Corrected Structure of Natural Hyacinthacine C1 via Total Synthesis.

Hyacinthacines C1 and C4 are natural products that were isolated from Hyacinthoides non-scripta and Scilla socialis in 1999 and 2007, respectively. Despite their different 1H NMR and 13C NMR spectroscopic data, these compounds have been assigned the same structures, including absolute configurations. This work details the total synthesis of natural (+)-hyacinthacine C1, whose structure is confirmed as being the C-6 epimer of that reported. The synthetic strategy focused on inverting the configuration at C-1 of the final hyacinthacines via operating the inversion at the corresponding carbon atom in three previously synthesized intermediates. To do this, the advanced intermediates were subjected to Swern oxidation, followed by a stereoselective reduction with L-Selectride. This approach led to the synthesis of (+)-5 -epi-hyacinthacine C1 (15), the corrected structure for (+)-hyacinthacine C1 (19), (+)-6,7-di- epi-hyacinthacine C1 (23), and (+)-7- epi-hyacinthacine C1 (29). Glycosidase inhibition assays revealed that (+)-hyacinthacine C1 (19) proved the most active, with IC50 values of 33.7, 55.5, and 78.2 µM, against the α-glucosidase of rice, human lysosome, and rat intestinal maltase, respectively.

Total Synthesis of Natural Hyacinthacine C5 and Six Related Hyacinthacine C5 Epimers.

The total synthesis of natural (+)-hyacinthacine C5 was achieved, which allowed correction of its initially proposed structure, as well as six additional hyacinthacine C-type compounds. These compounds were readily accessible from two epimeric anti-1,2-amino alcohols. Keeping a common A-ring configuration, chemical manipulation occurred selectively on the B-ring of the hyacinthacine C-type products through methods of syn-dihydroxylation, SN2 ring-opening of a cyclic sulfate, and also employing either ( R)- or ( R, S)-α-methylallyl amine for the Petasis borono Mannich reaction. Our small analogue library was then assessed for its glycosidase inhibitory potency against a panel of glycosidases. (-)-6- Epi-hyacinthacine C5 and (+)-7- epi-hyacinthacine C5 (compound names are based on the corrected structure of hyacinthacine C5) proved most active, with inhibitory activities ranging between weak (IC50 = 130 µM) and moderate (IC50 = 9.9 µM) against the α-glucosidases of rat intestinal maltase, isomaltase, and sucrase, thus identifying potential new leads for future antidiabetic drug development.

Strategy for designing selective α-l-rhamnosidase inhibitors: Synthesis and biological evaluation of l-DMDP cyclic isothioureas.

This study shows that the cyclization of l-DMDP thioureas to bicyclic l-DMDP isothioureas improved α-l-rhamnosidase inhibition which was further enhanced by increasing the length of the alkyl chain. The addition of a long alkyl chain, such as decyl or dodecyl, to the nitrogen led to the production of highly potent inhibitors of α-l-rhamnosidase; it also caused broad inhibition spectrum against ß-glucosidase and ß-galactosidase. In contrast, the corresponding N-benzyl-l-DMDP cyclic isothioureas display selective inhibition of α-l-rhamnosidase; 3',4'-dichlorobenzyl-l-DMDP cyclic isothiourea (3r) was found to display the most potent and selective inhibition of α-l-rhamnosidase, with IC50 value of 0.22µM, about 46-fold better than the positive control 5-epi-deoxyrhamnojirimycin (5-epi-DRJ; IC50=10µM) and occupied the active-site of this enzyme (Ki=0.11µM). Bicyclic isothioureas of ido-l-DMDP did not inhibit α-l-rhamnosidase. These new mimics of l-rhamnose may affect other enzymes associated with the biochemistry of rhamnose including enzymes involved in progression of tuberculosis.

[Two cases of juvenile-onset and adult-onset recurrent respiratory papillomatosis].

We recently experienced one each of 2 types of recurrent respiratory papillomatosis (RRP). Case 1 (juvenile-onset type): A 30-year-old woman presenting with bloody sputum and large tumors with cavities on her chest Xray film, was referred to our hospital. She had been diagnosed with laryngeal papillomatosis when she was three years old. According to our bronchoscopical examination biopsy, she was diagnosed with squamous cell carcinoma of the lung in addition to papillomatosis of the trachea and bronchus. Although chemotherapy was performed, she died 2 years after the diagnosis of lung cancer without any distinct treatment efficacy. Case 2 (adult-onset type): A 43 year-old woman presenting with fever and dry cough visited our hospital. Chest CT revealed that there was narrowing of bilateral main bronchi and hilar lymphadenopathy. Bronchoscopic examination revealed diffuse papilloma distributed extensively from the trachea to bilateral main bronchi. However, she recovered spontaneously in 6 months and has remained stable without recurrence. Both cases were diagnosed with RRP based on the separation of HPV in case 1 and pathological findings of koilocytosis in case 2. Case 1 was complicated with squamous cell carcinoma of the lung in the clinical course, presumably due to occurrence of malignant conversion of papillomatosis. Since RRP is a rare but refractory disease, novel effective treatment is necessary.

[A case of IgG4-related disease with deterioration in pulmonary and pituitary involvements during a 10-year clinical course of inflammatory pseudotumor].

A 71-year-old man underwent pleural biopsy due to left pleural effusion and pleural thickening in August, 2001. An inflammatory pseudotumor (IPT) was diagnosed, and therefore systemic oral steroid therapy (prednisolone [PSL] 30 mg/day) was initiated. However, after tapering PSL to 7.5 mg/day, a complication of secondary central diabetes insipidus due to hypophysitis developed in 2008. As his pulmonary condition deteriorated over time and he began to experience exertional dyspnea, he was admitted to our hospital for re-evaluation of the disease in October, 2010. High-resolution CT (HRCT) revealed pulmonary involvements distributed in the interstitium and a high serum IgG4 level (240 mg/dl). Upon re-evaluating the pleural biopsy specimens of the first visit, we found lymphoplasmacytic-type IPT with approximately 10% IgG4-positive plasma cells in the affected areas. After increasing the PSL dose up to 0.6 mg/kg/day, his serum IgG4 levels decreased, his dyspnea improved, and the radiological findings of his pulmonary and pituitary involvements improved. This case was diagnosed as lymphoplasmacytic type IPT which appeared to be highly homologous with IgG4-related disease due to high serum levels of IgG4, pituitary involvements and the observed efficacy of PSL.