Showing papers by "Justo Cobo published in 2012"

Synthesis of 1-substituted 3-aryl-5-aryl(hetaryl)-2-pyrazolines and study of their antitumor activity.

Abstract: Three series of novel 1,3,5-trisubstituted 2-pyrazoline derivatives containing thiophene and benzodioxol moieties as potential antitumor agents were synthesized. The in vitro antitumor activity of the obtained compounds was determined at the National Cancer Institute (NCI). The 5-(benzo[d][1,3]dioxol-5-yl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (9a) is the most prominent of the compounds due to its remarkable activity toward leukemia (RPMI-8226), renal cancer (UO-31) and prostate cancer (DU-145) cell lines with GI(50) values of 1.88, 1.91 and 1.94 µM, respectively.

Angiotensinase and vasopressinase activities in hypothalamus, plasma, and kidney after inhibition of angiotensin-converting enzyme: basis for a new working hypothesis.

Abstract: Reducing angiotensin II (Ang II) production via angiotensin-converting enzyme (ACE) inhibitors is a key approach for the treatment of hypertension. However, these inhibitors may also affect other enzymes, such as angiotensinases and vasopressinase, responsible for the metabolism of other peptides also involved in blood pressure control, such as Ang 2-10, Ang III, Ang IV, and vasopressin. We analyzed the activity of these enzymes in the hypothalamus, plasma, and kidney of normotensive adult male rats after inhibition of ACE with captopril. Aspartyl- (AspAP), glutamyl- (GluAP), alanyl- (AlaAP) and cystinyl-aminopeptidase (CysAP) activities were measured fluorimetrically using arylamides as substrates. Systolic blood pressure (SBP), water intake, and urine flow were also measured. Captopril reduced SBP and increased urine flow. In the hypothalamus, GluAP and AspAP increased, without significant changes in either AlaAP or CysAP. In contrast with effects in plasma, GluAP was unaffected, AspAP decreased, while AlaAP and CysAP increased. In the kidney, enzymatic activities did not change in the cortex, but decreased in the medulla. These data suggest that after ACE inhibition, the metabolism of Ang I in hypothalamus may lead mainly to Ang 2-10 formation. In plasma, the results suggest an increased formation of Ang IV together with increased vasopressinase activity. In the kidney, there is a reduction of vasopressinase activity in the medulla, suggesting a functional reduction of vasopressin in this location. The present data suggest the existence of alternative pathways in addition to ACE inhibition that might be involved in reducing BP after captopril treatment.

Stereoselective Synthesis of Novel 2-Alkenyl-2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepines and 2-Alkenyl-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ols

Abstract: New series of polyfunctionalized 2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepines and 2,3,4,5-tetrahydro-1H-1-benzazepin-4-ols substituted at C2 with 2-methylprop-1-enyl, (E)-styryl, and (E)-pent-1-enyl were synthesized starting from the corresponding N-alkenyl-substituted [prenyl, trans-cinnamyl, (E)-hex-2-enyl] 2-allylanilines by a three-step sequence consisting of selective oxidation of aromatic secondary amines, intramolecular nitrone–olefin 1,3-dipolar cycloaddition, and reductive cleavage. The intramolecular 1,3-dipolar cycloaddition is stereoselective favoring the exo-cycloadducts (ratio exo/endo 2–3:1). The stereochemistry was determined by exhaustive NMR analysis and X-ray diffraction.

(2RS,4RS)-7-Fluoro-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine and (2RS,4RS)-7-chloro-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine are isomorphous but not strictly isostructural.

Abstract: (2RS,4RS)-7-Fluoro-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(18)H(18)FNO, (I), and (2RS,4RS)-7-chloro-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-epoxy-1-benzazepine, C(18)H(18)ClNO, (II), are isomorphous but not strictly isostructural, as the slight differences in the unit-cell dimensions and molecular conformations are sufficient to preclude, in the structure of (I), the direction-specific intermolecular interactions present in the structure of (II), where the molecules are linked into sheets by a combination of C-H···N and C-H···π(arene) hydrogen bonds.

Chain formation by disordered, but correlated, hydrogen bonds in cis-(2RS,4SR)-2-(thiophen-2-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol and cis-(2RS,4SR)-2-(5-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol.

