RESUMO
An efficient synthetic procedure was adopted to synthesize a series of new molecules containing the pyrazolo[3,4-d]pyrimidine (PP) scaffold, which have been evaluated as promising human adenosine receptor (AR) antagonists. The effect of substitutions at the N(2), C(4) and C(6) positions of PPs on the affinity and selectivity towards the adenosine receptors were explored. Most of the pyrazolo[3,4-d]pyrimidine-4-carboxylates displayed from moderate to good affinity at the human A3AR (hA3AR), as indicated by the low micromolar range of Ki values (Ki hA3AR = 0.7-34 µM). In particular, compounds 60 and 62 displayed good affinity at the hA3AR (60, Ki hA3AR = 2.2 µM and 62, Ki hA3AR = 2.9 µM) and selectivity towards the other AR subtypes (60, >46-fold selective and 62, >34-fold selective, respectively). In view of these results, these novel PP analogues were docked both in the crystallographic structure of the hA2AAR and in a homology model of the hA3AR in order to support the structure activity relationship (SAR) analysis. These preliminary results demonstrated that pyrazolo[3,4-d]pyrimidine can be considered a promising scaffold to obtain new molecules with potent hA3AR antagonist activity.
Assuntos
Antagonistas do Receptor A3 de Adenosina/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Receptor A3 de Adenosina/metabolismo , Antagonistas do Receptor A3 de Adenosina/síntese química , Antagonistas do Receptor A3 de Adenosina/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
The anti-inflammatory activity of a new class of phenyl-pyrazolone derivatives, structurally related to phenidone, has been evaluated using the Croton oil ear test in mice as model of acute inflammation. Derivative 5h reduces the percentage of oedema similarly to indomethacin and more efficiently than phenylbutazone. The anti-inflammatory activity of these two reference drugs depends on their COX inhibition, but for the synthesized derivatives it has not been demonstrated a significant COX or LOX inhibition, as previously reported. While the anti-inflammatory activity of phenidone is correlated to its anti-oxidant properties, the redox potential of these compounds appears not decisive in the inflammatory process inhibition. In order to investigate the mechanism of action for these compounds, we quantified their anti-oxidant activity and the lipophilicity, and a relationship between the calculated logP and the percentage of oedema reduction was found. We hypothesize that the anti-inflammatory activity, recorded in vivo, could be related to lipophilic parameter of these compounds.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Edema/tratamento farmacológico , Pirazolonas/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/química , Antioxidantes/química , Relação Dose-Resposta a Droga , Edema/patologia , Masculino , Camundongos , Pirazolonas/químicaRESUMO
A computer-aided approach has been developed in order to understand the molecular pharmacology of human A3R, and specifically, to lead to the discovery and structural refinement of new, potent and selective human A3R antagonists. This review focuses on our combined target-based and ligand-based drug design strategy, recently applied to provide more accurate information about the recognition mode on human A3R of some pyrazolotriazolopyrimidine and triazoloquinoxalinone analogs. The 3D rhodopsin-based homology model of human A3R has represented the starting point of our approach. A high throughput molecular docking method on the considered antagonists has allowed us to generate a receptor-based pharmacophore model. A novel "Y-shaped" pharmacophore binding motif has been proposed for both pyrazolotriazolopyrimidine and triazoloquinoxalinone derivatives. Moreover, related receptor-based 3D-QSAR analysis has been carried out to provide a suitable tool for prediction of the antagonists binding affinity on human A3R.
