Synthesis and evaluation of tricyclic derivatives containing a non-aromatic amide as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1).

Highly potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors, including 9-hydroxy-1,2-dihydro-4H-thiopyrano[3,4-c]quinolin-5(6H)-one derivatives with a non-aromatic A-ring, were synthesized. Among the derivatives, 12a showed low nanomolar enzyme and cellular activity (IC(50) = 42 nM, ED(50) = 220 nM) with good water solubility. Further, 12a exhibited microsomal stability in vitro and brain permeability in vivo.

Structure-activity relationship studies of a series of novel delta-lactam-based histone deacetylase inhibitors.

We synthesized a series of delta-lactam-based HDAC inhibitors that were identified with various degrees of anti-inflammatory and cell growth inhibitory activities. Compounds possessing significant HDAC inhibitory activity exhibited both anti-inflammatory and cell growth inhibitory activities as well as significant tumor growth inhibition in the in vivo tumor xenograft experiments. Besides, these compounds demonstrated anti-inflammatory properties in vitro via suppression of the production of the proinflammatory cytokine TNF-alpha and nitric oxide by LPS-stimulated RAW264.7 cells.

Simultaneous laser in situ keratomileusis on the stromal bed and undersurface of the flap in eyes with high myopia and thin corneas.

PURPOSE: To evaluate simultaneous laser in situ keratomileusis (LASIK) on the stromal bed and the undersurface of the flap in eyes with high myopia and insufficient corneal thickness for conventional LASIK ablation. SETTING: 21 Century Eye Hospital, Seoul Paik Hospital, Inje University, Seoul, Korea. METHODS: Using intraoperative pachymetry, the residual stromal bed thickness was evaluated and simultaneous LASIK was performed on the stromal bed and undersurface of the flap without compromising the posterior 300 mum of the stromal bed. In a prospective series, outcomes in 43 eyes of 27 patients with mean spherical equivalent refraction ranging from -12.5 to -3.75 diopters were analyzed 1, 3, and 6 months after surgery. RESULTS: Postoperative uncorrected visual acuity was 20/30 or better in 35 eyes (81.4%) at 1 month, 36 eyes (83.7%) at 3 months, and 34 eyes (79.1%) at 6 months. During surgery and follow-up, no vision-threatening complications occurred. CONCLUSION: Simultaneous LASIK appears to be a useful surgical aid in LASIK treatment in eyes with high myopia with or without astigmatism when an adequate residual stromal bed does not exist.

Synthesis, enzymatic inhibition, and cancer cell growth inhibition of novel delta-lactam-based histone deacetylase (HDAC) inhibitors.

delta-Lactam-based hydroxamic acids, inhibitors of histone deacetylase (HDAC), have been synthesized via ring closure metathesis of key diene intermediates followed by conversion to hydroxamic acid analogues. The hydroxamic acids 12a, 12b, and 17c showed potent inhibitory activity in HDAC enzyme assay. The hydroxamic acid 12b exhibited growth inhibitory activity on five human tumor cell lines, showing good sensitivity on the MDA-MB-231 breast tumor cell.