Synthesis and antimalarial activity of calothrixins A and B, and their N-alkyl derivatives.

We synthesized calothrixin B using our developed biomimetic method and derived N-alkyl-calothrixins A and B. The in vitro antimalarial activity of the calothrixin derivatives, including calothrixins A and B, against the Plasmodium falciparum FCR-3 strain was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 6.4×10(-6)-1.2×10(-7) M.We synthesized calothrixin B using our developed biomimetic method and derived N-alkyl-calothrixins A and B. The in vitro antimalarial activity of the calothrixin derivatives, including calothrixins A and B, against the Plasmodium falciparum FCR-3 strain was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 6.4×10(-6)-1.2×10(-7) M

Discovery and Characterization of NK13650s, Naturally Occurring p300-Selective Histone Acetyltransferase Inhibitors

The histone acetyltransferase (HAT) activity of p300 is essential for androgen receptor (AR) function. Androgen-independent prostate cancer cells require AR-mediated transcriptional activation for their growth. These observations indicate that p300 HAT is a promising target to overcome such hormone-resistant cancer cells. We sought p300 HAT inhibitors among microbial metabolites. By culturing a production strain belonging to <i>Penicillium</i>, we identified two new compounds, NK13650A and NK13650B, which were obtained as specific p300 HAT inhibitors. Structural analyses of these compounds elucidated that NK13650s have novel chemical structures comprising several amino acids and citrate. We applied a newly developed biosynthesis-based method to reveal the absolute configuration at the citrate quaternary carbon. This was accomplished by feeding a ¹³C-labeled biosynthetic precursor of citrate. NK13650s selectively inhibited the activity of p300 HAT but not that of Tip60 HAT. NK13650s showed inhibitory activity against agonist-induced AR transcriptional activation, and NK13650A treatment inhibited hormone-dependent and -independent growth of prostate cancer cells

Efficient Large-Scale 2D Culture System for Human Induced Pluripotent Stem Cells and Differentiated Cardiomyocytes

Summary: Cardiac regenerative therapies utilizing human induced pluripotent stem cells (hiPSCs) are hampered by ineffective large-scale culture. hiPSCs were cultured in multilayer culture plates (CPs) with active gas ventilation (AGV), resulting in stable proliferation and pluripotency. Seeding of 1 × 106 hiPSCs per layer yielded 7.2 × 108 hiPSCs in 4-layer CPs and 1.7 × 109 hiPSCs in 10-layer CPs with pluripotency. hiPSCs were sequentially differentiated into cardiomyocytes (CMs) in a two-dimensional (2D) differentiation protocol. The efficiency of cardiac differentiation using 10-layer CPs with AGV was 66%–87%. Approximately 6.2–7.0 × 108 cells (4-layer) and 1.5–2.8 × 109 cells (10-layer) were obtained with AGV. After metabolic purification with glucose- and glutamine-depleted and lactate-supplemented media, a massive amount of purified CMs was prepared. Here, we present a scalable 2D culture system using multilayer CPs with AGV for hiPSC-derived CMs, which will facilitate clinical applications for severe heart failure in the near future. : In this article, Fujita and colleagues show that human induced pluripotent stem cells (hiPSCs) and hiPSC-derived cardiomyocytes (hiPSC-CMs) are stably and efficiently produced using multilayer culture plates with an active gas ventilation system because of stable CO2 and O2 concentration in culture media. Large numbers of obtained hiPSC-CMs are metabolically purified under glucose- and glutamine-depleted and lactate-supplemented conditions. Keywords: iPSCs, regenerative medicine, cardiomyocytes, purification, large scale, 2D cultur