Assuntos
Antagonistas do Receptor A3 de Adenosina , Desenho Assistido por Computador , Desenho de Fármacos , Humanos , Ligantes , Modelos Moleculares , Conformação Proteica , Estrutura Terciária de Proteína , Relação Quantitativa Estrutura-AtividadeRESUMO
A new series of potential adenosine receptor antagonists with a [1,2,4]-triazolo-[3,4-f]-purine structure bearing at the 1 and 3 position n-propyl groups have been synthesized, and their affinities at the four human adenosine receptor subtypes (A(1), A(2A), A(2B) and A(3)) have been evaluated. In this case the presence of n-propyl groups seems to induce potency at the A(2A) and A(3) adenosine receptor subtypes as opposed to our previously reported series bearing methyl substituents at the 1 and 3 positions. In particular the non-acylated derivative 17 showed affinity at these two receptor subtypes in the micromolar range. Indeed, preliminary molecular modeling investigations according to the experimental binding data indicate a modest steric and electrostatic antagonist-receptor complementarity.
Assuntos
Antagonistas do Receptor A3 de Adenosina , Desenho de Fármacos , Purinas , Antagonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A2 de Adenosina , Animais , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Humanos , Modelos Moleculares , Estrutura Molecular , Conformação Proteica , Estrutura Secundária de Proteína , Purinas/síntese química , Purinas/química , Purinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
This review describes recent advances in the development of DNA-photocleavage agents. Major mechanisms of photosensitized DNA photocleavage are presented and the most popular categories of compounds are considered, which include metal complexes and many organic functional derivatives. DNA-targeted conjugates of photosensitizers are also described and discussed.
Assuntos
Dano ao DNA , DNA/metabolismo , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Sequência de Bases/efeitos dos fármacos , Sítios de Ligação/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , FotoquímicaRESUMO
A series of pyrazolotriazolopyrimidines was previously reported to be highly potent and selective human A(3) adenosine receptor antagonists (Baraldi et al. J. Med. Chem. 2000, 43, 4768-4780). A derivative having a methyl group at the N(8) pyrazole combined with a 4-methoxyphenylcarbamoyl moiety at N(5) position, displayed a K(i) value at the hA(3) receptor of 0.2 nM. We now describe chemically reactive derivatives which act as irreversible inhibitors of this receptor. Electrophilic groups, specifically sulfonyl fluoride and nitrogen mustard (bis-(beta-chloroethyl)amino) moieties, have been incorporated at the 4-position of the aryl urea group. Membranes containing the recombinant hA(3) receptor were preincubated with the compounds and washed exhaustively. The loss of ability to bind radioligand following this treatment indicated irreversible binding. The most potent compound in irreversibly binding to the receptor was 14, which contained a sulfonyl fluoride moiety and a propyl group at the N(8) pyrazole nitrogen. The bis-(beta-chloroethyl)amino derivatives displayed a much smaller degree of irreversible binding than the sulfonyl fluoride derivatives. A computer-generated model of the human A(3) receptor was built and analyzed to help interpret these results. The model of the A(3) transmembrane region was derived using primary sequence comparison, secondary structure predictions, and three-dimensional homology building, using the recently published crystal structure of rhodopsin as a template. According to our model, sulfonyl fluoride derivatives could dock within the hypothetical TM binding domain, adopting two different energetically favorable conformations. We have identified two amino acids, Ser247 and Cys251, both in TM6, as potential nucleophilic partners of the irreversible binding to the receptor.
