Anhydrous 1:1 proton-transfer compounds of isonipecotamide with picric acid and 3,5-dinitrosalicylic acid: 4-carbamoylpiperidinium 2,4,6-trinitrophenolate and two polymorphs of 4-carbamoylpiperidinium 2-carboxy-4,6-dinitrophenolate

The structures of the anhydrous 1:1 proton-transfer compounds of isonipecotamide (4-carbamoylpiperidine) with picric acid and 3,5-dinitrosalicylic acid, namely 4-carbamoylpiperidinium 2,4,6-trinitrophenolate, C6H13N2O8+ C6H2N3O7- (I) and 4-carbamoylpiperidinium 2-carboxy-4,6-dinitrophenolate, C6H13N2O8+ C7H3N2O7-: two forms, the monoclinic alpha-polymorph (II) and the triclinic beta-polymorph (III) have been determined at 200 K. All compounds form hydrogen-bonded structures, one-dimensional in (II), two-dimensional in (I) and three-dimensional in (III). In (I), the cations form centrosymmetric cyclic head-to-tail hydrogen-bonded homodimers [graph set R2/2(14)] through lateral duplex piperidinium N---H...O(amide) interactions. These dimers are extended into a two-dimensional network structure through further interactions with anion phenolate-O and nitro-O acceptors, including a direct symmetric piperidinium N-H...O(phenol),O(nitro) cation--anion association [graph set R2/1(6)]. The monoclinic polymorph (II) has a similar R2/1(6) cation-anion hydrogen-bonding interaction to (I) but with an additional conjoint symmetrical R1/2(4) interaction as well as head-to-tail piperidinium N-H...O(amide) O hydrogen bonds and amide N-H...O(carboxyl) hydrogen bonds, give a network structure which include large R3/4(20) rings. The hydrogen bonding in the triclinic polymorph (III) is markedly different from that of monoclinic (II). The asymmetric unit contains two independent cation-anion pairs which associate through cyclic piperidinium N-H...O,O'(carboxyl) interactions [graph set R2/1(4)]. The cations also show the zig-zag head-to-tail piperidinium N-H...O(amide) hydrogen-bonded chain substructures found in (II) but in addition feature amide N-H...O(nitro) and O(phenolate) and amide N-H...O(nitro) associations. As well there is a centrosymmetric double-amide N-H...O(carboxyl) bridged bis(cation-anion) ring system [graph set R2/4(8)] in the three-dimensional framework. The structures reported here demonstrate the utility of the isonipecotamide cation as a synthon with previously unrecognized potential for structure assembly applications. Furthermore, the structures of the two polymorphic 3,5-dinitrosalicylic acid salts show an unusual dissimilarity in hydrogen-bonding characteristics, considering that both were obtained from identical solvent systems.

2-(4-Aminophenyl)-1-phenyldiazenium 2,4,6-trinitrophenolate

In the structure of the title salt, C12H12N3+ C6H2N3O7-, the diazenyl group of the 4-(phenyldiazenyl)aniline molecule is protonated and forms a hydrogen bond with the phenolate O acceptor of the picrate anion. Structure extension occurs through two symmetrical inter-ion three-centre amine N---H...O,O'(nitro) hydrogen-bonding associations [graph set R2/1(4)] giving a convoluted two-dimensional network structure.

2,3-Dimethoxy-10-oxostrychnidinium 2-(2,4,6-trinitroanilino)benzoate monohydrate : a 1:1 proton-transfer salt of brucine with o-picraminobenzoic acid

In the structure of the 1:1 proton-transfer compound of brucine with 2-(2,4,6-trinitroanilino)benzoic acid C23H27N2O4+ . C13H7N4O8- . H~2~O, the brucinium cations form the classic undulating ribbon substructures through overlapping head-to-tail interactions while the anions and the three related partial water molecules of solvation (having occupancies of 0.73, 0.17 and 0.10) occupy the interstitial regions of the structure. The cations are linked to the anions directly through N-H...O(carboxyl) hydrogen bonds and indirectly by the three water molecules which form similar conjoint cyclic bridging units [graph set R2/4(8)] through O-H...O(carbonyl) and O(carboxyl) hydrogen bonds, giving a two-dimensional layered structure. Within the anion, intramolecular N-H...O(carboxyl) and N H...O(nitro) hydrogen bonds result in the benzoate and picrate rings being rotated slightly out of coplanarity inter-ring dihedral angle 32.50(14)\%]. This work provides another example of the molecular selectivity of brucine in forming stable crystal structures and also represents the first reported structure of any form of the guest compound 2-(2,4,6-trinitroanilino)benzoic acid.