Abstract: The closely related compounds cis-(2RS,4SR)-2-(thio­phen-2-yl)-2,3,4,5-tetra­hydro-1H-1-benzazepin-4-ol, C14H15NOS, (I), and cis-(2RS,4SR)-2-(5-methyl­thio­phen-2-yl)-2,3,4,5-tetra­hy­dro-1H-1-benzazepin-4-ol, C15H17NOS, (II), both crystallize with Z′ = 2 in the space group P\overline{1}. In (I), the thienyl substituent in one of the two independent mol­ecules is disordered over two sets of atomic sites having occupancies of 0.856 (2) and 0.144 (2). In both compounds, the two independent hy­droxy O atoms are both within 2.8 A of the hy­droxy O atoms of two neighbouring mol­ecules, and all of the hy­droxy H atoms are disordered, each over two sites. The resulting O—H⋯O hydrogen bonds generate two similar but distinct C44(8) chains, depending upon which hy­droxy H-atom sites are occupied or vacant, with full correlation of the hy­droxy H-atom occupancies within each chain. Comparisons are made with the supra­molecular assembly in some related compounds.

Nine closely related tetrahydro-1,4-epoxy-1-benzazepines carrying pendant heterocyclic substituents: hydrogen-bonded supramolecular assembly in zero, one and two dimensions.

Abstract: The structures are reported of nine closely related tetra­hydro-1,4-ep­oxy-1-benzazepines carrying pendant heterocyclic sub­stituents, namely: 2-exo-(5-nitro­furan-2-yl)-2,3,4,5-tetra­hydro-1,4-ep­oxy-1H-1-benzazepine, C14H12N2O4, (I), 7-fluoro-2-exo-(1-methyl-1H-pyrrol-2-yl)-2,3,4,5-tetra­hydro-1,4-ep­oxy-1H-1-benzazepine, C15H15FN2O, (II), 7-fluoro-2-exo-(5-methyl­furan-2-yl)-2,3,4,5-tetra­hydro-1,4-ep­oxy-1H-1-benzazepine, C15H14FNO2, (III), 7-fluoro-2-exo-(3-methylthio­phen-2-yl)-2,3,4,5-tetra­hydro-1,4-ep­oxy-1H-1-benzazepine, C15H14FNOS, (IV), 7-fluoro-2-exo-(5-methyl­thio­phen-2-yl)-2,3,4,5-tetra­hy­dro-1,4-ep­oxy-1H-1-benzazepine, C15H14FNOS, (V), 7-chloro-2-exo-(5-methyl­furan-2-yl)-2,3,4,5-tetra­hydro-1,4-ep­oxy-1H-1-benzazepine, C15H14ClNO2, (VI), 2-exo-(5-methyl­furan-2-yl)-7-trifluoro­meth­oxy-2,3,4,5-tetrahydro-1,4-ep­oxy-1H-1-benzazepine, C16H14F3NO3, (VII), 2-exo-(3-methyl­thio­phen-2-yl)-7-trifluoro­meth­oxy-2,3,4,5-tetra­hydro-1,4-ep­oxy-1H-1-benzazepine, C16H14F3NO2S, (VIII), and 2-exo-(5-nitro­furan-2-yl)-7-trifluoro­meth­oxy-2,3,4,5-tetra­hydro-1,4-ep­oxy-1H-1-benzazepine, C15H11F3N2O5, (IX). All nine compounds crystallize in centrosymmetric space groups as racemic mixtures with configuration (2RS,4SR). There are no direction-specific inter­actions between the mol­ecules in (V). The mol­ecules in (III), (IV), (VI) and (VII) are linked into simple chains, by means of a single C—H⋯O hydrogen bond in each of (III), (VI) and (VII), and by means of a single C—H⋯π(arene) hydrogen bond in (IV), while the mol­ecules in (VIII) are linked into a chain of rings. In each of (I) and (II), a combination of one C—H⋯O hydrogen bond and one C—H⋯π(arene) hydrogen bond links the mol­ecules into sheets, albeit of completely different construction in the two compounds. In (IX), the sheet structure is built from a combination of four independent C—H⋯O hydrogen bonds and one C—H⋯π(arene) hydrogen bond. Comparisons are made with some related compounds.

(2RS,4SR)-7-bromo-2-exo-(2-chlorophenyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine: sheets built by the π-stacking of hydrogen-bonded chains.

