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Biomedical subjects

Sang Hyup Lee

Publications and source records attributed to Sang Hyup Lee.

15 recordsLinked to original sources
PubMed2005

Discovery of a biologically active thiostrepton fragment.

Design, synthesis, and biological evaluation of several domains of the thiopeptide antibiotic thiostrepton led to the discovery of a biologically active fragment. The biological properties of this novel small organic molecule include antibiotic activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VREF) bacterial strains, as well as cytotoxic action against a number of cancer cell lines.

Animals↗
PubMed2005

Total synthesis of thiostrepton. Retrosynthetic analysis and construction of key building blocks.

The first phase of the total synthesis of thiostrepton (1), a highly complex thiopeptide antibiotic, is described. After a brief introduction to the target molecule and its structural motifs, it is shown that retrosynthetic analysis of thiostrepton reveals compounds 23, 24, 26, 28, and 29 as potential key building blocks for the projected total synthesis. Concise and stereoselective constructions of all these intermediates are then described. The synthesis of the dehydropiperidine core 28 was based on a biosynthetically inspired aza-Diels-Alder dimerization of an appropriate azadiene system, an approach that was initially plagued with several problems which were, however, resolved satisfactorily by systematic investigations. The quinaldic acid fragment 24 and the thiazoline-thiazole segment 26 were synthesized by a series of reactions that included asymmetric and other stereoselective processes. The dehydroalanine tail precursor 23 and the alanine equivalent 29 were also prepared from the appropriate amino acids. Finally, a method was developed for the direct coupling of the labile dehydropiperidine key building block 28 to the more advanced and stable peptide intermediate 27 through capture with the highly reactive alanine equivalent 67 under conditions that avoided the initially encountered destructive ring contraction process.

Anti-Bacterial Agents↗
PubMed2005

Total synthesis of thiostrepton. Assembly of key building blocks and completion of the synthesis.

The completion of the total synthesis of thiostrepton (1) is described. The synthesis proceeded from key building blocks 2-5, which were assembled into a growing substrate that finally led to the target molecule. Thus, the dehydropiperidine peptide core 2 was, after appropriate manipulation, coupled to the thiazoline-thiazole fragment 3, and the resulting product was advanced to intermediate 11 possessing the thiazoline-thiazole macrocycle. The bis-dehydroalanine tail equivalent 4 and the quinaldic acid fragment 5 were then sequentially incorporated, and the products so obtained were further elaborated to forge the second macrocycle of the molecule. Several roadblocks encountered along the way were systematically investigated and overcome, finally opening the way, through intermediates 20, 32, 44, 45, and 46, to the targeted natural product, 1.

Anti-Bacterial Agents↗
PubMed2005

7-N,7'-N'-(1",2"-Dithianyl-3",6"-dimethylenyl)bismitomycin C: synthesis and nucleophilic activation of a dimeric mitomycin.

Dimeric alkylating agents that modify complementary DNA strands have engendered significant interest. We have prepared the novel dimeric mitomycin, 7-N,7'-N'-(1",2"-dithianyl-3",6"-dimethylenyl)bismitomycin C (9), in which the mitomycins are bridged by a dithiane unit. Dimer 9, like the clinically tested acyclic disulfides KW-2149 (3) and BMS-181174 (4), was designed to activate under nucleophilic and reductive conditions. Successive nucleophile-mediated disulfide cleavage transformations of 9 are expected to generate thiol species ideally positioned to render the two mitomycin systems vulnerable to nucleophilic attack and permit DNA interstrand cross-link formation. The dithiane linker, strategically positioned between the two mitomycins, distinguished 9 from 3 and 4. Nucleophilic activation of this cyclic disulfide permitted both activated mitomycins to remain tethered to one another. We report the synthesis of 9, and show that the nucleophile Et(3)P markedly enhances the activation and consumption of 9, compared with the reference compound 7-N, 7"-N'-(cyclohexanyl-trans-1",4"-dimethylenyl)bismitomycin C (27). We further demonstrated that provides higher levels of DNA interstrand cross-links than either the dimeric reference compounds, and 7-N,7-N'-(2",5"-dihydroxy-1",6"-hexanediyl)bismitomycin C (28), or the monomeric mitomycins, 1 and 3, when Et(3)P is added to solutions containing EcoRI-linearized pBR322 DNA.

