Synthesis and Importance of Bulky Aromatic Cap of Novel SAHA Analogs for HDAC Inhibition and Anticancer Activity

천부순,김형식,안미영,Ji Young Park,Hye Jin Lee,Jin-Ah Kang,Jungsu Kim,Won Hee Kim,문형룡 대한화학회 2011 Bulletin of the Korean Chemical Society Vol.32 No.6

On the basis of potent HDAC-inhibitory activity and anticancer activity of SAHA, novel SAHA derivatives 3a-d and 7 with a bulky cap such as p-dimethylaminophenyl, 4-phenylaminophenyl, 4-phenyloxyphenyl, 9Hfluorenyl or naphthalenyl ring were synthesized starting from the corresponding aryl amines or naphthalenyl acetic acid using an EDC-mediated amide coupling reaction in the presence of HOBt followed by a nucleophilic addition-elimination reaction with hydroxylamine. Compounds 3b, 3c and 3d showed more potent inhibitory activity on total HDACs (14~27-fold), HDAC1 (8~15-fold), HDAC2 (1.3~25-fold) and HDAC7 (1~3-fold) and more potent anticancer activity (2~22-fold) against MCF-7, MDA-MB-231, MCF-7/Dox, MCF-7/Tam, SK-OV-3, LNCaP and PC3 human cancer cell lines than SAHA.

Therapeutic effects of histone deacetylase inhibitors on heart disease

천부순 대한약학회 2020 Archives of Pharmacal Research Vol.43 No.12

A wide range of histone deacetylase (HDAC)inhibitors have been studied for their therapeutic potentialbecause the excessive activity and expression of HDACshave been implicated in the pathogenesis of cardiac diseases. An increasing number of preclinical studies have demonstratedthe cardioprotective effects of numerous HDACinhibitors, suggesting a wide variety of mechanisms bywhich the inhibitors protect against cardiac stress, such asthe suppression of cardiac fibrosis and fetal gene expression,enhancement of angiogenesis and mitochondrial biogenesis,prevention of electrical remodeling, and regulation of apoptosis,autophagy, and cell cycle arrest. For the developmentof isoform-selective HDAC inhibitors with high efficacy andlow toxicity, it is important to identify and understand themechanisms responsible for the effects of the inhibitors. Thisreview highlights the preclinical effects of HDAC inhibitorsthat act against Zn2+-dependent HDACs and the underlyingmechanisms of their protective effects against cardiac hypertrophy,hypertension, myocardial infarction, heart failure,and atrial fibrillation.

서울과 경기도 소재 상급종합병원과 종합병원의 필수실무실습 핵심역량교육 성과에 대한 장기적인 고찰

천부순,신혜연 한국임상약학회 2018 한국임상약학회지 Vol.28 No.4

Objective: As the demands of healthcare environment change, it is necessary to advance human health care by improvingstudents' essential competencies including knowledge, skills, abilities, inter-professional collaboration and patient centered care. This study identified long term accomplishment and improvement of the essential competencies in clinical pharmacy practiceeducation (CPPE) at Korean hospitals over time. Methods: This study was conducted for pharmacy students who completed CPPEevaluation related to tertiary hospitals and secondary hospitals located in Seoul and Gyeonggi-do regional area from 2014 to 2018. Results: Over the past 5 years, overall results of student evaluation on the essential competencies in CPPE at both tertiary andsecondary hospitals showed a decreasing trend or did not change. Essential competency in CPPE at tertiary hospitals had beenidentified as superior on ‘Learn clinical knowledge in the treatment of diseases’ to secondary hospitals [average number ofstudents (%): 210 (72.9%) vs 68 (68.0%)]. On the other hand, essential competencies in CPPE at secondary hospitals had beenidentified as better at ‘inter-professionals collaborative teamwork and direct patient care’ than tertiary hospitals [average numberof students (%): 64 (64.0%) and 56 (56.0%) vs 121 (42.0%) and 90 (31.3%)]. A total of 176 (61.1%) students in tertiary hospitals and66 (66.0%) in secondary hospitals evaluated that ‘patient-centered care’ education was good. Conclusion: In tertiary hospitals, allsix essential competency outcomes have not been improved, whereas four essential competency outcomes showed an increasingtrend in secondary hospitals. It will be necessary to develop outcome-based CPPE education program to better reflect theessential competencies.

제 2형 당뇨병 환자의 유방암 발생 위험 및 사망률에 대한 메트포민의 영향 : 체계적 문헌고찰 및 메타분석

천부순 한국임상약학회 2015 한국임상약학회지 Vol.25 No.3

Background: The protective effect of metformin against breast cancer is inconclusive. Objective: To evaluate the effect of metformin on breast cancer risk and mortality in patients with type 2 diabetes. Method: A comprehensive literature search was performed for pertinent articles published prior to June 30, 2014, using PubMed and EMBASE. Study heterogeneity was estimated with I2 statistic. The data from the included studies were pooled and weighted by random-effects model. The quality of each included study was assessed on the basis of the 9-star Newcastle-Ottawa Scale and publication bias was evaluated by visual inspection of a funnel plot. Results: Ten studies were included in the meta-analysis of the association of metformin and breast cancer risk. By synthesizing the data from the studies, the pooled odds ratio (OR) was 0.72 (95% CI: 0.59, 0.87) (p = 0.0005). Three cohort studies were included for meta-analysis of the association between metformin and breast cancer- related mortality. Metformin was associated with a significant decrease in mortality (Risk ratio: 0.68; 95% CI: 0.51, 0.90, p = 0.007). Conclusion: The present metaanalysis suggests that metformin appears to be associated with a lower risk of breast cancer incidence and mortality in patients with type 2 diabetes.

