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.

Diffusion-weighted imaging in the detection of lymph node metastasis in colorectal cancer.

Diffusion-weighted imaging (DWI) is a functional technique based on the ability to depict movement of water molecules. The magnitude of water molecule movement is expressed as apparent diffusion coefficient (ADC) value. Its usefulness in the diagnosis of malignant tumors has gained interest. The purpose of this study was to evaluate the usefulness of DWI in detecting lymph node metastases of colorectal cancer. The subjects were 46 consecutive patients (mean age 71.4 +/- 8.7 years) with colorectal cancer, treated by radical surgery from 2006 to 2008. The size of metastatic lymph nodes on DWI was significantly larger than non-metastatic lymph nodes (10.3 vs. 7.6 mm). The mean ADC value was significantly lower for metastatic lymph nodes than non-metastatic lymph nodes (1.36 vs. 1.85 x 10(-3) mm(2)/sec). In addition, for evaluation of lymph node metastasis that reflects the primary tumor characteristics, the LN/T ratio (defined as the ratio of lymph node ADC value to the primary tumor ADC value) was calculated. It was significantly lower for metastatic lymph nodes than non-metastatic lymph nodes (1.41 vs. 1.59). Receiver operating characteristic curve analysis revealed that the best performing cutoffs were 8.5 mm for lymph node size, 1.44 x 10(-3) mm(2)/sec for ADC value, and 1.495 for LN/T ratio. Accuracy was significantly greater for lymph nodes with LN/T ratio (78.5%) than for lymph node size (62.0%) or ADC value (74.8%). In conclusion, preoperative DWI, especially the LN/T ratio, is recommended for evaluation of lymph node metastasis in patients with colorectal cancer.

Piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine as orally-active adhesion molecule inhibitors.

Novel piperidine carboxylic acid derivatives of 10H-pyrazino[2,3-b][1,4]benzothiazine were prepared and evaluated for their inhibitory activity on the upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1). Replacement of the methanesulfonyl group on the piperidine ring of previously prepared derivatives with a carboxylic acid-containing moiety resulted in a number of potent adhesion molecule inhibitors. Of these, (anti) [3-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methyl-3-azabicyclo[3.3.1]non-9-yl]acetic acid 2q (ER-49890), showed the most potent oral inhibitory activities against neutrophil migration in an interleukin-1 (IL-1) induced paw inflammation model using mice, and leukocyte accumulation in a carrageenan pleurisy model in the rat, and therapeutic effect on collagen-induced arthritis in rats.

A new series of estrogen receptor modulators: effect of alkyl substituents on receptor-binding affinity.

New types of selective estrogen receptor modulators (SERMs) were synthesized and evaluated for their binding affinity and biological effect on reproductive cells. A proposed lead structure (B) was derivatized to provide compounds 30 and 44, which showed good estrogen-receptor binding affinity (K(i) values: 6.3 and 10 nM, respectively), as well as minimal impact on mammary and uterine carcinoma cells. Introduction of an alkyl group in the core structure considerably enhanced receptor-binding affinity of the compounds tested. Synthesis and structure-activity relationships of these compounds are described.

Inhibitors of adhesion molecules expression; the synthesis and pharmacological properties of 10H-pyrazino[2,3-b][1,4]benzothiazine derivatives.

During a search for novel, orally-active inhibitors of upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), we found a new series of 10H-pyrazino[2,3-b][1,4]benzothiazine derivatives to be potent ICAM-1 inhibitors. Of these compounds, N-[1-(10H-Pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)piperidin-4-yl]-N',N'-dimethylsulfamide 7p showed the potent oral inhibitory activities against neutrophil migration in a murine interleukin-1 (IL-1) induced paw inflammation model. The synthesis and structure-activity relationships of these amide derivatives are described.