Binding Sites↗
PubMed2005

[A case of intestinal tuberculosis presenting massive hematochezia controlled by endoscopic coagulation therapy].

The clinical manifestations of intestinal tuberculosis are non-specific. But, abdominal pain, low grade fever, weight loss, anorexia, and diarrhea are major symptoms of intestinal tuberculosis. Massive bleeding has been reported as a rare manifestation of intestinal tuberculosis. Massive hematochezia from intestinal tuberculosis has rarely been reported in the medical literature. Also, most of them were treated with anti-tuberculosis medication only or with surgery. We treated a case of intestinal tuberculosis presenting massive hematochezia with colonoscopic coagulation therapy and anti-tuberculosis medication. Here, we report a Korean man who presented with massive hematochezia from ileal tuberculosis and treated by endoscopic coagulation therapy.

Adult↗
PubMed2004

Cyclic disulfide C8 iminoporfiromycin: nucleophilic activation of a porfiromycin.

The clinical success of mitomycin C (1) and its associated toxicities and resistance have led to efforts to prepare semisynthetic analogues (i.e., KW-2149 (3), BMS-181174 (4)) that have improved pharmacological profiles. In this study, we report the preparation and evaluation of the novel 7-N-(1'-amino-4',5'-dithian-2'-yl)porfiromycin C(8) cyclized imine (6) and its reference compound, 7-N-(1'-aminocyclohex-2'-yl)porfiromycin C(8) cyclized imine (13). Porfiromycin 6 contains a disulfide unit that, upon cleavage, may provide thiol(s) that affect drug reactivity. We demonstrated that phosphines dramatically accelerated 6 activation and solvolysis in methanolic solutions ("pH 7.4") compared with 13. Porfiromycins 6 and 13 efficiently cross-linked EcoRI-linearized pBR322 DNA upon addition of Et3P. We found enhanced levels of interstrand cross-link (ISC) adducts for 6 and 13 compared with porfiromycin (7) and that 6 was more efficient than 13. The large Et3P-mediated rate enhancements for the solvolysis of 6 compared with 13 and a N(7)-substituted analogue of 1, and the increased levels of ISC adducts for 6 compared with 13 and 7 are attributed to a nucleophile-assisted disulfide cleavage process that permits porfiromycin activation and nucleophile (MeOH, DNA) adduction. The in vitro antiproliferative activities of 6 and 13 using the A549 tumor cell line (lung adenocarcinoma) were determined under aerobic and hypoxic conditions and then compared with 7. Both 6 and 13 were more cytotoxic than 7, with 13 being more potent than 6. The C(8) iminoporfiromycins 6 and 13 displayed anticancer profiles similar to 3.

Animals↗
PubMed2003

Sustained-release praziquantel tablet: pharmacokinetics and the treatment of clonorchiasis in beagle dogs.