상급종합병원과 종합병원 필수실무실습에 관한 학생들의 인식 평가

천부순,신혜연 한국임상약학회 2018 한국임상약학회지 Vol.28 No.1

Background: Clinical Pharmacy Practice Experience (CPPE) is an important curriculum that offers students patient-centered disease prevention and treatment with evidence-based optimal pharmacotherapy for better clinical outcomes. However, few studies have evaluated the perception of pharmacy students regarding CPPE in tertiary and secondary hospitals. This study aimed to evaluate the perception of pharmacy students regarding the learning program of CPPE. Methods: The survey questionnaire consisted of 15 self-administered questions regarding pharmacy practices, barriers, and improvement of practical training. Fourteen institutional pharmacies located in seven regions responded to a survey questionnaire from March 1 to June 30, 2017. The participants were pharmacy students doing clerkship in a hospital setting. Results: The response rate was 73.6%. Thirty-five participants (22.4%) had used a hospital library, but 121 (77.6%) had never used the library for drug information resources. Eightyone (50.0%) responded that clinical knowledge and drug information was the most beneficial practice. Thirty-seven (31.1%) respondents in the tertiary hospitals and 19 (46.3%) in the secondary hospitals answered that they were filling prescriptions during the daily break. On the other hand, 72 respondents (60.5%) in the tertiary hospitals and 17 (41.5%) in the secondary hospitals did literature research to prepare for presentation. Conclusion: More students in secondary hospitals continue to fill prescriptions during the daily break, as compared to those in tertiary hospitals. Therefore, the authors suggest self-directed learning to improve clinical performance and each institution considers offering onsite or online library service to improve evidence-based CPPE for pharmacy school students.

폐의약품 수거사업’을 통해 지역약국으로 회수된 처방전의약품의 성분 및 약가 분석

천부순 대한약학회 2014 약학회지 Vol.58 No.4

Unused medication disposal is a burden due to the cost of disposing as well as the cost of the drugs. Inves- tigating medication returns is expected to suggest areas of intervention to reduce unused medications. Purpose: The aim of this study was to examine types, quantity, costs, active pharmaceutical ingredients, and therapeutic category of the med-ications returned to community pharmacies. Method: From January 15, 2014 to February 28, 2014, the medications returned to the 17 community pharmacies in Gimhae, Jinju, and Incheon, Korea were examined. The pharmacists and stu-dent volunteers worked cooperatively to identify the medications and analyze drug cost of prescription pill medications returned to the pharmacies. Results: A total of 2,720 pills of prescription medication were analyzed and 91 active phar-maceutical ingredients were identified. According to the Anatomical Therapeutic Chemical (ATC) classification, the most predominant group was A (alimentary tract and metabolism) with 33.3%, followed by N (nervous system) with 15.0%. With regard to the drug cost of groups, group A was the highest with 26.6%, followed by J01 (antibacterials for systemic use) with 20.2% and N (nervous system) with 18.3%. The total cost of the oral pill prescription medications was 468,477 won. Conclusion: The result from this study implies that unused drugs impose a significant cost to the health care system in Korea. In this study, medicines used to treat gastrointestinal conditions were returned most frequently with the highest drug cost. Further research in nationwide level is necessary to establish strategies to reduce the wastage of unused medicines.

Histone deacetylase inhibitors in hematological malignancies and solid tumors

천부순 대한약학회 2015 Archives of Pharmacal Research Vol.38 No.6

Histone deacetylase (HDAC) inhibitors areemerging as promising anticancer drugs. Because aberrantactivity and expression of HDACs have been implicated invarious cancer types, a wide range of HDAC inhibitors arebeing investigated as anticancer agents. Furthermore, dueto the demonstrable anticancer activity in both in vitro andin vivo studies, numerous HDAC inhibitors have undergonea rapid phase of clinical development in variouscancer types, either as a monotherapy or in combinationwith other anticancer agents. Although preclinical trialsshow that HDAC inhibitors have a variety of biologicaleffects across multiple pathways, including regulation ofgene expression, inducing apoptosis and cell cycle arrest,inhibiting angiogenesis, and regulation of DNA damageand repair, the mechanism by which the clinical activity ismediated remains unclear. Understanding the mechanismsof anticancer activity of HDAC inhibitors is essential notonly for rational drug design for targeted therapies, but forthe design of optimized clinical protocols. This paperdescribes the links between HDACs and cancer, and theunderlying mechanisms of action of HDAC inhibitorsagainst hematological malignancies and solid tumors. Further, this review presents the clinical outcomes ofvorinostat, romidepsin, and belinostat, which are approvedby the United States Food and Drug Administration for thetreatment of lymphomas.