Assuntos
Compostos de Anilina/síntese química , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos de Fenilureia/síntese química , Antagonistas de Receptores Purinérgicos P1 , Pirimidinas/síntese química , Compostos de Anilina/química , Compostos de Anilina/metabolismo , Animais , Ligação Competitiva , Linhagem Celular , Cricetinae , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/metabolismo , Humanos , Modelos Moleculares , Compostos de Fenilureia/química , Compostos de Fenilureia/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Ensaio Radioligante , Receptor A3 de Adenosina , Receptores Purinérgicos P1/metabolismo , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , TransfecçãoRESUMO
1. The present work was devoted to the study of A3 adenosine receptors in Jurkat cells, a human leukemia line. 2. The A3 subtype was found by means of RT-PCR experiments and characterized by using the new A3 adenosine receptor antagonist [3H]-MRE 3008F20, the only A3 selective radioligand currently available. Saturation experiments revealed a single high affinity binding site with K(D) of 1.9+/-0.2 nM and B(max) of 1.3+/-0.1 pmol mg(-1) of protein. 3. The pharmacological profile of [3H]-MRE 3008F20 binding on Jurkat cells was established using typical adenosine ligands which displayed a rank order of potency typical of the A3 subtype. 4. Thermodynamic data indicated that [3H]-MRE 3008F20 binding to A3 subtype in Jurkat cells was entropy- and enthalpy-driven, according with that found in cells expressing the recombinant human A3 subtype. 5. In functional assays the high affinity A3 agonists Cl-IB-MECA and IB-MECA were able to inhibit cyclic AMP accumulation and stimulate Ca(2+) release from intracellular Ca(2+) pools followed by Ca(2+) influx. 6. The presence of the other adenosine subtypes was investigated in Jurkat cells. A1 receptors were characterized using [3H]-DPCPX binding with a K(D) of 0.9+/-0.1 nM and B(max) of 42+/-3 fmol mg(-1) of protein. A2A receptors were studied with [3H]-SCH 58261 binding and revealed a K(D) of 2.5+/-0.3 nM and a B(max) of 1.4+/-0.2 pmol mg(-1) of protein. 7. In conclusion, by means of the first antagonist radioligand [3H]-MRE 3008F20 we could demonstrate the existence of functional A3 receptors on Jurkat cells.
Assuntos
Receptores Purinérgicos P1/genética , Linfócitos T/metabolismo , Animais , Ligação Competitiva/efeitos dos fármacos , Células CHO , Cálcio/metabolismo , Cricetinae , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Guanosina Trifosfato/farmacologia , Humanos , Células Jurkat , Cinética , Compostos de Fenilureia/metabolismo , Compostos de Fenilureia/farmacologia , Agonistas do Receptor Purinérgico P1 , Pirimidinas/metabolismo , Pirimidinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor A2A de Adenosina , Receptor A3 de Adenosina , Receptores Purinérgicos P1/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Termodinâmica , Fatores de Tempo , Triazóis/metabolismo , Triazóis/farmacologia , Trítio , Xantinas/metabolismo , Xantinas/farmacologiaRESUMO
We have synthesized and evaluated a series of hybrids, denoted 22--27, for in vitro cytotoxic activity against a variety of cancer cell lines. These hybrids represent a molecular combination of polypyrrole minor groove binders structurally related to the natural antitumor agent distamycin A and two pyrazole analogues of the left-hand segment called cyclopropylpyrroloindole (CPI) of the potent antitumor antibiotic (+)-CC-1065. These novel water-soluble hybrids have been designed to enhance the minor groove binding ability of alkylating units 20 and 21, which should increase their clinical appeal by overcoming the administration problems of (+)-CC-1065 derivatives. The DNA alkylating and cytotoxic activities against several tumor cell lines are reported and discussed in terms of their structural differences in relation to both the number of N-methyl pyrrole rings and the type of the alkylating unit tethered to the oligopeptidic frame. It may be noted that, in general, and especially for 22--24, the cytotoxicity of the hybrids was much greater than that of the alkylating units alone. In only one case, compound 27, did the hybrid have cytotoxic activity comparable to that of the alkylating unit alone against FM3A/0 cells. The broadest spectrum of activity and greatest potency was shown by the hybrid 24, in which the alkylating unit 20 and the deformyl distamycin A are tethered by 1-methyl 2,5-dicarbonyl pyrazole, with IC(50) values for the different tumor cell lines ranging from 7 to 71 nM. For compounds 22--24, the increase of the length of the pseudopeptidic moiety from one to three N-methylpyrrole residues led to an increased cytotoxicity. Among the hybrids tested for their inhibitory effects on the proliferation of murine L1210 leukemia cell line, compound 24 proved to be the most active (IC(50) = 7.4 nM), and in the sequencing gel experiments, it showed the strongest and most highly sequence-specific DNA alkylation activity. For compounds 22-24, the sequence specificity of DNA alkylation appears to be affected by the modification of the number of pyrrole rings, and the correlation between cytotoxicity and alkylation pattern suggests that 24 exerts its cytotoxicity through DNA sequence-specific alkylation of the third adenine located in the sequence 5'-ACAAAAATCG-3'. The two other hybrids 22 and 23 were slightly less active for tumor cell proliferation, with IC(50) values of 58 and 19 nM, respectively. With only one exception, none of the compounds was endowed with antiviral activity at subtoxic concentrations. Compound 24 inhibited the effect of vaccinia virus at a concentration that was significantly lower than its minimum cytotoxic concentration for the E(6)SM host cells. These compounds gave distinct patterns of alkylation in AT-rich sequences, indicating that minor structural changes produced marked alterations in sequence selectivity.