Praziquantel is rapidly absorbed and secreted; and thus fractional doses are recommended for the treatment of cestode and trematode infections. In the present study, we developed a new praziquantel tablet formula allowing sustained-release (SRP). In vitro dissolution of SRP tablets showed that praziquantel at 300 mg/tablet combined with hydroxypropyl methylcellulose dissolved completely at a constant rate over 10 h, whereas the conventional praziquantel tablet (PZQ) was only 40% dissolved. Pharmacokinetic studies in dogs confirmed that SRP was absorbed more slowly than PZQ. The mean value of the area under the concentration/time curve from 0 h to the final observation time, the maximum concentration in serum, and the time of maximum concentration in serum for SRP were 3,471,500 ng/min for 0.25 ml, 10,300 ng for 0.25 ml, and 192 min, while the values for PZQ were 688,600 ng/min for 0.25 ml, 2,500 ng for 0.25 ml, and 135 min. The cure rate in dogs with a heavy infection (500 metacercariae) treated with a single dose of SRP (150 mg/tablet) at 50 mg/kg was 80%, while in dogs treated with a single dose of SRP (300 mg/tablet) at 30 mg/kg it was 60%, and the cure rate with PZQ was 20%. In each case, the egg reduction rate was similar (over 90%). No abnormal liver functions or hepatic or renal pathologies were observed in dogs administered with SRP at 30 mg/kg. The SRP tablet showed sustained release and slow absorption; and it had an improved anthelmintic efficacy against Clonorchis sinensis in experimental dogs, compared with conventional praziquantel.

Animals↗
PubMed2002

Relationship between intraocular pressure and systemic health parameters in a Korean population.

PURPOSE: This study aimed to evaluate the relationship between intraocular pressure (IOP) and age and obesity, adjusted for systemic health parameters such as sex and mean blood pressure, in a Korean population. METHODS: A total of 13 212 healthy participants underwent automated multiphasic tests, including tonometry, automated perimetry, fundus photography, blood pressure and body mass index (BMI). Six age groups were used, divided by decades ranging from 20-29 years to 70+ years. The association between IOP and systemic health para-meters was examined using cross-sectional analysis. RESULTS: The median age of participants was 47.6 years (range 20-84 years), and 6684 (50.6%) of participants were men. The mean IOP of participants was 15.5 mmHg. The mean IOP, blood pressure and BMI values were significantly higher in men than in women (P < 0.05). The overall prevalence of ocular hypertension, defined as IOP >21 mmHg without signs of glaucomatous visual field loss or optic disc damage, was 6.1% in men and 2.5% in women. Intraocular pressure was associated with mean blood pressure, sex, age and BMI by multiple regression analysis (P < 0.05). The relationship between IOP and age adjusted for sex, mean blood pressure and BMI had a significantly negative tendency for both sexes (P < 0.05). Body mass index had a significantly positive relation with IOP after controlling for age, sex and mean blood pressure in men (P < 0.05), but not in women. CONCLUSIONS: In this Korean population, after multiple adjustment, IOP was found to decrease with age and to increase with BMI in men.

Adult↗
PubMed2002

Relationship between intraocular pressure and systemic health parameters in the Korean population.

This study examined the influence of age, sex, blood pressure, and obesity index on intraocular pressure (IOP), in order to investigate the relationship between the upper limits of the following two conditions in the general Korean population: the "systolic or diastolic hypertensive and obese" group and the "systolic or diastolic hypotensive and lean" group. A total of 6828 healthy subjects (13,656 eyes) underwent automated multi-phasic tests, including tonometry, blood pressure, visual field, and body mass index. The 6,828 subjects were divided into five groups based on age; less than 40, 40 to 49, 50 to 59, 60 to 69, and over 70 years old. They were also divided into four categories on the basis of sex, age, blood pressure, and obesity index. The mean IOP in males (15.8+/-3.3 mmHg) was significantly higher than in females (14.8+/-3.1 mmHg) (P < 0.05), but this difference decreased proportionally with increasing age. IOP had a tendency to decrease with increasing age (P < 0.05). IOP increased significantly with increasing systolic blood pressure, diastolic blood pressure and obesity index (all, P < 0.05). The mean IOP of the "systolic or diastolic hypertensive and obese" group was higher than that of the "systolic or diastolic hypotensive and lean" group in the general Korean population (P < 0.05). These data could aid investigation into the epidemiological, etiologic and oriental influences related to the risk factors of glaucoma, especially in oriental populations.

Adult↗