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1.
Curr Med Chem ; 20(22): 2798-811, 2013.
Article in English | MEDLINE | ID: mdl-23597202

ABSTRACT

Agelasines, asmarines and related compounds 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.


Subject(s)
Purines/chemical synthesis , Animals , Diterpenes/chemical synthesis , Diterpenes/pharmacology , Guanidines/chemical synthesis , Guanidines/pharmacology , Humans , Purines/pharmacology
2.
Curr Med Chem ; 17(30): 3488-502, 2010.
Article in English | MEDLINE | ID: mdl-20738250

ABSTRACT

Adenosine is an important autocoid, exerting its physiological effects on the human body by activation of four different G-protein-coupled-receptors (GPCRs) classified as A(1), A(2A), A(2B), and A(3). These receptors are coupled to secondary messenger systems including adenylate cyclase, inositol phosphate metabolism, and K(+), K(ATP) and Ca(2+) channels. Pharmacological agents that increase the activation of A(1) adenosine receptors in response to adenosine would be useful for treatment of cardiovascular, central nervous system, and inflammatory pathologies. Compounds that are able to enhance the activity of the A(1)-adenosine receptors by the endogenous ligand within specific tissues may have potential therapeutic advantages over non-endogenous agonists. Such an opportunity for intervention is provided by the concept of allosteric modulation of GPCRs. Therefore the use of allosteric enhancers to increase the responsiveness of the A(1) receptors to endogenous adenosine at sites of its production is an appealing alternative to activation by exogenous agonists. This approach minimizes side effects because allosteric enhancers amplify the action of the agonist by stabilizing the agonist-A(1)-receptor-G protein ternary complex. The allosteric enhancement of the GABA(A) receptor by benzodiazepines is the most famous and successful example of this strategy. The aim of this article is to give an overview of the results obtained in this field and discuss the opportunities and challenges that this class of ligands might offer for medicinal chemistry and pharmacology.


Subject(s)
Receptor, Adenosine A1/chemistry , Allosteric Regulation , Humans , Receptor, Adenosine A1/metabolism , Thiazoles/chemistry , Thiazoles/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology
3.
Br J Pharmacol ; 158(6): 1621-8, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19845671

ABSTRACT

BACKGROUND AND PURPOSE: The transient receptor potential ankyrin receptor 1 (TRPA1) is a cation channel, co-expressed with the pro-tussive transient receptor potential vanilloid type 1 (TRPV1) channel in primary sensory neurons. TRPA1 is activated by a series of irritant exogenous and endogenous alpha,beta-unsaturated aldehydes which seem to play a role in airway diseases. We investigated whether TRPA1 agonists provoke cough in guinea pigs and whether TRPA1 antagonists inhibit this response. EXPERIMENTAL APPROACH: Animals were placed in a Perspex box, and cough sounds were recorded and counted by observers unaware of the treatment used. KEY RESULTS: Inhalation of two selective TRPA1 agonists, allyl isothiocyanate and cinnamaldehyde, dose-dependently caused cough in control guinea pigs, but not in those with airway sensory nerves desensitized by capsaicin. Coughs elicited by TRPA1 agonists were reduced by non-selective (camphor and gentamicin) and selective (HC-030031) TRPA1 antagonists, whereas they were unaffected by the TRPV1 antagonist, capsazepine. Acrolein and crotonaldehyde, two alpha,beta-unsaturated aldehydes recently identified as TRPA1 stimulants and contained in cigarette smoke, air pollution or produced endogenously by oxidative stress, caused a remarkable tussive effect, a response that was selectively inhibited by HC-030031. Part of the cough response induced by cigarette smoke inhalation was inhibited by HC-030031, suggesting the involvement of TRPA1. CONCLUSIONS AND IMPLICATIONS: A novel pro-tussive pathway involves the TRPA1 channel, expressed by capsaicin-sensitive airway sensory nerves and is activated by a series of exogenous (cigarette smoke) and endogenous irritants. These results suggest TRPA1 may be a novel target for anti-tussive medicines.


Subject(s)
Antitussive Agents/pharmacology , Cough/chemically induced , Drug Delivery Systems , Transient Receptor Potential Channels/agonists , Acrolein/administration & dosage , Acrolein/analogs & derivatives , Acrolein/pharmacology , Administration, Inhalation , Animals , Capsaicin/pharmacology , Dose-Response Relationship, Drug , Guinea Pigs , Isothiocyanates/administration & dosage , Isothiocyanates/pharmacology , Male , Oxidative Stress , Smoke/adverse effects , Transient Receptor Potential Channels/antagonists & inhibitors , Transient Receptor Potential Channels/metabolism
4.
J Med Chem ; 44(17): 2735-42, 2001 Aug 16.
Article in English | MEDLINE | ID: mdl-11495585

ABSTRACT

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.