Assuntos
Antineoplásicos Alquilantes/síntese química , DNA/química , Indazóis/síntese química , Indóis/síntese química , Leucomicinas/química , Pirazóis/síntese química , Pirróis/síntese química , Animais , Antineoplásicos Alquilantes/química , Antineoplásicos Alquilantes/farmacologia , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Duocarmicinas , Humanos , Indazóis/química , Indazóis/farmacologia , Indóis/química , Indóis/farmacologia , Camundongos , Modelos Moleculares , Pirazóis/química , Pirazóis/farmacologia , Pirróis/química , Pirróis/farmacologia , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , ÁguaRESUMO
We report the synthesis of three novel, versatile fullerene intermediates whose main feature is the presence of an amino end group. Simple condensation reactions of these intermediates under standard conditions produce new derivatives that are useful for applications in materials science and medicinal chemistry.
Assuntos
Carbono/química , Fulerenos , Aminas/química , DNA/metabolismo , DNA/efeitos da radiação , Sondas Moleculares/química , Fotólise , Fármacos Fotossensibilizantes/químicaRESUMO
An enlarged series of pyrazolotriazolopyrimidines previously reported, in preliminary form (Baraldi et al. J. Med. Chem. 1999, 42, 4473-4478), as highly potent and selective human A(3) adenosine receptor antagonists is described. The synthesized compounds showed A(3) adenosine receptor affinity in the sub-nanomolar range and high levels of selectivity evaluated in radioligand binding assays at human A(1), A(2A), A(2B), and A(3) adenosine receptors. In particular, the effect of the chain at the N(8) pyrazole nitrogen was analyzed. This study allowed us to identify the derivative with the methyl group at the N(8) pyrazole combined with the 4-methoxyphenylcarbamoyl moiety at the N(5) position as the compound with the best binding profile in terms of both affinity and selectivity (hA(3) = 0.2 nM, hA(1)/hA(3) = 5485, hA(2A)/hA(3) = 6950, hA(2B)/hA(3) = 1305). All the 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. The new compounds are among the most potent and selective A(3) antagonists so far described. The derivatives with higher affinity at human A(3) adenosine receptors proved to be antagonists, in the cAMP assay, capable of inhibiting the effect of IB-MECA with IC(50) values in the nanomolar range, with a trend strictly similar to that observed in the binding assay. Also a molecular modeling study was carried out, with the aim to identify possible pharmacophore maps. In fact, a sterically controlled structure-activity relationship was found for the N(8) pyrazole substituted derivatives, showing a correlation between the calculated molecular volume of pyrazolo[4,3-e]1,2, 4-triazolo[1,5-c]pyrimidine derivatives and their experimental K(i) values.