Abstract: The molecules of the title compound, C(20)H(15)BrClNO, are linked into chains by a C-H...π(arene) hydrogen bond, in which the acceptor is the brominated ring of the naphthalene unit, and these chains are linked by an aromatic π-π stacking interaction, again involving the naphthalene unit, into a sheet structure.

2-Amino-6-methoxy-4-(4-methylanilino)-5-nitrosopyrimidine and ethyl N-[4-(adamantan-1-ylamino)-2-amino-5-nitrosopyrimidin-6-yl]-3-aminopropionate: polarized electronic structures and hydrogen-bonded supramolecular assembly in one and two dimensions.

Abstract: In both 2-amino-6-meth­oxy-4-(4-methyl­anilino)-5-nitroso­py­rimidine, C12H13N5O2, (I), and ethyl N-[4-(1-adamantylamino)-2-amino-5-nitroso­pyrimidin-6-yl]-3-amino­propionate, C19H28N6O3, (II), the nitroso­pyrimidine unit is planar and the bond distances provide evidence for significant polarization of the electronic structures. In (II), the eth­oxy­carbonyl fragment of the mol­ecule is disordered over two sets of sites with occupancies of 0.910 (4) and 0.090 (4). In the mol­ecules of both compounds, there is an intra­molecular N—H⋯O hydrogen bond. The mol­ecules of (I) are linked into a chain of rings by a combination of N—H⋯O and C—H⋯O hydrogen bonds, while the mol­ecules of (II) are linked by a two-centre N—H⋯N hydrogen bond and a three-centre N—H⋯(N,O) hydrogen bond to form sheets containing four distinct types of ring.

Methyl (3aRS,3cRS,6cSR,7RS,8RS,8aSR)-2,5-bis(4-chlorophenyl)-7,9-bis(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4,6-tetraoxododecahydro-1H-dipyrrolo[3,4-a:3',4'-f]pyrrolizine-3b-carboxylate dimethylformamide disolvate: a three-dimensional hydrogen-bonded framework.

Abstract: The racemic title dipyrrolopyrrolizine compound crystallizes from dimethylformamide as a disolvate, C(55)H(39)Cl(2)N(7)O(6)·2C(3)H(7)NO. None of the four fused heterocyclic rings is planar; one adopts an envelope conformation, two others adopt half-chair conformations and the fourth adopts a conformation intermediate between an envelope and a half-chair. The arrangement of the ring fusions is such as to preclude the possibility of internal mirror symmetry. The three independent molecular components are weakly linked by C-H···O hydrogen bonds, and the dipyrrolopyrrolizine molecules are linked by a combination of four C-H···O and one C-H···π(arene) hydrogen bond to form a three-dimensional framework, from which the dimethylformamide solvent molecules are pendent. However, aromatic π-π stacking interactions are absent in the structure.

(Z)-5-[(5-Methyl-1H-imidazol-4-yl)methylidene]-2-sulfanylidene-1,3-thiazolidin-4-one monohydrate: a three-dimensional hydrogen-bonded framework structure.

Abstract: The non-H atoms in the organic component of the title compound, C(8)H(7)N(3)OS(2)·H(2)O, are almost coplanar, as the dihedral angle between the two ring planes is only 1.8 (2)°; there is a wide C-C-C angle of 127.8 (3)° at the methine C atom linking the two rings. The molecular components are linked into a three-dimensional framework structure by two-centre hydrogen bonds of N-H···O and O-H···N types, together with a three-centre O-H···(N,S) system. Comparisons are made with some (Z)-5-arylmethylidene-2-sulfanylidene-1,3-thiazolidin-4-ones.

Solvent-Free Microwave-Assisted Synthesis of Substituted Pyridines Using NH4OAc as Nitrogen Source.

Abstract: The compounds (III) are synthesized by a tandem Claisen—Schmidt condensation/ Michael addition reaction.

Hydrogen-bonded assembly in six closely related pyrazolo[3,4-b]pyridine derivatives; a simple chain, three types of chains of rings and a complex sheet structure.

