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Synthesis of Nonclassical Quinazolinone Antifolates as Thymidylate Synthase Inhibitors and Their Antitumor Activity In Vitro

  • Baek, Du-Jong;Kang, Tae-Beom;Kim, Hyun-Ju
    • Bulletin of the Korean Chemical Society
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    • v.25 no.12
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    • pp.1898-1906
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    • 2004
  • Nonclassical quinazolinone analogs I, II, and III, in which the glutamic acid moiety of the classical antifolates is substituted by phenylglycine, phenylalanine or aminobenzoic acid and their methyl esters, were synthesized and evaluated as lipophilic inhibitors of thymidylate synthase (TS). The target compounds were generally potent inhibitors of L. casei and human TS with $IC_{50}$ values within the narrow range of 0.2-10 ${\mu}$M and 0.003-0.03 ${\mu}$M, respectively. Further, most of the target compounds showed cytotoxicity against tumor cell lines of murine and human origin with $IC_{50}$ values of as low as 0.050 ${\mu}$M. Substitution of another hydroxyl or carboxylic acid/ester group at the phenyl ring further increased the potency of TS inhibition and cell growth inhibition. Most effective were compounds If and Ic in which extra carboxylic acid/ester was present at the phenyl ring with nanomolar $IC_{50}$ values of 0.0044 and 0.0093 ${\mu}$M against human TS and submicromolar cytotoxic growth inhibition against all four tumor cell lines.

Job Shop Scheduling by Tabu Search Combined with Constraint Satisfaction Technique (Tabu Search와 Constraint Satisfaction Technique를 이용한 Job Shop 일정계획)

  • 윤종준;이화기
    • Journal of Korean Society of Industrial and Systems Engineering
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    • v.25 no.2
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    • pp.92-101
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    • 2002
  • The Job Shop Scheduling Problem(JSSP) is concerned with schedule of m different machines and n jobs where each job consists of a chain of operations, each of which needs to be processed during an uninterrupted time period of a given length on a given machine. The purpose of this paper is to develop the efficient heuristic method for solving the minimum makespan problem of the large scale job shop scheduling. The proposed heuristic method is based on a Tabu Search(TS) and on a Constraint Satisfaction Technique(CST). In this paper, ILOG libraries is used to embody the job shop model, and a CST is developed for this model to generate the increased solution. Then, TS is employed to overcome the increased search time of CST on the increased problem size md to refine the next-current solution. Also, this paper presents the new way of finding neighbourhood solution using TS. On applying TS, a new way of finding neighbourhood solution is presented. Computational experiments on well known sets of MT and LA problem instances show that, in several cases, our approach yields better results than the other heuristic procedures discussed In literature.

Rheological Properties of Traditional kochujang (전통 고추장의 레올로지 특성)

  • Kim, Youn-Chung;Yoo, Byoung-Seung
    • Korean Journal of Food Science and Technology
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    • v.32 no.6
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    • pp.1313-1318
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    • 2000
  • 총고형분 함량$(TS:\;50{\sim}57%)$을 달리하여 숙성시킨 고추장의 유동특성, 정적 및 동적점탄특성을 관찰하였다. 고추장의 TS가 증가함에 따라서 점조도 지수(K)와 겉보기 점도$({\eta}_{a.5})$는 증가하였으며 유동성 지수(n)는 1보다 훨씬 낮은 0.24-0.31의 범위를 나타내어 고추장은 shear-thinning 성질을 보여주었다. 고추장의 항복응력 측정에서는 고추장의 TS가 증가함에 따라 Casson 항복응력$({\sigma}_{oc})$은 증가하는 경향을 나타내었으며, 또한 고추장의 액상 매개체인 serum 점도$({\eta}_{se})$는 고추장의 TS와 매우 좋은 상관관계$(R^2=0.97)$를 나타내었다. 고추장의 동적점탄성 실험에서는 주파수$({\omega})$가 증가함에 따라 저장탄성률(G#)와 손실탄성률(G@)은 증가하였으며 양(+) 기울기로 G#수치가 G@수치보다 높게 나타났다. 이는 고추장이 약한 겔과 같은 구조적 특성을 갖고 있으며 또한 shear-thinning 거동을 가지고 있음을 나타낸다. 정적점탄성 실험에서 고추장의 총고형분 함량에 따라서 순간탄성 변형$(J_0)$과 지연탄성변형$(J_1)$은 총고형분 함량이 증가함에 따라서 감소하였으며 점도$({\eta}_N)$와 지연시간 $({\tau}_1)$은 증가하였다. 따라서 고추장은 농도가 증가함에 따라 보다 탄력적이며 안정된 구조를 형성하고 있음을 알 수 있었다.

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Theoretical Studies on the Nucleophilic Substitution Reactions of 1-Phenylethyl Chlorides

  • 김왕기;류왕선;박형연;한인석;김창곤;이익준
    • Bulletin of the Korean Chemical Society
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    • v.18 no.8
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    • pp.868-873
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    • 1997
  • Nucleophilic substitution reactions of 1-phenylethyl chlorides (1-PEC; YC6H4CH(CH3)Cl) with phenoxides (XC6H4O-) and thiophenoxides (XC6H4S-) are investigated theoretically using the PM3 method. The Bronsted α and β values are greater for the phenoxides indicating a more advanced reaction in the transition state (TS) than for the thiophenoxides. This is supported by a greater magnitude of ρX (- 6.4 ∼ - 7.4) and ρXY (- 0.76) for the phenoxides than for the thiophenoxides (ρX = - 3.6 ∼ - 4.4 and ρXY = - 0.60). The percentage bond order changes, %Δn≠, suggest that the extents of bond making and breaking are similar for the phenoxides and hence the TS is symmetrical, but bond making is somewhat greater than bond cleavage for the thiophenoxides indicating an unsymmetrical TS. The reactions in the gas phase for both nucleophile series proceed by a SN2 mechanism with a tight TS and negative charge development on the reaction center carbon, Cα. The reactions in water investigated with model systems of benzyl and 1-phenylethyl chlorides using the Cramer-Truhlar solvation model (PM3-SM3) indicate that the reactions of 1-PEC are far more complex due to enhanced stabilization of the carbocation by the methyl substitution for a benzylic hydrogen.