Assuntos
Antagonistas de Receptores Purinérgicos P1 , Pirazóis/química , Pirimidinas/síntese química , Animais , Células CHO , Cricetinae , AMP Cíclico/biossíntese , Humanos , Modelos Moleculares , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Ensaio Radioligante , Receptor A3 de Adenosina , Relação Estrutura-AtividadeAssuntos
Encéfalo/metabolismo , Pirazóis/síntese química , Pirimidinas/síntese química , Receptores Purinérgicos P1/metabolismo , Animais , Encéfalo/anatomia & histologia , Células CHO , Radioisótopos de Carbono , Linhagem Celular , Cricetinae , Desenho de Fármacos , Humanos , Marcação por Isótopo , Ligantes , Pirazóis/metabolismo , Pirazóis/farmacocinética , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos , Receptor A2A de Adenosina , Proteínas Recombinantes/metabolismo , Distribuição Tecidual , Tomografia Computadorizada de Emissão , TransfecçãoRESUMO
We designed and synthesized the hybrid 6, prepared combining the minor groove binders distamycin A and pyrrolo [2,1-c][1,4] benzodiazepine (PBD) 4, related to the natural occurring anthramycin (2) and DC-81 (3). In this paper, the effects of the compound 6 on molecular interactions between DNA and transcription factor Sp1 were studied. The results obtained demonstrate that PBD-distamycin hybrid is a powerful inhibitor of Sp1/DNA interactions.
Assuntos
Antineoplásicos/farmacologia , Benzodiazepinonas/farmacologia , DNA de Neoplasias/efeitos dos fármacos , Distamicinas/farmacologia , Fator de Transcrição Sp1/antagonistas & inibidores , Animais , Antineoplásicos/química , Benzodiazepinonas/síntese química , Benzodiazepinonas/química , Linfoma de Burkitt/patologia , Divisão Celular/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Distamicinas/síntese química , Distamicinas/química , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células K562/efeitos dos fármacos , Leucemia L1210/patologia , Espectroscopia de Ressonância Magnética , Camundongos , Fator de Transcrição Sp1/metabolismo , Transcrição Gênica/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
The linkage of an heterocycle, like N-methylimidazole, to minor DNA groove binders containing two or three pyrroles lead to a new class of oligopeptides with reduced antitumor activity both in vitro and in vivo if compared to tallimustine (CAS 115308-98-0) and its tetrapyrrole homologue 9. In the present paper is reported the correlation between the cytoxicity of tallimustine and its derivatives 9-11 with their ability to inhibit polymerase chain reaction (PCR) amplification of oestrogen receptor and Ha-ras gene sequences, containing A + T rich and G + C rich regions, respectively. Tallimustine and its tetrapyrrole homologue 9 were found to have higher sequence selectivity for the human oestrogen receptor (ER) gene with respect to the relative imidazole-containing analogues.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Distamicinas/farmacologia , Imidazóis/farmacologia , Compostos de Mostarda Nitrogenada/farmacologia , Pirróis/farmacologia , Animais , Antineoplásicos Alquilantes/química , DNA/genética , Primers do DNA , Feminino , Genes ras/efeitos dos fármacos , Genes ras/genética , Humanos , Leucemia L1210/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Reação em Cadeia da Polimerase , Pirróis/química , Receptores de Estrogênio/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The lack of a radiolabeled selective A(3) adenosine receptor antagonist is a major drawback for an adequate characterization of this receptor subtype. This paper describes the pharmacological and biochemical characterization of the tritiated form of a new potent A(3) adenosine receptor antagonist, the pyrazolo triazolo pyrimidine derivative [(3)H]5N-(4-methoxyphenylcarbamoyl)amino-8-propyl-2-(2-furyl )pyrazolo [4,3-e] -1,2,4- triazolo[1,5-c]pyrimidine ([(3)H]MRE 3008F20). [(3)H]MRE 3008F20 bound specifically to the human adenosine A(3) receptor expressed in CHO cells (hA(3)CHO), and saturation analysis revealed a single high affinity binding site, K(D) = 0.80 +/- 0.06 nM, with a B(max) = 300 +/- 33 fmol/mg protein. This new ligand displayed high selectivity (1294-, 165-, and 2471-fold) in binding assay to human A(3) versus A(1), A(2A), and A(2B) receptors, respectively, and binds to the rat A(3) receptors with a K(i) > 10 microM. The pharmacological profile of [(3)H]MRE 3008F20 binding to hA(3)CHO cells was evaluated using known adenosine receptor agonists and antagonists with a rank order of potency consistent with that typically found for interactions with the A(3) adenosine receptors. In the adenylyl cyclase assay the same compounds exhibited a rank order of potency identical with that observed in binding experiments. Thermodynamic data indicated that [(3)H]MRE 3008F20 binding to hA(3)CHO is entropy- and enthalpy-driven in agreement with the typical behavior of other adenosine antagonists to A(1) and A(2A) receptors. These results show that [(3)H]MRE 3008F20 is the first antagonist radioligand with high affinity and selectivity for the human A(3) adenosine receptor and may be used to investigate the physiopathological role of A(3) adenosine receptors.
