We have discovered seven novel 12-membered macrolides, pladienolides A to G, from Streptomyces platensis Mer-11107, with pladienolide B the most potently inhibiting hypoxia induced-VEGF expression and proliferation of the U251 cancer cell line. A growth inhibitory study using a 39-cell line drug-screening panel demonstrated that pladienolide B has strong antitumor activities in vitro. A COMPARE analysis reveals that it has a unique antitumor spectrum that sets it apart from anticancer drugs currently in clinical use. This result suggests that pladienolide B has a novel mechanism of action. A series of xenograft studies were conducted to evaluate the in vivo potency of pladienolides. Pladienolide B extensively inhibited tumor growth in xenograft models. In the most sensitive model, using BSY-1 xenografts, tumors were completely regressed by administration of pladienolide B. For the reason of their novel mechanism of action and excellent in vivo efficacy, pladienolides appear to have major potential for use in cancer treatment.Tumor cells are frequently exposed to severe hypoxia. To survive and grow under hypoxic conditions, tumors adapt to their environment by activating a series of cascading events.This opens the possibility of creating novel antitumor drugs that interfere with the signaling involved in these adaptation processes. One key regulator for hypoxia adaptation is known to be hypoxia-inducible factor-1 (HIF-1)1). HIF-1 is an essential transcription factor and is composed of two basic helix-loop-helix (HLH) PAS transcription subunits, as targets for antitumor drug development2,3). However, it is difficult for small molecules to inhibit HIF-1 directly, since it is an HLH transcription factor. Accordingly, several groups are searching for compounds that inhibit the HIF-1 pathway, using a reporter gene assay controlled by hypoxiaresponsive element (HRE), an HIF-1 binding sequence4).We also have developed a cell-base screening system using VEGF promoter (2.3kb) containing endogenous HRE to search for HIF pathway modulators. The system is based on genetically engineered U251 human glioma cells that stably express a recombinant vector in which the placental alkaline phosphatase (PLAP) reporter gene is placed under the control of the human VEGF promoter. We performed a high throughput screening and as a result identified a series of microbial products that inhibit hypoxia-induced PLAP expression5). They are structurally novel 12-membered macrolides, which we designate as pladienolides5,6)In this report, we describe the in vitro and in vivo antitumor activities of pladienolides. These substances show highly potent antitumor activity both in vitro and in vivo, and may thus have potential for use in anticancer therapy.

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We have developed a very active bifunctional porphyrin catalyst showing a high turnover number (TON = 103,000) for the synthesis of cyclic carbonates from CO(2) and epoxides under solvent-free conditions.

For the proper diagnosis or treatment of hip joint disorders caused by anatomical abnormalities, the normal hip joint morphology must be studied to understand its influence on the maximum range of motion (ROM) until bony impingement by focusing on gender differences. Acetabular and femoral morphologies were analyzed from 3D CT images of 106 normal hip joints from elderly men (n ¼ 36 joints) and women (n ¼ 70 joints), and measurements of ROM until bony impingement were made in four directions (flexion, extension, and external and internal rotation at 908 flexion) using surface models of the pelvis and femur reconstructed from the CT data. Gender differences were found not only in joint orientation, including anteversion and inclination of the acetabulum and femoral neck anteversion, but also in the shape around the joint, including the acetabular rim and the femoral neck. This ROM study also showed gender differences in all four standard directions. In conclusion, significant gender differences were observed in the acetabular and femoral morphology, which led to significant gender differences in ROM until bony impingement. ß

[reaction: see text] We have found new conditions for the Suzuki-Miyaura coupling reaction applicable to pentafluorophenylboronic acid (C(6)F(5)B(OH)(2)) (1), which is an inactive substrate under normal conditions. The reactions of 1 with phenyl iodide or bromide under Pd(PPh(3))(4)/CsF/Ag(2)O or Pd(2)(dba)(3)/P(t-Bu)(3)/CsF/Ag(2)O catalytic system conditions gave 2,3,4,5,6-pentafluoro-1,1'-biphenyl (3a) in more than 90% yields. Combination of CsF and Ag(2)O was essential for promoting these reactions.