Letters in Drug Design & Discovery - Volume 5, Issue 8, 2008

Advanced glycation end product (AGE) and receptor (RAGE) axis play a central role in the pathogenesis of diabetic vascular complications. Since peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have been reported to reduce RAGE gene expression and subsequently suppress the downstream signalings in human umbilical vein endothelial cells (HUVECs), we examined here whether telmisartan, a unique angiotensin II type 1 receptor blocker with PPAR-γ agonistic activity, could inhibit the AGE-induced up-regulation of plasminogen activator inhibitor-1 (PAI-1) mRNA levels in HUVECs by suppressing RAGE gene expression. Telmisartan completely blocked the AGE-induced RAGE gene up-regulation in HUVECs, which was partly prevented by GW9662, an inhibitor of PPAR-γ. Further, telmisartan was also found to inhibit up-regulation of mRNA levels for PAI-1 in AGE-exposed HUVECs, which was completely prevented by GW9662. These results suggest that telmisartan inhibits the AGE-induced PAI-1 gene induction in HUVECs by down-regulating RAGE expression via PPAR-γ activation. Our present study suggests that telmisartan works as an anti-thrombogenic agent against AGEs, which may play a protective role against vascular complications in diabetes.

We report herein the synthesis of a series of eight novel compounds based on the coupling of 6-mercaptopurine (4), 2-mercaptopyrimidine (5), 4-mercaptopyridine (6) and 2-mercaptobenzimidazole (7) with 6-deoxy-6-iodo-1,2:3,4-di- O-isopropylidene-γ-D-psicofuranose and subsequent deprotection. The compounds were evaluated in vitro for activity against Leishmania amazonensis and L. chagasi promastigotes and for cytotoxic activity against Kb and Vero cells.

The anticancer activities of six imido-substituted 2-chloro-1,4-naphthoquinone derivatives on one androgendependent, LNCaP, and two androgen-independent, PC3 and DU145, human prostate cancer cell lines are reported. The open chain imides (2-4) showed more potency in all three cell lines. In addition the microwave-assisted synthesis of five of these compounds is reported.

The para-methoxybenzyl-substituted titanocene oxalate (Oxali-Titanocene Y) was tested in vitro in an antiangiogenesis assay against human umbilical vein endothelial cells, HUVEC, delivering an IC50 value of 14 μM and in a cytotoxicity assay against the human renal cancer cells, CAKI-1, which demonstrated an IC50 value greater than 100 μM. Then Oxali-Titanocene Y was given at 30 mg/kg/d, which is the maximum tolerable dose, on five consecutive days per week for three weeks to one cohort of eight CAKI-1 tumor-bearing female NMRI:nu/nu mice, while a second cohort was treated with solvent only. The titanocene-treated mouse cohort showed a statistically significant tumor growth reduction with respect to the solvent-treated control group with an optimal T/C value of 38% at the end of the experiment. Immunohistological analysis revealed that the expression of the proliferation marker Ki-67 was reduced by 30%. Furthermore, an anti-angiogenic activity was identified by CD31 staining; the number of micro vessels in a defined tumor area was significantly decreased due to Oxali-Titanocene Y treatment.

A consensus QSAR combining traditional 2D-QSAR with CoMFA and CoMSIA was developed for N, N'- bis substituted guanidines reported with NMDA receptor ion channel blocker activity. Two new statistics r²wμp (leverage weighted mean r²pred) and r²μp (mean r²pred) were defined. A slight improvement in predictive ability was observed for all the combinations while using r²wμp (0.630, 0.691, 0.672) rather than r²μp (0.622, 0.644, 0.658) however the approach has to be validated using more datasets.

A novel series of dual PPARα/γ agonists was designed through the modification of our previously described family of 8-HETE analogs. The combination of the structural elements of this family and of the classical PPAR ligands produced compounds with a quinoxaline core and two sides chains. Structure-activity relationship studies have been carried out on the new series and compounds belonging to this new family have been tested in vitro on both subtypes of PPAR nuclear receptors. Corresponding results indicated a strong decrease in the activity towards both subtypes, especially on PPARγ. However, they have also clearly shown the central role of the bottom side chain in the activity.

Molecular modeling of flavonoid/β-cyclodextrin complexes was used for rationalization of 1H-NMR data. We describe an algorithm that allows exact definition of the starting host-guest orientation. We used this algorithm to build complexes of two flavonoids, quercetin and myricetin. Subsequent molecular dynamics simulations yielded structures consistent with NMR data for the flavonoid position in the β-cyclodextrin cavity.