Assuntos
Compostos de Fenilureia/farmacologia , Antagonistas de Receptores Purinérgicos P1 , Triazóis/farmacologia , Adenosina/análogos & derivados , Adenosina/farmacologia , Inibidores de Adenilil Ciclases , Animais , Ligação Competitiva , Células CHO , Cricetinae , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Humanos , Compostos de Fenilureia/química , Ensaio Radioligante , Ratos , Receptor A3 de Adenosina , Receptores Purinérgicos P1/metabolismo , Triazóis/química , TrítioRESUMO
The synthesis and the preliminary biological evaluation of the first high affinity radioligand antagonist for the human A3 adenosine receptor, named [3H]-MRE 3008-F20 are reported. [3H]-MRE 3008-20 bound human A3 receptors expressed in CHO cells with K(D) and Bmax value of 0.82 +/- 0.08 nM and 297 +/- 28 fmol/mg of protein, respectively. [3H]-MRE 3008-F20 represents a useful tool for a further characterization of A3 adenosine receptor subtype.
Assuntos
Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Antagonistas de Receptores Purinérgicos P1 , Triazóis/síntese química , Triazóis/farmacologia , Animais , Células CHO , Cricetinae , Humanos , Compostos de Fenilureia/metabolismo , Ensaio Radioligante , Receptor A3 de Adenosina , Receptores Purinérgicos P1/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/metabolismo , Triazóis/metabolismo , TrítioRESUMO
Adenosine regulates many physiological functions through specific cell membrane receptors. On the basis of pharmacological studies and molecular cloning, four different adenosine receptors have been identified and classified as A(1), A(2A), A(2B), and A(3). These adenosine receptors are members of the G-protein-coupled receptor family. While adenosine A(1) and A(2A) receptor subtypes have been pharmacologically characterized through the use of selective ligands, the A(3) adenosine receptor subtype is presently under study in order to better understand its physio-pathological functions. Activation of adenosine A(3) receptors has been shown to stimulate phospholipase C and D and to inhibit adenylate cyclase. Activation of A(3) adenosine receptors also causes the release of inflammatory mediators such as histamine from mast cells. These mediators are responsible for processes such as inflammation and hypotension. It has also been suggested that the A(3) receptor plays an important role in brain ischemia, immunosuppression, and bronchospasm in several animal models. Based on these results, highly selective A(3) adenosine receptor agonists and/or antagonists have been indicated as potential drugs for the treatment of asthma and inflammation, while highly selective agonists have been shown to possess cardioprotective effects. The updated material related to this field of research has been rationalized and arranged in order to offer an overview of the topic.