Subject(s)
Aniline Compounds/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Phenylurea Compounds/chemical synthesis , Purinergic P1 Receptor Antagonists , Pyrimidines/chemical synthesis , Aniline Compounds/chemistry , Aniline Compounds/metabolism , Animals , Binding, Competitive , Cell Line , Cricetinae , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/metabolism , Humans , Models, Molecular , Phenylurea Compounds/chemistry , Phenylurea Compounds/metabolism , Pyrimidines/chemistry , Pyrimidines/metabolism , Radioligand Assay , Receptor, Adenosine A3 , Receptors, Purinergic P1/metabolism , Recombinant Proteins/metabolism , Structure-Activity Relationship , Transfection
5.
Br J Pharmacol ; 134(1): 116-26, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11522603

ABSTRACT

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.


Subject(s)
Receptors, Purinergic P1/genetics , T-Lymphocytes/metabolism , Animals , Binding, Competitive/drug effects , CHO Cells , Calcium/metabolism , Cricetinae , Cyclic AMP/metabolism , Dose-Response Relationship, Drug , Guanosine Triphosphate/pharmacology , Humans , Jurkat Cells , Kinetics , Phenylurea Compounds/metabolism , Phenylurea Compounds/pharmacology , Purinergic P1 Receptor Agonists , Pyrimidines/metabolism , Pyrimidines/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, Adenosine A2A , Receptor, Adenosine A3 , Receptors, Purinergic P1/metabolism , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , Thermodynamics , Time Factors , Triazoles/metabolism , Triazoles/pharmacology , Tritium , Xanthines/metabolism , Xanthines/pharmacology
6.
J Med Chem ; 44(16): 2536-43, 2001 Aug 02.
Article in English | MEDLINE | ID: mdl-11472207

ABSTRACT

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.


Subject(s)
Antineoplastic Agents, Alkylating/chemical synthesis , DNA/chemistry , Indazoles/chemical synthesis , Indoles/chemical synthesis , Leucomycins/chemistry , Pyrazoles/chemical synthesis , Pyrroles/chemical synthesis , Animals , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Drug Design , Drug Screening Assays, Antitumor , Duocarmycins , Humans , Indazoles/chemistry , Indazoles/pharmacology , Indoles/chemistry , Indoles/pharmacology , Mice , Models, Molecular , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Solubility , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, Cultured , Water
7.
Bioorg Med Chem Lett ; 11(10): 1329-32, 2001 May 21.
Article in English | MEDLINE | ID: mdl-11392548

ABSTRACT

Highly selective arabinofuranosyl nucleosides, which inhibit the mitochondrial thymidine kinase (TK-2) without affecting the closely related herpes simplex virus type 1 thymidine kinase (HSV-1 TK), varicella-zoster virus thymidine kinase (VZV-TK), cytosolic thymidine kinase (TK-1) or the multifunctional Drosophila melanogaster deoxyribonucleoside kinase (Dm-dNK), have been obtained. SAR studies indicate a close relation between the length of the substituent at the 2' position of the arabinofuranosyl moiety and the inhibitory activity.


Subject(s)
Arabinonucleosides/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Mitochondria/enzymology , Thymidine Kinase/antagonists & inhibitors , Arabinonucleosides/pharmacology , Catalytic Domain , Drug Design , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Models, Molecular , Structure-Activity Relationship , Viral Proteins/antagonists & inhibitors
8.
Farmaco ; 56(1-2): 87-90, 2001.
Article in English | MEDLINE | ID: mdl-11347973

ABSTRACT

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.


Subject(s)
Purinergic P1 Receptor Antagonists , Animals , Humans , Neurodegenerative Diseases/drug therapy , Purines/pharmacology , Pyrimidines/pharmacology , Receptor, Adenosine A2A , Triazoles/pharmacology
9.
J Med Chem ; 43(25): 4768-80, 2000 Dec 14.
Article in English | MEDLINE | ID: mdl-11123985

ABSTRACT

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.