Inhibition of form-deprivation myopia by a GABAAOr receptor antagonist, (1,2,5,6-tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA), in guinea pigs

Purpose To investigate the effects of the relatively selective GABAAOr receptor antagonist (1,2,5,6-tetrahydropyridin-4-yl) methylphosphinic acid (TPMPA) on form-deprivation myopia (FDM) in guinea pigs. Methods A diffuser was applied monocularly to 30 guinea pigs from day 10 to 21. The animals were randomized to one of five treatment groups. The deprived eye received daily sub-conjunctival injections of 100 μl TPMPA at a concentration of (i) 0.03 %, ( ii) 0.3 %, or (iii) 1 %, a fourth group (iv) received saline injections, and another (v) no injections. The fellow eye was left untreated. An additional group received no treatment to either eye. Prior to and at the end of the treatment period, refraction and ocular biometry were performed. Results Visual deprivation produced relative myopia in all groups (treated versus untreated eyes, P < 0.05). The amount of myopia was significantly affected by the drug treatment (one-way ANOVA, P < 0.0001); myopia was less in deprived eyes receiving either 0.3 % or 1 % TPMPA (saline = −4.38 ± 0.57D, 0.3 % TPMPA = −3.00 ± 0.48D, P < 0.01; 1 % TPMPA = −0.88 ± 0.51D, P < 0.001). The degree of axial elongation was correspondingly less (saline = 0.13 ± 0.02 mm, 0.3 % TPMPA = 0.09 ± 0.01 mm, P < 0.01, 1 % TPMPA = 0.02 ± 0.01 mm, P < 0.001) as was the VC elongation (saline = 0.08 ± 0.01 mm, 0.3 % TPMPA = 0.05 ± 0.01 mm, P < 0.01, 1 % TPMPA = 0.01 ± 0.01 mm; P < 0.001). ACD and LT were not affected (one-way ANOVA, P > 0.05). One percent TPMPA was more effective at inhibiting myopia than 0.3 % (P < 0.01), and 0.03 % did not appreciably inhibit the myopia (0.03 % TPMPA versus saline, P > 0.05). Conclusions Sub-conjunctival injections of TPMPA inhibit FDM in guinea pig models in a dose-dependent manner.

2,4,6-Trinitro-N-[4-(phenyldiazenyl)phenyl)phenyl]aniline

The title compound, C18H12N6O6 was prepared from the reaction of 4-(phenyldiazenyl)aniline (aniline yellow) with picrylsulfonic acid. The dihedral angle formed by the two benzene rings of the diphenyldiazenyl ring system 6.55(13)deg. and that formed by the rings of the picrate-aniline ring system is 48.76(12)deg. The molecule contains an intramolecular aniline-nitro N-H...O hydrogen bond.

Molecular recognition of 2,4,6-trinitrotoluene by 6-aminohexanethiol and surface-enhanced Raman scattering sensor

2,4,6-trinitrotoluene (TNT) is one of the most commonly used nitro aromatic explosives in landmine, military and mining industry. This article demonstrates rapid and selective identification of TNT by surface-enhanced Raman spectroscopy (SERS) using 6-aminohexanethiol (AHT) as a new recognition molecule. First, Meisenheimer complex formation between AHT and TNT is confirmed by the development of pink colour and appearance of new band around 500 nm in UV-visible spectrum. Solution Raman spectroscopy study also supported the AHT:TNT complex formation by demonstrating changes in the vibrational stretching of AHT molecule between 2800-3000 cm−1. For surface enhanced Raman spectroscopy analysis, a self-assembled monolayer (SAM) of AHT is formed over the gold nanostructure (AuNS) SERS substrate in order to selectively capture TNT onto the surface. Electrochemical desorption and X-ray photoelectron studies are performed over AHT SAM modified surface to examine the presence of free amine groups with appropriate orientation for complex formation. Further, AHT and butanethiol (BT) mixed monolayer system is explored to improve the AHT:TNT complex formation efficiency. Using a 9:1 AHT:BT mixed monolayer, a very low detection limit (LOD) of 100 fM TNT was realized. The new method delivers high selectivity towards TNT over 2,4 DNT and picric acid. Finally, real sample analysis is demonstrated by the extraction and SERS detection of 302 pM of TNT from spiked.