Assuntos
Receptores Purinérgicos P1/metabolismo , Animais , Humanos , Ligantes , Agonistas do Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Receptor A3 de Adenosina , Receptores Purinérgicos P1/genéticaAssuntos
Antagonistas de Receptores Purinérgicos P1 , Pirazóis/síntese química , Pirimidinas/síntese química , Animais , Ligação Competitiva , Encéfalo/metabolismo , Células CHO , Cricetinae , AMP Cíclico/biossíntese , Humanos , Técnicas In Vitro , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Ratos , Receptor A3 de Adenosina , Receptores Purinérgicos P1/metabolismo , Relação Estrutura-AtividadeRESUMO
The synthesis, biological activity, and DNA-binding properties of a series of four hybrids prepared by combining polypyrrole minor groove binders and pyrrolo[2,1-c][1,4]benzodiazepine (PBD) 13, related to the naturally occurring anthramycin (3) and DC-81 (4), have been described, and structure-activity relationships have been discussed. These hybrids 22-25 contain from one to four pyrrole units, respectively. To investigate sequence selectivity and stability of drug/DNA complexes, DNase I footprinting and arrested polymerase chain reaction (PCR) were performed on human c-myc oncogene, estrogen receptor gene, and human immunodeficiency virus type 1 long terminal repeat (HIV-1 LTR) gene sequences. The antiproliferative activity of the hybrids has been tested in vitro on human myeloid leukemia K562 and T-lymphoid Jurkat cell lines and compared to antiproliferative effects of the natural product distamycin A 1, its tetrapyrrole homologue 17, DC 81 (4), and the PBD methyl ester 12. The results obtained demonstrate that the hybrids 22-25 exhibit different DNA-binding activity with respect to both distamycin A 1 and PBD 12. In addition, a direct relationship was found between number of pyrrole rings present in the hybrids 22-25 and stability of drug/DNA complexes. With respect to antiproliferative effects, it was found that the increase in the length of the polypyrrole backbone leads to an increase of in vitro antiproliferative effects, i.e., the hybrid 25 containing the four pyrroles is more active than 22, 23, and 24 both against K562 and Jurkat cell lines.
Assuntos
Antineoplásicos/farmacologia , Benzodiazepinonas/química , Divisão Celular/efeitos dos fármacos , DNA/metabolismo , Pirróis/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Sequência de Bases , Benzodiazepinonas/metabolismo , Benzodiazepinonas/farmacologia , Pegada de DNA , Ensaios de Seleção de Medicamentos Antitumorais , Repetição Terminal Longa de HIV , Humanos , Células Jurkat , Células K562 , Reação em Cadeia da Polimerase , Pirróis/metabolismo , Pirróis/farmacologia , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/genética , Análise Espectral , Relação Estrutura-AtividadeRESUMO
The chemical resolution, using N-tosyl-L-proline as a chiral auxiliary, of a racemate of the pyrazole analog (+/-)-N-Boc-CPzI of the left hand segment (CPI) of the antitumor agent CC-1065, and the cytotoxic evaluation of both enantiomers are described. The reported results further validate the direct relationship between chemical solvolytic stability of the cyclopropane ring and cytotoxicity proposed by Boger and coworkers.
Assuntos
Antibióticos Antineoplásicos/química , Antineoplásicos Alquilantes/química , Indóis , Leucomicinas/química , Pirazóis/isolamento & purificação , Animais , Duocarmicinas , Leucemia L1210 , Camundongos , Estrutura Molecular , Prolina/análogos & derivados , Pirazóis/farmacologia , Estereoisomerismo , Streptomyces/química , Células Tumorais CultivadasRESUMO
The design, synthesis, in vitro and in vivo activity against L1210 murine leukaemia of the dibromo nitrogen mustard derivative of 2, called PNU 157977, is described and the structure-activity relationship discussed. This dibromo derivative is almost two orders of magnitude more cytotoxic than the dichloro counterpart having the same oligopeptidic chain (IC50 2.7 ng/ml versus 225 ng/ml), and it showed in vivo an increased survival time which is 5- and 3-fold longer than that of tallimustine and 2 (and T/C 750 versus 133 and 213) respectively. Moreover PNU 157977 shows activity against the M5076 solid tumour markedly inferior to that of the closely analogous 2. Footprinting experiments conducted using the oestrogen receptor PCR probe as the footprinting target molecule show that PNU 157977 possesses a different sequence-specific alkylation and greater cleavage activity than either 2 or tallimustine.