Highly potent 4-amino-indolo[2,3-c]azepin-3-one-containing somatostatin mimetics with a range of sst receptor selectivities

The synthesis, biological evaluation, and conformational analysis of 4-amino-indolo[2,3-c]azepin-3-one (Aia)-containing SRIF mimetics are reported. Different subtype selectivities are observed depending on the N- and C-terminal substituents of the D-Aia-Lys dipeptide mimetic. An sst(5)-selective analogue with subnanomolar binding affinity was obtained that is the most potent agonist reported to date. A nonselective mimetic with high potency was also identified. This study allows a better definition of the bioactive conformation of the essential D-Trp side chain in the somatostatin pharmacophore.

Incorporation of 2,4,6-trinitrotoluene (TNT) transforming bacteria into explosive formulations

Pseudomonas putida GG04 and Bacillus SF have been successfully incorporated into an explosive formulation to enhance biotransformation of TNT residues and/or explosives which fail to detonate due to technical faults. The incorporation of the microorganisms into the explosive did not affect the quality of the explosive (5 years storage) in terms of detonation velocity while complete biotransformation of TNT moieties upon transfer in liquid media was observed after 5 days. The incorporated microorganisms reduced TNT sequentially leading to the formation of hydroxylaminodinitrotoluenes (HADNT), 4-amino-2,6-dinitrotoluenes; 2-amino-4,6-dinitrotoluenes, different azoxy compounds; 2,6-diaminonitrotoluenes (2,4-DAMNT) and 2,4-diaminonitrotoluenes (2,6-DAMNT). However, the accumulation of AMDNT and DAMNT (major dead-end metabolites) was effectively prevented by incorporating guaiacol and catechol during the biotransformation process.

2,3-Dichloro-1,4-hydroquinone 2,3-dichloro-1,4-benzoquinone monohydrate: a quinhydrone-type 1:1 donor-acceptor [D-A] charge-transfer complex

In the crystal structure of the title compound (systematic name: 2,3-dichlorobenzene-1,4-diol 2,3-dichlorocyclohexa-2,5-diene-1,4-dione monohydrate), C(6)H(4)Cl(2)O(2)center dot C(6)H(2)Cl(2)O(2)center dot H(2)O, the 2,3-dichloro-1,4-hydroquinone donor (D) and the 2,3-dichloro-1,4-benzoquinone acceptor (A) molecules form alternating stacks along [100]. Their molecular planes [maximum deviations for non-H atoms: 0.0133 (14) (D) and 0.0763 (14) angstrom (A)] are inclined to one another by 1.45 (3)degrees and are thus almost parallel. There are pi-pi interactions involving the D and A molecules, with centroid-centroid distances of 3.5043 (9) and 3.9548 (9) angstrom. Intermolecular O-H center dot center dot center dot O hydrogen bonds involving the water molecule and the hydroxy and ketone groups lead to the formation of two-dimensional networks lying parallel to (001). These networks are linked by C-H center dot center dot center dot O interactions, forming a three-dimensional structure.

Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891)

OBJECTIVE: EORTC trial 30891 compared immediate versus deferred androgen-deprivation therapy (ADT) in T0-4 N0-2 M0 prostate cancer (PCa). Many patients randomly assigned to deferred ADT did not require ADT because they died before becoming symptomatic. The question arises whether serum prostate-specific antigen (PSA) levels may be used to decide when to initiate ADT in PCa not suitable for local curative treatment. METHODS: PSA data at baseline, PSA doubling time (PSADT) in patients receiving no ADT, and time to PSA relapse (>2 ng/ml) in patients whose PSA declined to <2 ng/ml within the first year after immediate ADT were analyzed in 939 eligible patients randomly assigned to immediate (n=468) or deferred ADT (n=471). RESULTS: In both arms, patients with a baseline PSA>50 ng/ml were at a>3.5-fold higher risk to die of PCa than patients with a baseline PSA12 mo. Time to PSA relapse after response to immediate ADT correlated significantly with baseline PSA, suggesting that baseline PSA may also reflect disease aggressiveness. CONCLUSIONS: Patients with a baseline PSA>50 ng/ml and/or a PSADT<12 mo were at increased risk to die from PCa and might have benefited from immediate ADT, whereas patients with a baseline PSA<50 ng/ml and a slow PSADT (>12 mo) were likely to die of causes unrelated to PCa, and thus could be spared the burden of immediate ADT.

Cooperative Effects of Electron Donors and Acceptors for the Stabilization of Elusive Metal Cluster Frameworks: Synthesis and Solid-State Structures of Pt-19(CO)(24)(mu(4)-AuPPh3)(3)](-) and Pt-19(CO)(24){mu(4)-Au-2(PPh3)(2)}(2)]

The anionic cluster Pt-19(CO)(22)](4-) (1), of pentagonal symmetry, reacts with CO and AuPPh3+ fragments. Upon increasing the Au:Pt-19, molar ratio, different species are sequentially formed, but only the last two members of the series could be characterized by X-ray diffraction, namely, Pt-19(CO)(24)(mu(4)-AuPPh3)(3)](-) (2) and Pt-19(CO)(24){mu(4)-Au-2(PPh3)(2)}(2)] (3).The metallic framework of the starting cluster is completely modified after the addition of CO and AuL+, and both products display the same platinum core of trigonal symmetry, with closely packed metal atoms. The three AuL+ units cap three different square faces in 2, whereas four AuL+ fragments are grouped in two independent bimetallic units in the neutral cluster 3. Electrochemical and spectroelectrochemical studies on 2 showed that its redox ability is comparable with that of the homometallic 1.

CCK2 receptor splice variant with intron 4 retention in human gastrointestinal and lung tumours

The wild-type cholecystokinin type 2 (CCK(2)) receptor is expressed in many gastrointestinal and lung tumours. A splice variant of the CCK(2) receptor with retention of intron 4 (CCK(2)Ri4sv) showing constitutive activity associated with increased tumour growth was described in few colorectal, pancreatic and gastric cancers. Given the potential functional and clinical importance of this spliceoform, its occurrence was quantitatively characterized in a broad collection of 81 gastrointestinal and lung tumours, including insulinomas, ileal carcinoids, gastrointestinal stromal tumours (GIST), gastric, colorectal and pancreatic ductal adenocarcinomas, cholangiocellular and hepatocellular carcinomas, small cell lung cancers (SCLC), non-SCLC (nSCLC) and bronchopulmonary carcinoids, as well as 21 samples of corresponding normal tissues. These samples were assessed for transcript expression of total CCK(2) receptor, wild-type CCK(2) receptor and CCK(2)Ri4sv with end-point and real-time RT-PCR, and for total CCK(2) receptor protein expression on the basis of receptor binding with in vitro receptor autoradiography. Wild-type CCK(2) receptor transcripts were found in the vast majority of tumours and normal tissues. CCK(2)Ri4sv mRNA expression was present predominantly in insulinomas (incidence 100%), GIST (100%) and SCLC (67%), but rarely in pancreatic, colorectal and gastric carcinomas and nSCLC. It was not found in wild-type CCK(2) receptor negative tumours or any normal tissues tested. CCK(2)Ri4sv transcript levels in individual tumours were low, ranging from 0.02% to 0.14% of total CCK(2) receptor transcripts. In conclusion, the CCK(2)Ri4sv is a marker of specific gastrointestinal and lung tumours. With its high selectivity for and high incidence in SCLC and GIST, it may represent an attractive clinical target.