R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies.

R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21waf1,cip1, a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.

Diastereoselective intramolecular Ritter reaction: generation of a cis-fused hexahydro-4aH-indeno[1,2-b]pyridine ring system with 4a,9b-diangular substituents.

Indanol intermediates 5, prepared via Michael addition of 1-indanone beta-ketoester and acrylonitrile followed by reduction or Grignard reaction of the ketone group, were submitted to intramolecular Ritter reaction using various acid reaction conditions to produce tricyclic lactams 4. This cis-fused hexahydro-4aH-indeno[1,2-b]pyridine ring system, substituted at both angular positions 4a and 9b, provides access to constrained analogues of non-peptide NK(1)-antagonists with monocyclic piperidine structure.

[Villonodular synovitis of the knee in a 5-year-old child. Apropos of a case]. / Synovite villonodulaire du genou d'un enfant de 5 ans. A propos d'un cas.

PURPOSE OF THE STUDY: Case report of a five-year-old boy presenting with a painless swelling of the left knee with decreased range of motion. METHOD: Joint aspiration: fluid rich in red blood cells. X-ray--CT-scan--MRI: pigmented villonodular synovitis suspected. Arthroscopy with synovectomy and biopsy confirmed diagnosis. Because of remaining swelling one month after arthroscopy, intra-articular injection of triamcinolone hexacetonide gave a good result which has been maintained after 2 years. DISCUSSION: Hypothesis on etiology and pathophysiology, differential diagnosis and treatment of Pigmented villonodular synovitis are discussed based on a study of the literature. CONCLUSION: Pigmented villonodular synovitis is a rare condition in children. Association with other congenital disorders such as polyarticular localizations and family-history have been described. The diagnosis has to be proved by a biopsy. MRI seems to be the examination which gives the best information. Surgical treatment is indicated and consists of an arthroscopic synovectomy but which is often incomplete. A postoperative injection of triamcinolone hexacetonide may be the solution to avoid recurrence of Pigmented villonodular synovitis.