Subject(s)
Purinergic P1 Receptor Antagonists , Pyrazoles/chemistry , Pyrimidines/chemical synthesis , Animals , CHO Cells , Cricetinae , Cyclic AMP/biosynthesis , Humans , Models, Molecular , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/pharmacology , Radioligand Assay , Receptor, Adenosine A3 , Structure-Activity Relationship
11.
Nucleosides Nucleotides Nucleic Acids ; 19(8): 1219-29, 2000 Aug.
Article in English | MEDLINE | ID: mdl-11097052

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/pharmacology , Benzodiazepinones/pharmacology , DNA, Neoplasm/drug effects , Distamycins/pharmacology , Sp1 Transcription Factor/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Benzodiazepinones/chemical synthesis , Benzodiazepinones/chemistry , Burkitt Lymphoma/pathology , Cell Division/drug effects , DNA, Neoplasm/metabolism , Distamycins/chemical synthesis , Distamycins/chemistry , Drug Screening Assays, Antitumor , Gene Expression Regulation, Neoplastic/drug effects , Humans , K562 Cells/drug effects , Leukemia L1210/pathology , Magnetic Resonance Spectroscopy , Mice , Sp1 Transcription Factor/metabolism , Transcription, Genetic/drug effects , Tumor Cells, Cultured/drug effects
13.
Bioorg Med Chem Lett ; 10(17): 1953-7, 2000 Sep 04.
Article in English | MEDLINE | ID: mdl-10987425

ABSTRACT

New derivatives of PD 81,723, an allosteric enhancer of agonist binding to the A1-adenosine receptor, have been synthesized and evaluated in an intact cell assay. Compounds 3a, 3o and 3p appeared to be more potent than PD 81,723 and at a concentration of 0.1 microM caused significant reductions of cAMP content of CHO cells expressing the human A1-adenosine receptor. Compounds 4e and 4o appeared to be allosteric enhancers at a low concentration and antagonists at a higher concentration, whereas compounds 3c, 3g, 3s and 4l appeared to be weak antagonists that are also allosteric enhancers at the higher concentration of 10 microM.


Subject(s)
Receptors, Purinergic P1/drug effects , Thiophenes/chemical synthesis , Allosteric Regulation , Animals , CHO Cells , Cricetinae , Cyclic AMP/analysis , Humans , Structure-Activity Relationship , Thiophenes/pharmacology
14.
Nucleosides Nucleotides Nucleic Acids ; 19(4): 705-22, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10960030

ABSTRACT

Continuing our studies on the structure-activity relationships (SAR) of 4-iodo-1-beta-D-ribofuranosyl-3-carboxymethyl pyrazole (IPCAR), the ribofuranosyl moiety has been substituted with acyclic chains, namely 1-[(2-hydroxyethoxy)methyl]- and 1-[(1,3-dihydroxy-2-propoxy)methyl]-pyrazole derivatives (4, 5 and 8, 9 respectively), with the 2'-deoxy-beta-D-ribofuranosyl group (12 and 13) and finally with the 2',3'-dideoxy-D-glycero-pentofuranosyl-moiety (16 and 17). None of the new compounds display any interesting biological activity.


Subject(s)
Nucleosides/chemical synthesis , Nucleosides/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Bacteria/drug effects , HIV-1/drug effects , Humans , Structure-Activity Relationship , Tumor Cells, Cultured/drug effects , Yeasts/drug effects
15.
J Med Chem ; 43(14): 2675-84, 2000 Jul 13.
Article in English | MEDLINE | ID: mdl-10893305

ABSTRACT

The design, synthesis, and in vivo and in vitro antileukemic activity of a novel series of compounds (13-22 and 34), in which different benzoheterocyclic rings, bearing a nitrogen mustard or a benzoyl nitrogen mustard or an alpha-bromoacryloyl group as alkylating moieties, are tethered to a distamycin frame, are reported, and structure-activity relationships are discussed. The new derivatives were prepared by coupling nitrogen mustard-substituted, benzoyl nitrogen mustard-substituted, or alpha-bromoacryloyl-substituted benzoheterocyclic carboxylic acids 23-32 with desformyldistamycin (33) or in one case with its two-pyrrole analogue 35. With very few exceptions, the activities of compounds bearing the same alkylating moiety are slightly affected by the kind of the heteroatom present on the benzoheterocyclic ring. All novel compounds, with one exception, showed in vitro activity against L1210 murine leukemia cell line comparable to or better than that of tallimustine. The compounds in which the nitrogen mustard and the alpha-bromoacryloyl moieties are directly linked to benzoheterocyclic ring showed potent cytotoxic activities (IC(50) ranging from 2 to 14 nM), while benzoyl nitrogen mustard derivatives of benzoheterocycles showed reduced cytotoxic activities, and one compound (16) of this cluster was the sole derivative devoid of significant activity. Compound 18, a 5-nitrogen mustard N-methylindole derivative of distamycin, showed the best antileukemic activity in vivo, with a very long survival time (%T/C = 457), significantly increased in comparison to tallimustine (%T/C = 133), and was selected for further extensive evaluation. Arrested polymerase chain reaction and direct DNA fragmentation assays were performed for compound 18 and the structurally related compounds 13-17 and 19. The results obtained have shown that both alkylating groups and oligopeptide frames play a crucial role in the sequence selectivity of these compounds.


