Biomimetic total synthesis of cyanosporaside aglycons from a single enediyne precursor through site-selective p-benzyne hydrochlorination.

The cyanosporasides A-F are a collection of monochlorinated benzenoid derivatives isolated from the marine actinomycetes Salinispora and Streptomyces sp. All derivatives feature one of two types of cyanocyclopenta[a]indene frameworks, which are regioisomeric in the position of a single chlorine atom. It is proposed that these chloro-substituted benzenoids are formed biosynthetically through the cycloaromatization of a bicyclic nine-membered enediyne precursor. Herein, we report the synthesis of such a bicyclic precursor, its spontaneous transannulation into a p-benzyne, and its differential 1,4 hydrochlorination reactivity under either organochlorine or chloride-salt conditions. Our bioinspired approach culminated in the first regiodivergent total synthesis of the aglycons A/F and B/C, as well as cyanosporasides D and E. In addition, empirical insights into the site selectivity of a natural-like p-benzyne, calculated to be a ground-state triplet diradical, to hydrogen, chlorine, and chloride sources are revealed.

[A surgical (right lobectomy) case of liver metastasis of colon cancer after chemotherapy using mFOLFIRI and cetuximab].

A man in his early seventies underwent low anterior resection and partial resection of the liver for the rectal cancer and liver metastasis. However, 4 months after the surgery, he was found to have a liver tumor at S5 and S7 by abdominal CT scan. Then, he underwent chemotherapy (mFOLFOX6), but the metastatic tumor was progressive. We selected FOLFIRI + cetuximab regimen for second-line therapy to resect the metastatic tumor. As the metastatic lesion was become smaller after 4-course of the regimen including cetuximab, we decided to perform a radical resection. We conducted a right lobectomy of the liver, and the tumor was completely resected.

[A surgical (pancreatoduodenectomy) case of lymph node metastatic recurrence of colon cancer after chemotherapy].

A woman in her fifties underwent a right hemicolectomy (D3) for cancer of the ascending colon in October 2007, definitively and pathologically diagnosed as papillary adenocarcinoma invading to the subserosa, and no metastasis was detected to lymph node. But 13 months after the surgery, she was found to have a mass near the anastomosis by an abdominal CT scan. Colonoscopy showed an evaluating lesion with ulcer in the anal side of the anastomosis. We tried to resect the metastasis, but it was not resectable because of the invasion to the pancreas. The mFOLFOX regimen was effective. After the chemotherapy (6 courses), we decided to perform a radical resection. We conducted pancreatoduodenectomy in May 2009. She is still alive 12 months after surgery.

Strong Dependence of Hydration State of F-Actin on the Bound Mg(2+)/Ca(2+) Ions.

Understanding of the hydration state is an important issue in the chemomechanical energetics of versatile biological functions of polymerized actin (F-actin). In this study, hydration-state differences of F-actin by the bound divalent cations are revealed through precision microwave dielectric relaxation (DR) spectroscopy. G- and F-actin in Ca- and Mg-containing buffer solutions exhibit dual hydration components comprising restrained water with DR frequency f2 (fw). The hydration state of F-actin is strongly dependent on the ionic composition. In every buffer tested, the HMW signal Dhyme (≡ (f1 - fw)δ1/(fwδw)) of F-actin is stronger than that of G-actin, where δw is DR-amplitude of bulk solvent and δ1 is that of HMW in a fixed-volume ellipsoid containing an F-actin and surrounding water in solution. Dhyme value of F-actin in Ca2.0-buffer (containing 2 mM Ca(2+)) is markedly higher than in Mg2.0-buffer (containing 2 mM Mg(2+)). Moreover, in the presence of 2 mM Mg(2+), the hydration state of F-actin is changed by adding a small fraction of Ca(2+) (∼0.1 mM) and becomes closer to that of the Ca-bound form in Ca2.0-buffer. This is consistent with the results of the partial specific volume and the Cotton effect around 290 nm in the CD spectra, indicating a change in the tertiary structure and less apparent change in the secondary structure of actin. The number of restrained water molecules per actin (N2) is estimated to be 1600-2100 for Ca2.0- and F-buffer and ∼2500 for Mg2.0-buffer at 10-15 °C. These numbers are comparable to those estimated from the available F-actin atomic structures as in the first water layer. The number of HMW molecules is roughly explained by the volume between the equipotential surface of -kT/2e and the first water layer of the actin surface by solving the Poisson-Boltzmann equation using UCSF Chimera.