The enantioselective total synthesis of aplyronine A (1), a potent antitumor substance of marine origin, was achieved by a convergent approach. Three segments 4, 5, and 6, corresponding to the C5−C11, C21−C27, and C28−C34 portions of aplyronine A (1), were prepared using the Evans aldol reaction and the Sharpless epoxidation as key steps. The coupling reaction of 4 with iodide 7 followed by Julia olefination with sulfone 8 gave the C5−C20 segment 9, while the Julia coupling reaction between segments 5 and 6 provided the C21−C34 segment 10. Julia olefination between segments 9 and 10 and the subsequent four-carbon homologation reaction led to seco acid 83, which was converted into aplyronine A (1) by Yamaguchi lactonization followed by the introduction of two amino acids. The use of the [(3,4-dimethoxybenzyl)oxy]methyl group as a protecting group for the hydroxyl at C29 was crucial for this synthesis. The enantioselective synthesis of two natural congeners, aplyronines B (2) and C (3), was also carried out using the intermediates for the synthesis of 1, which determined the absolute stereostructures of 2 and 3 unambiguously. To study the structure−cytotoxicity relationships of aplyronines, artificial analogues of 1 were synthesized and their cytotoxicities were evaluated: the trimethylserine moiety, two hydroxyl groups, and the side-chain portion in 1 turned out to be important in the potent cytotoxicity shown by 1. Biological studies with aplyronine A (1) showed that 1 inhibited polymerization of G-actin to F-actin and depolymerized F-actin to G-actin.
The genomic duplication of the ␣-synuclein gene (SNCA) has been shown to cause familial parkinsonism. 1,2 Although patients with SNCA duplication often exhibit similar features to those with idiopathic Parkinson disease (PD), we and others previously reported that patients with SNCA duplication may develop the phenotype of PD dementia (PDD). 3,4 We identified a new family with SNCA duplication who developed parkinsonism, visual hallucination, and cognitive fluctuation, which are the characteristic phenotypes in patients with dementia with Lewy bodies (DLB). A PET study of this family revealed a pattern of cerebral glucose hypometabolism similarly described in patients with DLB. 5 Case reports. Patient 1. The proband had symptoms of generalized anxiety disorder including palpitation, restlessness, sensation of dyspnea, and excessive worry 5 years prior to his first visit to our hospital with complaint of gait disturbance at age 47 years. On neurologic examination, poor facial expression, rigidity, and bradykinesia in his right extremities were noted. His cognitive function was apparently normal. At age 49, his bradykinesia has progressed and shuffling gait, impaired postural balance, and postural tremor were present. These symptoms were improved by treatment with L-dopa and cabergoline. At age 50, he developed visual hallucinations and delirium followed by obvious deficits in attention and verbal fluency, and prosopagnosia was occasionally noted. These psychiatric symptoms including his hallucinations were apparently unrelated to L-dopa therapy. He also exhibited fluctuating cognitive decline, as shown by his Mini-Mental State Examination (MMSE) score of 24 and Raven Colored Progressive Matrices score of 27. Patient 2. The mother of the proband had depression from the age of 68 (figure, A). She first visited our hospital owing to memory disturbance at age 72. She developed fluctuating cognitive deficits in immediate recall, calculation, performance tasks, and mental flexibility. At age 73, she presented with mild cogwheel rigidity and tremor in her upper limbs. These symptoms were improved by treatment with L-dopa. At age 74, she presented with well-formed visual hallucinations and was unable to recognize her relatives; her MMSE score was 21. L-Dopa therapy improved her motor symptoms without worsening her hallucinations.Genetic analysis. Genomic DNA was extracted from peripheral blood leukocytes after written informed consent was obtained. SNCA gene dosage analysis was performed as previously described. 4 Real-time PCR analysis revealed that the dosages of SNCA exon 2 were 1.52 in the proband and 1.49 in his mother, which were higher than those in control individuals (figure e-1 on the Neurology ® Web site at www.neurology.org). The dosage of SNCA exon 6 was also high in the patients. The genomic region of duplication determined by real-time PCR analysis contains MMRN1 and KIAA1680 exon 1, ranging in size from a minimum of ϳ0.5 Mb to a maximum of ϳ1.6 Mb (figure e-1). The APOE genotype was 3/3 in both the prob...
The Japanese Pharmacopoeia defines byakujutsu (Atractylodes rhizome) as the rhizome of Atractylodes japonica or A. macrocephala and sojutsu (Atractylodes lancea rhizome) as the rhizome of A. lancea, A. chinensis, or their interspecific hybrids. Because their pharmaceutical uses differ in traditional Japanese Kampo medicine and traditional Chinese medicine, with less apparent scientific evidence, we compared the pharmacological properties between byakujutsu and sojutsu. Crude drug specimens of byakujutsu (n = 40) and sojutsu (n = 49) obtained in markets were identified by their species using DNA profiling. Their pharmacological properties were evaluated by the inhibitory effect of a MeOH extract of the samples on nitric oxide (NO) production by lipopolysaccharide-stimulated murine macrophage-like RAW264.7 cells and by the inducing effect of boiling water extract of the samples on granulocyte-colony stimulating factor (G-CSF) secretion from murine normal colonic epithelial MCE301 cells. We authenticated A. macrocephala (n = 8), A. japonica (n = 35), and the hybrid between A. macrocephala and A. japonica (n = 1), and they were used as byakujutsu. We authenticated A. chinensis (n = 25), A. lancea (n = 14), and the hybrid between A. chinensis and A. lancea (n = 6), and they were used as sojutsu. The inhibitory effects of byakujutsu on NO production were significantly higher than those of sojutsu (P < 0.05). This activity of A. japonica rhizome was significantly higher than that of A. macrocephala rhizome and A. lancea rhizome (P < 0.01). The activity of A. chinensis rhizome was significantly higher than that of A. lancea rhizome (P < 0.05). The extract of A. japonica rhizome significantly induced G-CSF secretion from MCE301 cells in a concentration-dependent manner. These effects of byakujutsu samples were not significantly different from those of sojutsu samples. A. japonica rhizome had significantly higher activity than A. macrocephala rhizome; however, there were no statistically significant differences among A. japonica, A. chinensis, and A. lancea. The pharmacological differences of byakujutsu and sojutsu may not be large among highly variated crude drug samples with average values, and quality control with the identification of the original plant species of byakujutsu and sojutsu may guarantee their pharmacological properties.
Extrahepatic delivery of small interfering RNAs (siRNAs) may have applications in the development of novel therapeutic approaches. However, reports on such approaches are limited, and the scarcity of reports concerning the systemically targeted delivery of siRNAs with effective gene silencing activity presents a challenge. We herein report for the first time the targeted delivery of CD206-targetable chemically modified mannose–siRNA (CMM–siRNA) conjugates to macrophages and dendritic cells (DCs). CMM–siRNA exhibited a strong binding ability to CD206 and selectively delivered contents to CD206-expressing macrophages and DCs. Furthermore, the conjugates demonstrated strong gene silencing ability with long-lasting effects and protein downregulation in CD206-expressing cells in vivo. These findings could broaden the use of siRNA technology, provide additional therapeutic opportunities, and establish a basis for further innovative approaches for the targeted delivery of siRNAs to not only macrophages and DCs but also other cell types.
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