Subject(s)
Acrylamides/chemical synthesis , Antineoplastic Agents/chemical synthesis , Distamycins/chemical synthesis , Nitrogen Mustard Compounds/chemical synthesis , Acrylamides/chemistry , Acrylamides/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , DNA Fragmentation/drug effects , Distamycins/chemistry , Distamycins/pharmacology , Drug Screening Assays, Antitumor , Mice , Neoplasm Transplantation , Nitrogen Mustard Compounds/chemistry , Nitrogen Mustard Compounds/pharmacology , Polymerase Chain Reaction , Structure-Activity Relationship , Tumor Cells, Cultured
16.
Bioorg Med Chem Lett ; 10(12): 1397-400, 2000 Jun 19.
Article in English | MEDLINE | ID: mdl-10890173

ABSTRACT

The synthesis of a hybrid constituted by distamycin A and cysteine labeled with the gamma-emitting radionuclide 99mTc to afford the conjugate complex 5 is reported. This new radiopharmaceutical is of potential interest as tumor imaging agent in diagnostic nuclear medicine. The preparation of the hybrid distamycin A-cysteine 4 has been achieved by coupling deformyldistamycin A and Boc-Dmt-OH. Compound 4 was then successfully labeled with 99mTc by reaction with the novel, high-electrophilic, metal-containing fragment [99mTc(N)(PP)]2+ (PP = diphosphine ligand) yielding the 1:1 complex 5.


Subject(s)
Cysteine/chemistry , Distamycins/chemistry , Neoplasms/diagnostic imaging , Organotechnetium Compounds/chemistry , Radiopharmaceuticals/chemical synthesis , Humans , Radionuclide Imaging
17.
Mol Pharmacol ; 57(5): 968-75, 2000 May.
Article in English | MEDLINE | ID: mdl-10779381

ABSTRACT

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.


Subject(s)
Phenylurea Compounds/pharmacology , Purinergic P1 Receptor Antagonists , Triazoles/pharmacology , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adenylyl Cyclase Inhibitors , Animals , Binding, Competitive , CHO Cells , Cricetinae , Cyclic AMP/metabolism , Dose-Response Relationship, Drug , Humans , Phenylurea Compounds/chemistry , Radioligand Assay , Rats , Receptor, Adenosine A3 , Receptors, Purinergic P1/metabolism , Triazoles/chemistry , Tritium
18.
Arzneimittelforschung ; 50(3): 309-15, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10758785

ABSTRACT

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.


Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Distamycins/pharmacology , Imidazoles/pharmacology , Nitrogen Mustard Compounds/pharmacology , Pyrroles/pharmacology , Animals , Antineoplastic Agents, Alkylating/chemistry , DNA/genetics , DNA Primers , Female , Genes, ras/drug effects , Genes, ras/genetics , Humans , Leukemia L1210/drug therapy , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Polymerase Chain Reaction , Pyrroles/chemistry , Receptors, Estrogen/drug effects , Structure-Activity Relationship
19.
Bioorg Med Chem Lett ; 10(7): 681-4, 2000 Apr 03.
Article in English | MEDLINE | ID: mdl-10762053

ABSTRACT

Conformationally constrained analogues of KN62 containing 1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid with S configuration in position 3 were synthesized and their antagonist activities were tested on human macrophage cells. While KN62 is a potent antagonist of the P2X7 receptor, these analogues were inactive as antagonists and only one compound showed appreciable activity as P2X7 antagonist, which was 30 times weaker than that reported for KN62.


Subject(s)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , Macrophages/drug effects , Purinergic P2 Receptor Antagonists , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/chemical synthesis , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/chemistry , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Calcium/metabolism , Humans , Macrophages/metabolism , Receptors, Purinergic P2X7 , Structure-Activity Relationship
20.
Bioorg Med Chem Lett ; 10(3): 209-11, 2000 Feb 07.
Article in English | MEDLINE | ID: mdl-10698437

ABSTRACT

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.


Subject(s)
Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/pharmacology , Purinergic P1 Receptor Antagonists , Triazoles/chemical synthesis , Triazoles/pharmacology , Animals , CHO Cells , Cricetinae , Humans , Phenylurea Compounds/metabolism , Radioligand Assay , Receptor, Adenosine A3 , Receptors, Purinergic P1/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Triazoles/metabolism , Tritium
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