Facile synthesis, ex-vivo and in vitro screening of 3-sulfonamide derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (SR141716) a potent CB1 receptor antagonist

Facile synthesis of biaryl pyrazole sulfonamide derivative of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (SR141716, 1) and an investigation of the effect of replacement of the –CO group in the compound 1 by the –SO2 group in the aminopiperidine region is reported. Primary ex-vivo pharmacological testing and in vitro screening of sulfonamide derivative 2 showed the loss of CB1 receptor antagonism.

Proton-transfer compounds with 4-amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (sulfamethazine): the structures and hydrogen-bonding in the salts with 5-nitrosalicylic acid and picric acid

The structures of the anhydrous proton-transfer compounds of the sulfa drug sulfamethazine with 5-nitrosalicylic acid and picric acid, namely 2-(4-aminobenzenesulfonamido)-4,6-dimethylpyrimidinium 2-hydroxy-5-nitrobenzoate, C12H15N4O2S(+)·C7H4NO4(-), (I), and 2-(4-aminobenzenesulfonamido)-4,6-dimethylpyrimidinium 2,4,6-trinitrophenolate, C12H15N4O2S(+)·C6H2N3O7(-), (II), respectively, have been determined. In the asymmetric unit of (I), there are two independent but conformationally similar cation-anion heterodimer pairs which are formed through duplex intermolecular N(+)-H...Ocarboxylate and N-H...Ocarboxylate hydrogen-bond pairs, giving a cyclic motif [graph set R2(2)(8)]. These heterodimers form separate and different non-associated substructures through aniline N-H...O hydrogen bonds, one one-dimensional, involving carboxylate O-atom acceptors, the other two-dimensional, involving both carboxylate and hydroxy O-atom acceptors. The overall two-dimensional structure is stabilized by π-π interactions between the pyrimidinium ring and the 5-nitrosalicylate ring in both heterodimers [minimum ring-centroid separation = 3.4580 (8) Å]. For picrate (II), the cation-anion interaction involves a slightly asymmetric chelating N-H...O R2(1)(6) hydrogen-bonding association with the phenolate O atom, together with peripheral conjoint R1(2)(6) interactions between the same N-H groups and O atoms of the ortho-related nitro groups. An inter-unit amine N-H...Osulfone hydrogen bond gives one-dimensional chains which extend along a and inter-associate through π-π interactions between the pyrimidinium rings [centroid-centroid separation = 3.4752 (9) Å]. The two structures reported here now bring to a total of four the crystallographically characterized examples of proton-transfer salts of sulfamethazine with strong organic acids.

P2 purinergic receptor mRNA in rat and human sinoatrial node and other heart regions.

It is known that adenosine 5'-triphosphate (ATP) is a cotransmitter in the heart. Additionally, ATP is released from ischemic and hypoxic myocytes. Therefore, cardiac-derived sources of ATP have the potential to modify cardiac function. ATP activates P2X(1-7) and P2Y(1-14) receptors; however, the presence of P2X and P2Y receptor subtypes in strategic cardiac locations such as the sinoatrial node has not been determined. An understanding of P2X and P2Y receptor localization would facilitate investigation of purine receptor function in the heart. Therefore, we used quantitative PCR and in situ hybridization to measure the expression of mRNA of all known purine receptors in rat left ventricle, right atrium and sinoatrial node (SAN), and human right atrium and SAN. Expression of mRNA for all the cloned P2 receptors was observed in the ventricles, atria, and SAN of the rat. However, their abundance varied in different regions of the heart. P2X(5) was the most abundant of the P2X receptors in all three regions of the rat heart. In rat left ventricle, P2Y(1), P2Y(2), and P2Y(14) mRNA levels were highest for P2Y receptors, while in right atrium and SAN, P2Y(2) and P2Y(14) levels were highest, respectively. We extended these studies to investigate P2X(4) receptor mRNA in heart from rats with coronary artery ligation-induced heart failure. P2X(4) receptor mRNA was upregulated by 93% in SAN (P < 0.05), while a trend towards an increase was also observed in the right atrium and left ventricle (not significant). Thus, P2X(4)-mediated effects might be modulated in heart failure. mRNA for P2X(4-7) and P2Y(1,2,4,6,12-14), but not P2X(2,3) and P2Y(11), was detected in human right atrium and SAN. In addition, mRNA for P2X(1) was detected in human SAN but not human right atrium. In human right atrium and SAN, P2X(4) and P2X(7) mRNA was the highest for P2X receptors. P2Y(1) and P2Y(2) mRNA were the most abundant for P2Y receptors in the right atrium, while P2Y(1), P2Y(2), and P2Y(14) were the most abundant P2Y receptor subtypes in human SAN. This study shows a widespread distribution of P2 receptor mRNA in rat heart tissues but a more restricted presence and distribution of P2 receptor mRNA in human atrium and SAN. This study provides further direction for the elucidation of P2 receptor modulation of heart rate and contractility.