Abstract: Six closely related pyrazolo[3,4-b]pyridine derivatives, namely 6-chloro-3-methyl-1,4-diphenylpyrazolo[3,4-b]pyridine-5-carbaldehyde, C(20)H(14)ClN(3)O, (I), 6-chloro-3-methyl-4-(4-methylphenyl)-1-phenylpyrazolo[3,4-b]pyridine-5-carbaldehyde, C(21)H(16)ClN(3)O, (II), 6-chloro-4-(4-chlorophenyl)-3-methyl-1-phenylpyrazolo[3,4-b]pyridine-5-carbaldehyde, C(20)H(13)Cl(2)N(3)O, (III), 4-(4-bromophenyl)-6-chloro-3-methyl-1-phenylpyrazolo[3,4-b]pyridine-5-carbaldehyde, C(20)H(13)BrClN(3)O, (IV), 6-chloro-4-(4-methoxyphenyl)-3-methyl-1-phenylpyrazolo[3,4-b]pyridine-5-carbaldehyde, C(21)H(16)ClN(3)O(2), (V), and 6-chloro-3-methyl-4-(4-nitrophenyl)-1-phenylpyrazolo[3,4-b]pyridine-5-carbaldehyde, C(20)H(13)ClN(4)O(3), (VI), which differ only in the identity of a single small substituent on one of the aryl rings, crystallize in four different space groups spanning three crystal systems. The molecules of (I) are linked into a chain of rings by a combination of C-H···N and C-H···π(arene) hydrogen bonds; those of (II), (IV) and (V), which all crystallize in the space group P 1, are each linked by two independent C-H···O hydrogen bonds to form chains of edge-fused rings running in different directions through the three unit cells; the molecules of (III) are linked into complex sheets by a combination of two C-H···O hydrogen bonds and one C-H···π(arene) hydrogen bond; finally, the molecules of (VI) are linked by a single C-H···O hydrogen bond to form a simple chain.

Two closely related, and unexpected, quinolinone derivatives: a three-dimensional hydrogen-bonded framework structure and a hydrogen-bonded molecular ribbon of R(2)(2)(18) and R(4)(4)(24) rings.

Abstract: 1,5-Bis(4-chlorophenyl)-3-(2-oxo-1,2-dihydroquinolin-3-yl)pentane-1,5-dione, (Ia), and 1,5-bis(2-chlorophenyl)-3-(2-oxo-1,2-dihydroquinolin-3-yl)pentane-1,5-dione, (Ib), crystallize as an 84:16 mixture, 0.84C(26)H(19)Cl(2)NO(3)·0.16C(26)H(19)Cl(2)NO(3), in the space group I4(1)/a, where the molecules of the two isomers occupy very similar sites in the unit cell. A combination of one N-H...O hydrogen bond and one C-H...O hydrogen bond links the molecules, regardless of isomeric form, into a single three-dimensional framework structure. The molecules of (9RS,10RS)-8,9-bis(4-chlorobenzyl)-10-(2-oxo-1,2-dihydroquinolin-3-yl)-5,6,9,10-tetrahydrophenanthridine, C(36)H(22)Cl(2)N(2)O(4), (II), are linked by two hydrogen bonds, one each of the N-H...O and C-H...O types, into a molecular ribbon in which centrosymmetric rings of R(2)(2)(18) and R(4)(4)(24) types alternate. The hydrogen-bonded ribbons enclose channels, which contain highly disordered solvent molecules.

Synthesis of 1‐Substituted 3‐Aryl‐5‐aryl(hetaryl)‐2‐pyrazolines and Study of Their Antitumor Activity.

Abstract: Among a variety of 3-aryl-5-(het)arylpyrazolines, e.g. (III) and (V), derivative (IIIa) exhibits important activity against various cancer cell lines with remarkable values in leukemia, renal and prostate cancer panels.

Synthesis of Novel 1,2,5‐Trisubstituted Benzimidazoles as Potential Antitumor Agents.

Abstract: Novel methyl 1-(5-tert-butyl-1H-pyrazol-3-yl)-2-(aryl)-1H-benzo[d]imidazole-5-carboxylates 11 were synthesized by following a four-step strategy involving a nucleophilic aromatic displacement (S(N)Ar) and a solvent free approach as key steps for the formation of the desired products. Structure of intermediates and products were confirmed by X-ray diffraction as well as the tautomeric rearrangement suffered by the pyrazole moiety during the curse of the final cyclization process. Several of the obtained compounds were screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines. Products 11b and 11n exhibited the highest activity against a range of cancer cell lines with remarkable values in panels of Non-Small Cell Lung Cancer, Melanoma and Leukemia, with GI(50) range of 1.15-7.33 μM and 0.167-7.59 μM, respectively, and suitable LC(50) with values greater than 100 μM.