine bearing substituted pyrazole and imidazole at C-4 position was synthesized and characterized as inotropic, chronotropic and calcium antagonist agents, in order to evaluate the effect on pharmacological activity of replacement of the 4-aryl group of nifedipine-like drugs by pyrazole and imidazole moieties. All compounds were tested on myocardial muscle and vascular smooth muscle of guinea-pigs. The new compounds showed both significant selective negative inotropic activity and fairly good negative chronotropic effects. All compounds elicited weak calcium antagonist activity, except compound 9 which is a selective bradycardic agent.

Animals↗
PubMed1991

Synthesis, antibacterial activity and structure-activity relationships of N-substituted 4-diazo-pyrazole-5-carboxamides. 2.

A series of 4-diazopyrazole-5-carboxamides 1 d-n has been synthesized and their antibacterial activity against a number of Gram-negative and Gram-positive strains has been tested. Some of the compounds resulted quite active and the whole set allowed to further study the SAR of the class. Substituents in position 5 affect Gram-negative and Gram-positive activities via bulk and electronic properties respectively; position 3 mostly affects the Gram-negative activity, while the presence of the charged diazo group in position 4 is crucial for both antibacterial activities.

Amides↗
PubMedDate not supplied

Selective adenosine A2A receptor antagonists.

In the early 1990s it became clear that the A2A adenosine receptor had characteristics that made it distinct from the other A1, A2B and A3 adenosine receptors. Great progress has been made with the discovery of selective A2A receptor antagonists. A variety of synthetic substitutions on the xanthine moiety led the chemists of Kyowa-Hakko to discover that introduction of the styryl group in the 8 position of xanthines was critical in achieving compounds endowed with selective A2A receptor antagonistic properties. One compound, KW 6002, (E)1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine, is currently being developed for treatment of Parkinson's disease. A number of non-xanthine heterocycles have also been synthesized starting from the non-selective adenosine antagonist CGS 15943, a triazoloquinazoline. Thus, replacement of the phenyl ring of CGS 15943 with a heterocyclic ring such as pyrazole or imidazole, led to a series of interesting compounds whose prototype, SCH 58261, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, has become a reference A2A receptor antagonist. Modification of N7 substituents has progressed to optimize A2A receptor selectivity and pharmacokinetic characteristics. A related class of compounds having a bicyclic instead of the tricyclic ring structure is also of interest. The prototype of these triazintriazolo derivatives, ZM 241385, is a potent A2A receptor antagonist; however, it also shows interactions with A2B receptors. The relevance of the A2A receptors in specific disease states, especially in the central nervous system, makes this class of adenosine receptor blockers of interest for treatment of neurodegenerative disorders such as Parkinson's disease.

Animals↗
PubMedDate not supplied

DNA minor-groove binders: results and design of new antitumor agents.

DNA minor-groove binding drugs have been extensively studied in the last years in order to influence the regulation of gene expression in neoplastic disorders by means of specific interactions with DNA bases. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs), CC-1065 and distamycins are three classes of minor-groove alkylating agents which showed interesting cytotoxicity profiles, but they cannot be used in humans for various toxicity problems. For this reason many groups applied heterocyclic substitutions extensively, in order to either modify the reactivity profile or introduce extra interactions within the minor groove, thus changing the binding site or modulating the binding sequence.

Animals↗