Simple and highly effective methods for the synthesis of polycyclic ring systems via two types of intramolecular domino reactions are developed and presented. The first example is an intramolecular double Michael reaction, whose scope-limitation, mechanism and application to natural product synthesis are discussed. The intramolecular Michael-aldol reaction is the second case, which provides a nice method for the preparation of polycyclic compounds having a four-membered ring system. In addition, some related reactions of these methods are described.
In this review, I have attempted to provide an overview of the pathways by which cytotoxic drugs induce emesis. The mechanisms of serotonin 5-HT3 antagonists and new antiemetics are also discussed. Old data especially from the experiments employing area postrema ablation must be re-evaluated because it is likely that the operation has damaged other important nucleus in the brain stem. Therefore, the concept of the chemoreceptor trigger zone and "vomiting center" proposed by Borison et al. in 1950s is questionable. Nausea and vomiting caused by cytotoxic drugs have been a serious problem in anti-cancer therapy and prompted lots of scientists to find the mechanism and to develop antiemetics. Effectiveness of 5-HT3 antagonists were shown in late 1980s, and now they are clinically available. I have investigated their mechanisms using Suncus murinus and proposed that the pathways by which cisplatin, one of most emetogenic drugs, induces emesis are as follows : 1) cisplatin is converted to an active metabolite (s), 2) the metabolite (s) somehow produces oxygen free radicals in the enterochromaffin cells, 3) the free radicals release serotonin, 4) the released serotonin stimulates 5-HT3 receptors located on the vagus afferents, 5) impulses are transmitted to the brain stem, or emetic pattern generator and initiate emetic reflex. Therefore, scavengers of free radicals and antioxidants can be a new type of antiemetic drug.
Aqueous extracts prepared from the murine kidney (MKE) promoted colony formation derived from murine hematopoietic progenitor cells in serum-free cultures stimulated by interleukin-3 (IL-3) and erythropoietin (Epo). MKE itself did not stimulate any colony formation. MKE preferentially enhanced granulocyte-macrophage colony forming units (CFU-GM), but did not promote any erythroid colony formation. The CFU-GM colony promotion by MKE was observed at day 6 after the culture started, and the colony-promoting activity (CPA) was maintained at the same level until day 16. MKE showed no CPA in the cultures using cells obtained from 5-FU-injected mice and from c-kit+-enriched treatment. Furthermore, MKE acted synergistically with granulocyte-colony-stimulating factor (CSF), macrophage-CSF, IL-6 and IL-11 on colony formation, but did not act with GM-CSF, stem cell factor and Epo. From the results of various experiments and gel-filtration chromatography, it is estimated that the colony-promoting factor detected in MKE is a heat stable protein with about 20 KDa molecular weight. These results suggest that MKE promotes colony formation by murine myeloid progenitor cells, and that the target cell populations of MKE are relatively mature in the hematopoietic differentiation pathway.
Determination of volatile components in essential oils from Atractylodis plants was studied by headspace gas chromatography. The crude drug of 0.20 g with 1.0 ml of water in a capped vial was heated at 130°C for 45 min. Then 0.5 ml of vaporized components were collected by gas tightsillinge, and were applied into the injection port of GC or GC/MS. Consequently we could analyze and confirm the following components ; hinesol and β-eudesmol were found to be contained in Atractylodis Lanceae Rhizoma and atractylon in Atractylodis Rhizoma. β-Eudesmol was analyzed by headspace gas chromatography, and the obtained calibration curve showed good linearity over the range from 2.5 μg to 10.0 mg. The result agreed with those obtained using numerical analyses by the steam distillation method. Atractylodis was found to have a wide variety of components depending on the available sources and on the stored conditions. This method was, therefore, more rapid and simpler determination of essential oils in crude drugs using headspace gas chromatography than those used previously. The method was useful means of the analyses of components in crude drugs such as Atractylodis plants and quality control.
A number of benzimidazole derivatives were synthesized and tested for cholecystokinin A (CCK-A) receptor inhibitory activity in order to study structure-activity relationships. Significant CCK-A receptor inhibitory activities were found in the compounds having carboxyl or tetrazolyl group. As the most preferred compound, 4-(5, 6-dichlorobenzimidazol-2-yl)-N-(3-methoxypropyl)-N-pentylglutaramic acid (4g) was selected.
In connection with our another project a relatively large quantity of 5 was required. We, therefore, investigated the reaction of 3 with TsOH ; this gave a diene mixture 7a, 7b, 6 and 5 in a ratio of 8 : 2 : 4 : 1. Almost the same 8 : 2 : 1"equilibrium mixture"of the dienes 7a, 7b and 5 was also obtained when the purified samples of 5 and 7a were independently treated with TsOH under the same conditons. The above results suggest that the dienes might be produced in the following way ; β-elimination of H2O from 3 gives a homoannular diene 5. The protonation to the more electron-rich tetrasubstituted C4-C5 double bond of 5 from the less hindered α-side followed by the isomerization of the double bond gives 7a. 7b is formed via 7a and/or 5 by the double bond isomerizations. On the other hand, 6 is formed by concerted elimination of H2O between C3-OH and C6-H. As a result of these studies, the synthetic precursor of dihydrocostunolide 7b which was already prepared by Corey in 6 steps (ca. 7%) from santonin was synthesized in 3 steps (ca. 6%) from the latter.