Platinum-based chemotherapy in metastatic breast cancer : the Leicester (UK) experience

Aims: After failure of anthracycline- and taxane-based chemotherapy in metastatic breast cancer, treatment options until recently were limited. Until the introduction of capecitabine and vinorelbine, no standard regimen was available. We conducted a retrospective study to determine the efficacy and toxicity of platinum-based chemotherapy in metastatic breast cancer. Materials and methods: Forty-two women with metastatic breast cancer previously treated with anthracyclines (93%) and/or taxanes (36%) received mitomycin-vinblastine-cisplatin (MVP) (n = 23), or cisplatin-etoposide (PE) (n = 19), as first-, second- and third-line treatment at a tertiary referral centre between 1997 and 2002. Chemotherapy was given every 3 weeks as follows: mitomycin-C (8 mg/m 2) (cycles 1, 2, 4, 6), vinblastine (6 mg/m 2), and cisplatin (50 mg/m 2) all on day 1; and cisplatin (75 mg/m 2) and etoposide (100 mg/m 2) on day 1 and (100 mg/m 2) orally twice a day on days 2-3. Results: The response rate for 40 evaluable patients (MVP: n = 23; PE: n = 17) was 18% (95% confidence interval [CI]: 9-32%). The response rate to MVP was 13% (95% CI: 5-32%, one complete and two partial responses) and to PE 24% (10-47%, four partial responses). Disease stabilised in 43% (26-63%) and 47% (26-69%) of women treated with MVP and PE, respectively. After a median follow-up of 18 months, 37 women (MVP: n = 19; PE: n = 18) died from their disease. Median (range) progression-free survival and overall survival were 6 months (0.4-18.7) and 9.9 months (1.3-40.8), respectively. Median progression-free survival for the MVP and PE groups was 5.5 and 6.2 months (Log-rank, P = 0.82), and median overall survival was 10.2 and 9.4 months (Log-rank, P = 0.46), respectively. The main toxicity was myelosuppression. Grades 3-4 neutropenia was more common in women treated with PE than in women treated with MVP (74% vs 30%; P = 0.012), but the incidence of neutropenic sepsis, relative to the number of chemotherapy cycles, was low (7% overall). The toxicity-related hospitalisation rate was 1.2 admissions per six cycles of chemotherapy. No treatment-related deaths occurred. MVP and PE chemotherapy have modest activity and are safe in women with metastatic breast cancer. © 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Bis(benzylaminium) 4,5-dichlorobenzene-1,2-dicarboxylate monohydrate

In the structure of the title salt 2C7H10N+.C8H2Cl2O4(2-) .H2O the two benzylaminium anions have different conformations, one being essentially planar the other having the side-chain rotated out of the benzene plane (minimum ring to side-chain C-C-C-N torsion angles = -3.6(6) and 50.1(5)\%, respectively). In the 4,5-dichlorophthalate dianion the carboxyl groups make ihedral angles of 23.0(2) and 76.5(2)\% with the benzene ring. Aminium N-H...O and water O-H...O hydrogen-bonding associations with carboxyl O-atom acceptors give a two-dimensional duplex sheet structure which extends along the (011) plane. Weak pi-pi interactions are also present between the benzene ring and one of the cation rings [minimum ring centroid separation = 3.749(3)Ang.

Proton-transfer versus nontransfer in compounds of the diazo-dye precursor 4-(phenyldiazenyl) aniline (aniline yellow) with strong organic acids: the 5-sulfosalicylate and the dichroic benzenesulfonate salts, and the 1:2 adduct with 3,5-dinitrobenzoic

