Histone deacetylase (HDAC) inhibitors have been shown to have antitumor activity in vitro and in vivo. Various studies related to their antitumor activity and mechanism of action have been reported for HDAC inhibitors, but the relationship of their antitumor effects to their pharmacodynamic and pharmacokinetic properties in vivo has not ever fully characterized. We report here the discovery of a novel cyclic-peptide-based HDAC inhibitor, YM753. YM753 is a bacteria-derived natural product containing a disulfide bond. It potently inhibited HDAC enzyme with an IC 50 of 2.0 nM in the presence of dithiothreitol. YM753 was rapidly converted to a reduced form in tumor cells, and then induced accumulation of acetylated histones, followed by p21 WAF1/Cip1 expression, tumor cell growth inhibition and tumor-selective cell death. In an in vitro washout study, YM753 showed prolonged accumulation of acetylated histones in WiDr human colon carcinoma cells. In vivo YM753 dosing of mice harboring WiDr colon tumor xenografts significantly inhibited the tumor growth via sustained accumulation of acetylated histones in the tumor tissue. In a pharmacokinetic study, YM753 rapidly disappeared from the plasma, but its reduced form remained in the tumor tissue. Moreover, the accumulation of acetylated histones induced by YM753 was tumor tissue selective compared to several normal tissues. This study provides evidence that YM753 has antitumor activity that is the result of selective, sustained accumulation of acetylated histones in tumor tissues despite rapid disappearance of the drug from the plasma. These results suggest that the novel HDAC inhibitor, YM753 has attractive pharmacodynamic and pharmacokinetic properties giving it potential as an antitumor agent.

YM-216391, a novel cytotoxic cyclic peptide, has been isolated from the cultured mycelium of Streptomyces nobilis JCM 4274. The planar structure of YM-216391 was assigned on the basis of 1D and 2D NMR spectroscopic techniques. The absolute configuration of the amino acid residues in YM-216391 was determined by Marfey's analysis and chiral HPLC analysis of its acid hydrolysate.

1. The human mass balance of (14)C-labelled ASP015K ([(14)C]ASP015K), an orally bioavailable Janus kinase (JAK) inhibitor, was characterized in six healthy male subjects after a single oral dose of [(14)C]ASP015K (100 mg, 3.7 MBq) in solution. [(14)C]ASP015K was rapidly absorbed with tmax of 1.6 and 1.8 h for ASP015K and total radioactivity in plasma, respectively. Mean recovery in urine and feces amounted to 36.8% and 56.6% of the administered dose, respectively. The main components of radioactivity in plasma and urine were ASP015K and M2 (5'-O-sulfo ASP015K). In feces, ASP015K and M4 (7-N-methyl ASP015K) were the main components. 2. In vitro study of ASP015K metabolism showed that the major isozyme contributing to the formation of M2 was human sulfotransferase (SULT) 2A1 and of M4 was nicotinamide N-methyltransferase (NNMT). 3. The in vitro intrinsic clearance (CLint_in vitro) of M4 formation from ASP015K in human liver cytosol (HLC) was 11-fold higher than that of M2. The competitive inhibitory effect of nicotinamide on M4 formation in the human liver was considered the reason for high CLint_in vitro of M4 formation, while each metabolic pathway made a near equal contribution to the in vivo elimination of ASP015K. ASP015K was cleared by multiple mechanisms.

YM-216391, a novel cyclic peptide, was isolated from the cultured mycelium of Streptomyces nobilis JCM 4274. It was purified by solvent extraction, silica gel and ODS flash column chromatographies, followed by preparative HPLC. YM-216391 dosedependently inhibited the growth of human cervical cancer HeLa S3 cells with an IC 50 value of 14 nM. YM-216391 also showed potent cytotoxic activity against a human cancer cell line panel.

The structures of newantitumor antibiotics, leptofuranins A, B, C and D were elucidated to be as shown in Fig. 1 by NMRspectral analysis including a variety of two-dimensional techniques. The leptofuranins are novel leptomycin-related substances containing a tetrahydrofuran ring. Leptofuranins C and D were revealed to be in tautomeric isomerism and their relative stereochemistries were analyzed by NOESYexperiments. In the preceding paper1}, we have described the fermentation, isolation and biological activities of new antitumor antibiotics, leptofuranins A, B, C and D, as well as the taxonomy of the producing organism, Streptomyces tanashiensis 3007-H1. This paper describes the physicochemical properties and structure elucidation of the leptofuranins (Fig. 1). Physicochemical Properties The physicochemical properties of the leptofuranins are summarized in Table 1. The high resolution FAB-MS established the molecular formulae of leptofuranins A, B, C and D as C32H48O5, C33H50O5, C32H46O5 and C33H48O5, respectively. Each leptofuranin exhibited IR absorption peaks due to hydroxyls (3450-3460cm"1) and carbonyls (1720cm"1). Structure Elucidation The 13C NMRspectrum of leptofuranin A confirmed the presence of 32 carbons. A heteronuclear multiplequantum coherency (HMQC)2)experiment established all one-bond 1H-13Cconnectivities as shown in Tables 2 and 3. A COSYexperiment revealed five spin networks I Rv.

Peptides U 0400 YM-216391, a Novel Cytotoxic Cyclic Peptide from Streptomyces nobilis. Part 2. Physico-Chemical Properties and Structure Elucidation. -(SOHDA*, K.-Y.; HIRAMOTO, M.; SUZUMURA, K.-I.; TAKEBAYASHI, Y.; SUZUKI, K.-I.; TANAKA, A.; J. Antibiot. 58 (2005) 1, 32-36; Inst. Drug Discovery Res., Yamanouchi Pharm. Co., Ltd., Itabashi, Tokyo 174, Japan; Eng.) -C. Oppel 22-193

For Abstract see ChemInform Abstract in Full Text.

This study determined the pharmacokinetics, metabolism and excretion of an a-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor antagonist zonampanel monohydrate (YM872) after intravenous infusion of [14C]YM872 at 1 mg kg-1 h-1 for 2 h to four healthy male volunteers. Mean pharmacokinetic parameters of unchanged YM872 were 0.78 h for terminal half-life, 25.9 l h-1 for total clearance, 22.9 l h-1 for renal clearance, and 15.6 l for volume of distribution at steady-state. Urinary excretion of radioactivity accounted for 94.9% of the dose, and faecal excretion for only 0.5% of the dose. Measurement of YM872 concentrations by a high-performance liquid chromatography (HPLC)-ultraviolet method and radiometric HPLC metabolite profiling revealed that almost all of [14C]YM872 was excreted unchanged in the urine and that unchanged [14C]YM872 was the major circulating [14C] component in the plasma. Two minor metabolites, H1 and H2, detected in the urine and identified as the same chemical structures as those of the rat urinary metabolites, have a hydroxyamino group and an amino group, respectively, which were probably formed by reduction of the nitro group of YM872. These results show that virtually all of the administered YM872 remains unchanged, with urinary excretion representing the major elimination pathway. The high renal clearance implies tubular secretion of this drug.