Role of sirtuins in chronic obstructive pulmonary disease

천부순 대한약학회 2015 Archives of Pharmacal Research Vol.38 No.1

Chronic obstructive pulmonary disease (COPD)is characterized by airflow limitation that is associated withchronic inflammatory response to noxious particles or gases. The airflow limitation may be explained by hypersecretionof mucus, thickening and fibrosis of small airways andalveolar wall destruction in emphysema. Sirtuins, a group ofclass III deacetylases, have gained considerable attention fortheir positive effects on aging-related disease, such as cancer,cardiovascular disease, neurodegenerative diseases,osteoporosis and COPD. Among the seven mammalian sirtuins,SIRT1–SIRT7, SIRT1 and SIRT6 are considered tohave protective effects against COPD. In the lungs, SIRT1inhibits autophagy, cellular senescence, fibrosis, andinflammation by deacetylation of target proteins usingNAD? as co-substrate and is therefore linked to the redoxstate. In addition to SIRT1, SIRT6 have also been shown toimprove or slow down COPD. SIRT6 is associated withredox state and inhibits cellular senescence and fibrosis. Therefore, activation of SIRT1 and SIRT6 might be anattractive approach for novel therapeutic targets for COPD. The present review describes the protective effects of SIRT1and SIRT6 against COPD and their target proteins involvedin the pathophysiology of COPD.

와파린과 생약제의 약물 상호작용 리뷰

천부순,김종윤,김정태,구본기,유기연 한국병원약사회 2013 病院藥師會誌 Vol.30 No.5

Objectives: Concerns on drug interaction with herbal preparations are increasing as herbs are becoming more widely used as dietary supplements. Drug-herb interactions can alter therapeutic effects on patients, particularly in medications with narrow therapeutic index (NTI),such as warfarin. However, the potential risks from drug-herb interactions are often ignored or underestimated even when known. As there is limited documented information on potential herb-drug interactions, it is essential to provide clinical practices with the updated information as well as the mechanism on potential herb-drug interactions. The goals of this article are: (1) To review the evidence-based data and biomedical reports on herb-warfarin interactions in humans,and (2) To further provide the documented mechanisms and consequences of drug-herb interactions Methods: PubMed was used to search the clinical trials and the case reports on herb-warfarin interactions in humans. This article focused on the data conducted in humans as well as the studies in animal models, in vitro, in vivo are cited, where relevant. Results: There are several mechanisms for the occurrence of herb-drug interactions. Herbs which may affect warfarin therapy include the following: green tea, black tea, chamomile, cranberry,danshen, dong quai, ginseng, lyceum, noni, pomegranate, and St John’s wort. A vast majority of clinically significant PK herb-drug interactions involve cytochrome P450 (CYP)enzymes, UDP-glucuronosyltransferases (UGT), and drug transporters. Conclusion: The reported effects of herbs on warfarin are contradictory. Clinical effects of herbdrug interactions depend on different factors, such as genotypes of patients, origins and constituents of herbs, and doses of administered drugs. Hence, further controlled clinical studies in humans are needed in order to verify the potential herbal interactions with conventional drugs.

항혈소판약물과 생약제의 상호작용: 리뷰

천부순,김종윤,김정태,유기연 한국병원약사회 2014 病院藥師會誌 Vol.31 No.2

Objectives : Antiplatelet agents are commonly used worldwide for the prevention ofcardiovascular or cerebrovascular diseases by inhibiting platelet aggregation and thrombus formation. As the herbal medicine and crude drug market is gradually expanding with increasedpopularity, drug-herb interaction has become a rising topic. The most frequently interactingdrugs with herbs were reported to be antiplatelet agents and anticoagulants. The purpose of thisresearch is to focus on the interactions in antiplatelet agents with herbal medicines in order topresent safe use of these agents, including aspirin or clopidogrel, along with the effective use ofCAM (Complementary and Alternative Medicine). Methods : This research includes literatures on only the clinical results of drug interactions, primarilyassembled from PubMed and additionally from MedlinePlus Drugs and Supplements Directory, Martindale, Natural Standard, BNF, Stockely’s Herbal Medicines, etc. Results : Herbs that resulted in teractions with an antiplatelet agent were as follows : aloe vera,garlic, ginger, ginkgo, ginseng, and St. John’s wort. The results were all clinical and had morethan one case. Studies on garlic, ginger, and ginkgo were conducted on healthy adult subjectswhereas the clinical study on St. John’s wort was conducted on patients with stent placed ontheir coronary artery. Conclusions : Although clinical studies and cases on drug-herb interaction had varied results, theresults could lead to the conclusion that many herbal medicines will have interactions withantiplatelet agents. Therefore, potential interactions should be considered when simultaneouslyusing herbal medicine and conventional medicine prior to treatment. Further research using alarger population is required for more accurate results.