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Hydroxypyr(id)ones are a pharmaceutically important class of compounds that have shown potential in diverse areas of drug discovery. We investigated the 3-hydroxy-4-pyridones 1a–1c and 3-hydroxy-4-thiopyridones 1d–1f as well as their Ru(η6-p-cymene)Cl complexes 2a–2f, and report here the molecular structures of 1b and 1d as determined by X-ray diffraction analysis. Detailed cell biological investigations revealed potent cytotoxic activity, in particular of the 3-hydroxy-4-thiopyridones 1d–1f, while the Ru complexes of both compound types were less potent, despite still showing antiproliferative activity in the low μM range. The compounds did not modulate the cell cycle distribution of cancer cells but were cytostatic in A549 and cytotoxic in NCI-H522 non-small lung cancer cells, among other effects on cancer cells.

Metastatic castration-resistant prostate cancer (CRPC) has a five-year survival rate of 28%. As histone deacetylases (HDACs) are overexpressed in CRPC, the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was trialled in CRPC patients but found to be toxic and inefficacious. Previously, we showed that novel HDAC inhibitors (Jazz90 (N1-hydroxy-N8-(4-(pyridine-2-carbothioamido)phenyl)octanediamide) and Jazz167 ([chlorido(η5-pentamethylcyclopentadieny[1–4](N1-hydroxy-N8-(4-(pyridine-2-carbothioamido-κ2N,S)phenyl)octanediamide)rhodium(III)] chloride) had a higher cancer-to-normal-cell selectivity and superior anti-angiogenic effects in CRPC (PC3) cells than SAHA. Thus, this study aimed to further investigate the efficacy and toxicity of these compounds. HUVEC tube formation assays revealed that Jazz90 and Jazz167 significantly reduced meshes and segment lengths in the range of 55–88 and 43–64%, respectively. However, Jazz90 and Jazz167 did not affect the expression of epithelial-to-mesenchymal transitioning markers E-cadherin and vimentin. Jazz90 and Jazz167 significantly inhibited the growth of PC3 and DU145 spheroids and reduced PC3 spheroid branching. Jazz90 and Jazz167 (25, 50 and 75 mg/kg/day orally for 21 days) were non-toxic in male BALB/c mice. The efficacy and safety of these compounds demonstrate their potential for further in vivo studies in CRPC models.

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1520 Background: Chemoprevention is crucial for reducing lung cancer mortality. The implementation and conduct of such trials is complex. We evaluated accrual in an ongoing trial. Methods: We are conducting a study evaluating if enzastaurin, a protein kinase C beta inhibitor, decreases the Ki-67 labeling index in bronchial epithelium after 6 months of therapy compared to placebo. Eligibility includes age 45 or younger, smoking 30 or fewer packs per year, quit for less than one 1 year, and bronchial meta/dysplasia. Results: Two-thousand eight hundred and nine potential subjects were selected from our database. Between December 2007 and November 2009, 1,242 were invited to participate by an introductory letter and at least 3 attempted telephone contacts. Phone contact was established with 621 (50%) subjects. 245 (39%) declined, 238 (38%) were ineligible, and 138 (22%) were interested in trial participation. At the first face-to-face visit, 57 out of 138 (38%) were eligible, 71 (51%) had not quit smoking for less than 1 year, one (1%) was ineligible for other reasons, and nine (7%) visits are pending. All 57 eligible subjects had an induced sputum exam: 36 had atypia, 19 were normal, and two were inadequate. Bronchoscopies with white light and laser-induced fluorescence and three or fewer biopsies have been done on 22 subjects (4 pending, 4 withdrew, 6 ineligible for bronch). Three had normal histology at all sites, 16 had metaplasia, and two had dysplasia in at least one site (84% abnormal bronchial histology rate, 1 pending). No occult cancers were identified. Conclusions: Of 1,242 preselected potential participants, 11% presented for a first face-to-face visit, 4.6% were eligible after a sputum exam, and 2.4% were fully eligible for randomization. Thus, to reach the accrual goal of 186 patients, we estimate that we will need to contact 7,700 subjects. During our 12-month period, we accessed 1,242 patients with 2.0 FTE for study coordinators (not including the pathologist, bronchoscopist, and laboratory personnel). Our expectation had been to accomplish accrual over a period of 42 months from a pool of 2,809 existing putative patients. Unless our eligibility rate of 2.4% increases, further sources of patients must be identified to accomplish our accrual goal. No significant financial relationships to disclose.