The structures of two 1:1 proton-transfer red-black dye compounds formed by reaction of aniline yellow [4-(phenyldiazenyl)aniline] with 5-sulfosalicylic acid and benzenesulfonic acid, and a 1:2 nontransfer adduct compound with 3,5-dinitrobenzoic acid have been determined at either 130 or 200 K. The compounds are 2-(4-aminophenyl)-1-phenylhydrazin-1-ium 3-carboxy-4-hydroxybenzenesulfonate methanol solvate, C12H12N3+.C7H5O6S-.CH3OH (I), 2-(4-aminophenyl)-1-hydrazin-1-ium 4-(phenydiazinyl)anilinium bis(benzenesulfonate), 2C12H12N3+.2C6H5O3S-, (II) and 4-(phenyldiazenyl)aniline-3,5-dinitrobenzoic acid (1/2) C12H11N3.2C~7~H~4~N~2~O~6~, (III). In compound (I) the diaxenyl rather than the aniline group of aniline yellow is protonated and this group subsequently akes part in a primary hydrogen-bonding interaction with a sulfonate O-atom acceptor, producing overall a three-dimensional framework structure. A feature of the hydrogen bonding in (I) is a peripheral edge-on cation-anion association involving aromatic C--H...O hydrogen bonds, giving a conjoint R1/2(6)R1/2(7)R2/1(4)motif. In the dichroic crystals of (II), one of the two aniline yellow species in the asymmetric unit is diazenyl-group protonated while in the other the aniline group is protonated. Both of these groups form hydrogen bonds with sulfonate O-atom acceptors and thee, together with other associations give a one-dimensional chain structure. In compound (III), rather than proton-transfer, there is a preferential formation of a classic R2/2(8) cyclic head-to-head hydrogen-bonded carboxylic acid homodimer between the two 3,5-dinitrobenzoic acid molecules, which in association with the aniline yellow molecule that is disordered across a crystallographic inversion centre, result in an overall two-dimensional ribbon structure. This work has shown the correlation between structure and observed colour in crystalline aniline yellow compounds, illustrated graphically in the dichroic benzenesulfonate compound.

Ethane-1,2-diaminium 4,5-dichlorophthalate

In the structure of the title compound, C2H10N22+·C8H2Cl2O42-, the dications and dianions form hydrogen-bonded ribbon substructures which enclose conjoint cyclic R21(7), R12(7) and R42(8) associations and extend down the c-axis direction. These ribbons inter-associate down b, giving a two-dimensional sheet structure. In the dianions, one of the carboxylate groups is essentially coplanar with the benzene ring, while the other is normal to it [C-C-C-O torsion angles = 177.67 (12) and 81.94 (17)°, respectively].

Low-dimensional hydrogen-bonded structures in the 1:1 and 1:2 proton-transfer compounds of 4,5-dichlorophthalic acid with the aliphatic Lewis bases triethylamine, diethylamine, n-butylamine and piperidine

The structures of proton-transfer compounds of 4,5-dichlorophthalic acid (DCPA) with the aliphatic Lewis bases triethylamine, diethylamine, n-butylamine and piperidine, namely triethylaminium 2-carboxy-4,5-dichlorobenzoate C~6~H~16~N^+^ C~8~H~3~Cl~2~O~4~^-^ (I), diethylaminium 2-carboxy-4,5-dichlorobenzoate C~4~H~12~N^+^ C~8~H~3~Cl~2~O~4~^-^ (II), bis(n-butylaminium) 4,5-dichlorophthalate monohydrate 2(C~4~H~12~N^+^) C~8~H~2~Cl~2~O~4~^2-^ . H~2~O (III) and bis(piperidinium) 4,5-dichlorophthalate monohydrate 2(C~5~H~12~N^+^) C~8~H~2~Cl~2~O~4~^2-^ . H~2~O (IV)have been determined at 200 K. All compounds have hydrogen-bonding associations giving in (I) discrete cation-anion units, linear chains in (II) while (III) and (IV) both have two-dimensional structures. In (I) a discrete cation-anion unit is formed through an asymmetric R2/1(4) N+-H...O,O' hydrogen-bonding association whereas in (II), one-dimensional chains are formed through linear N-H...O associations by both aminium H donors. In compounds (III) and (IV) the primary N-H...O linked cation-anion units are extended into a two-dimensional sheet structure via amide N-H...O(carboxyl) and ...O(carbonyl) interactions. In the 1:1 salts [(I) and (II)], the hydrogen 4,5-dichlorophthalate anions are essentially planar with short intramolecular carboxylic acid O-H...O(carboxyl) hydrogen bonds [O...O, 2.4223(14) and 2.388(2)A respectively]. This work provides a further example of the uncommon zero-dimensional hydrogen-bonded DCPA-Lewis base salt and the one-dimensional chain structure type, while even with the hydrate structures of the 1:2 salts with the primary and secondary amines, the low dimensionality generally associated with 1:1 DCPA salts is also found.