Ten-Gram-Scale Total Synthesis of the Anticancer Drug Candidate E7130 to Supply Clinical Trials.

E7130 is a novel drug candidate with an exceedingly complex chemical structure of the halichondrin class, discovered by a total synthesis approach through joint research between the Kishi group at Harvard University and Eisai. Only 18 months after completion of the initial milligram-scale synthesis, ten-gram-scale synthesis of E7130 was achieved, providing the first good manufacturing practice (GMP) batch to supply clinical trials. This paper highlights the challenges in developing ten-gram-scale synthesis from the milligram-scale synthesis.

Maintenance issues of elderly patients requiring nursing care with implant treatments in dental visiting: position paper.

PURPOSE: Japan, with an increasing number of elderly people needing long-term care in a super-aged society, urgent needs to develop the clinical guidelines on implant maintenance for elderly people with declining independence. The purpose is to categorize the troubles encountered in the care of patients with dental implants and to indicate actual practices and points of note. METHODS: From the members of the Japanese Society of Oral Implantology, 12 expert panelists who were experienced with many problems of implant maintenance during dental visits and were familiar with their solutions were selected. Through repeated discussions in the many panel meetings, the problems of implant maintenance during dental visits were distilled. RESULTS: During a dental visit, the oral cavity, general conditions, and background of elderly patients who cannot orally care for themselves must be grasped, and medical staff, care managers, and patients should understand the changes in these factors as time goes by. The solutions and responses that can be made differ greatly depending on the medical care facilities, the environment, differences in the experience of medical staff, and the patient's background. Thus, it is necessary to select safe treatments appropriate to each situation. CONCLUSIONS: This paper features many opinions based on clinical experiences. However, clinical guidelines on implant management during dental visits should be formulated in the future based on the accumulation of evidence through the implementation of clinical research.

A landmark in drug discovery based on complex natural product synthesis.

Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.

A possible origin population of pathogenic intestinal nematodes, Strongyloides stercoralis, unveiled by molecular phylogeny.

Humans and dogs are the two major hosts of Strongyloides stercoralis, an intestinal parasitic nematode. To better understand the phylogenetic relationships among S. stercoralis isolates infecting humans and dogs and to assess the zoonotic potential of this parasite, we analyzed mitochondrial Cox1, nuclear 18S rDNA, 28S rDNA, and a major sperm protein domain-containing protein genes. Overall, our analyses indicated the presence of two distinct lineages of S. stercoralis (referred to as type A and type B). While type A parasites were isolated both from humans and dogs in different countries, type B parasites were found exclusively in dogs, indicating that the type B has not adapted to infect humans. These epidemiological data, together with the close phylogenetic relationship of S. stercoralis with S. procyonis, a Strongyloides parasite of raccoons, possibly indicates that S. stercoralis originally evolved as a canid parasite, and later spread into humans. The inability to infect humans might be an ancestral character of this species and the type B might be surmised to be an origin population from which human-infecting strains are derived.

E7090, a Novel Selective Inhibitor of Fibroblast Growth Factor Receptors, Displays Potent Antitumor Activity and Prolongs Survival in Preclinical Models.

The FGFR signaling pathway has a crucial role in proliferation, survival, and migration of cancer cells, tumor angiogenesis, and drug resistance. FGFR genetic abnormalities, such as gene fusion, mutation, and amplification, have been implicated in several types of cancer. Therefore, FGFRs are considered potential targets for cancer therapy. E7090 is an orally available and selective inhibitor of the tyrosine kinase activities of FGFR1, -2, and -3. In kinetic analyses of the interaction between E7090 and FGFR1 tyrosine kinase, E7090 associated more rapidly with FGFR1 than did the type II FGFR1 inhibitor ponatinib, and E7090 dissociated more slowly from FGFR1, with a relatively longer residence time, than did the type I FGFR1 inhibitor AZD4547, suggesting that its kinetics are more similar to the type V inhibitors, such as lenvatinib. E7090 showed selective antiproliferative activity against cancer cell lines harboring FGFR genetic abnormalities and decreased tumor size in a mouse xenograft model using cell lines with dysregulated FGFR Furthermore, E7090 administration significantly prolonged the survival of mice with metastasized tumors in the lung. Our results suggest that E7090 is a promising candidate as a therapeutic agent for the treatment of tumors harboring FGFR genetic abnormalities. It is currently being investigated in a phase I clinical trial. Mol Cancer Ther; 15(11); 2630-9. ©2016 AACR.

Secure route to the epoxybicyclo[7.3.0]dodecadienediyne core of the kedarcidin chromophore.

Formation of an epoxide before 9-membered ring cyclization and SmI2 mediated reductive olefination in the presence of the epoxide successfully produced the epoxybicyclo[7.3.0]dodecadienediyne core of the kedarcidin chromophore.

Synthesis of the entire carbon framework of the kedarcidin chromophore aglycon.

In advanced studies directed toward the total synthesis of the kedarcidin chromophore, we have successfully achieved the late-stage installation of the nine-membered diyne ring in the presence of the highly functionalised ansamacrocyclic bridge.

[A ninety-eight-year-old woman with ruptured pancreatic anaplastic mucinous cystadenocarcinoma].

A 98-year-old woman was admitted to our hospital complaining of anorexia, epigastralgia, and vomiting. An elastic hard tumor was palpable in her epigastric region. CT and US examination revealed a huge cystic lesion adjacent to the left lobe of the liver and the stomach. Her serum levels of CEA (13.6 ng/ml), CA19-9 (95 U/ml) and CA125 (99 U/ml) were high. She suffered from aspiration pneumonia on the 10th day of admission, which progressed to acute respiratory distress syndrome. On the 20th day of admission, the epigastric tumor suddenly disappeared. She passed away on the 31st day due to respiratory failure. Autopsy revealed that she had a ruptured pancreatic anaplastic mucinous cystadenocarcinoma. To the best of our knowledge, this is the oldest reported case of ruptured pancreatic cystadenocarcinoma in the world.

Efficient construction of the kedarcidin chromophore ansamacrolide.

[Structure: see text] The streamlined assembly of the ansamacrolide framework of the kedarcidin chromophore via an efficient atropselective Sonogashira coupling step is described. To this end, two newly improved practical syntheses of the cyclopentene and diyne fragments have been developed, which feature 0.2 mol % catalytic loadings for an RCM step and i-PrMgCl/CH2I2 as a new entry to gem-disubstituted epoxides from ketones, both being applicable to 49-g scales.

Use of polystyrene-supported DBU in the synthesis and alpha-selective glycosylation study of the unstable Schmidt donor of L-kedarosamine.

In the alpha-glycosylation study of the unusual, 2-deoxy amino sugar of kedarcidin, polystyrene-supported DBU (PDBU) was found to be invaluable to the clean preparation of the highly labile Schmidt donor of l-kedarosamine. By further recognition that the C4-alcohol should be left free for favorable acceptor reactivity, we could for the first time successfully assemble the C13-O-alpha-glycoside of the ansamacrolide substructure of the kedarcidin chromophore. [reaction: see text]