Michael-type Reactions of 1-(X-substituted phenyl)-2-propyn-1-ones with Alicyclic Secondary Amines in MeCN and H2O: Effect of Medium on Reactivity and Transition-State Structure

  • Kim, Song-I;Hwang, So-Jeong;Park, Yoon-Min;Um, Ik-Hwan
    • Bulletin of the Korean Chemical Society
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    • v.31 no.5
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    • pp.1199-1203
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    • 2010
  • Second-order rate constants ($k_N$) have been measured spectrophotometrically for Michael-type reactions of 1-(X-substituted phenyl)-2-propyn-1-ones (2a-f) with a series of alicyclic secondary amines in MeCN at $25.0{\pm}0.1^{\circ}C$. The $k_N$ value increases as the incoming amine becomes more basic and the substituent X changes form an electron-donating group (EDG) to an electron-withdrawing group (EWG). The Br${\o}$nsted-type plots are linear with ${\beta}_{nuc}$ = 0.48 - 0.51. The Hammett plots for the reactions of 2a-f exhibit poor correlations but the corresponding Yukawa-Tsuno plots result in much better linear correlations with ${\rho}$ = 1.57 and r = 0.46 for the reactions with piperidine while ${\rho}$ = 1.72 and r = 0.39 for those with morpholine. The amines employed in this study are less reactive in MeCN than in water for reactions with substrates possessing an EDG, although they are ca. 8 pKa units more basic in the aprotic solvent. This indicates that the transition state (TS) is significantly more destabilized than the ground state (GS) in the aprotic solvent. It has been concluded that the reactions proceed through a stepwise mechanism with a partially charged TS, since such TS would be destabilized in the aprotic solvent due to the electronic repulsion between the negative-dipole end of MeCN and the negative charge of the TS. The fact that primary deuterium kinetic effect is absent supports a stepwise mechanism in which proton transfer occurs after the rate-determining step.

Thymidylate Synthase Polymorphisms and Risk of Lung Cancer among the Jordanian Population: a Case Control Study

  • Qasem, Wiam Al;Yousef, Al-Motassem;Yousef, Mohammad;Manasreh, Ihab
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.18
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    • pp.8287-8292
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    • 2016
  • Background: Thymidylate synthase (TS) catalyzes the methylation of deoxyuridylate to deoxythymidylate and is involved in DNA methylation, synthesis and repair. Two common polymorphisms have been reported, tandem repeats in the promoter-enhancer region (TSER), and 6bp ins/del in the 5'UTR, that are implicated in a number of human diseases, including cancer. The association between the two polymorphisms in risk for lung cancer (LC) was here investigated in the Jordanian population. Materials and Methods: An age, gender, and smoking-matched case-control study involving 84 lung cancer cases and 71 controls was conducted. The polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) technique was used to detect the polymorphism of interest. Results: Individuals bearing the ins/ins genotype were 2.5 times more likely to have lung cancer [(95%CI: 0.98-6.37), p=0.051]. Individuals who were less than or equal to 57 years and carrying ins/ins genotype were 4.6 times more susceptible to lung cancer [OR<57 vs >57years: 4.6 (95%CI: 0.93-22.5), p=0.059)]. Genotypes and alleles of TSER were distributed similarly between cases and controls. Weak linkage disequilibrium existed between the two loci of interest (Lewontin's coefficient [D']) (LC: D' =0.03, r2: 0. 001, p=0.8; Controls: D' =0.29, r2: 0.08, p=0.02). Carriers of the "3 tandem repeats_insertion" haplotype (3R_ins) were 2 times more likely to have lung cancer [2 (95%CI: 1.13-3.48), p=0.061]. Conclusions: Genetic polymorphism of TS at 3 'UTR and its haplotype analysis may modulate the risk of lung cancer in Jordanians. The 6bp ins/del polymorphism of TS at 3 'UTR is more informative than TSER polymorphism in predicting increased risk.

Chemical Properties of Dairy Slurry for Liquid Composting (液狀콤포스트化 處理에 있어서 乳牛糞尿의 化學的 特性)

  • 홍지형;최병민
    • Journal of Animal Environmental Science
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    • v.1 no.2
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    • pp.165-171
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    • 1995
  • Aerobic treatment of animal slurries represents an increasingly popular option for farmers in the management of animal wastes. This study was performed to find out the chemical characteristics of dairy slurry associated with liquid-solid separation. Total solids concentration varies widely depending on the slurry manure handling systems. Hydrogen ion exponent(pH), volatile solids(VS), ammonia nitrogen(NH$_3$-N), nitrate nitrogen (NO$_3$-N), and chemical oxygen demand(COD) essentially depends on the total solids content of animal liquid wastes. Total solids content of the dairy slurry ranges from 6.6 to 7.5% depending on the feed slurry and separator. Separated liquids from dairy slurry have been successfully downed for up to about 21, 900mg/$\ell$ of the COD value. It has also been found that separated slurry decreased from 37.8 to 26.0mg/$\ell$ of the NO$_3$-N concentration.

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Fabrication of Coated Conductor by Continuous PVD Methods (연속 공정 PVD 방법에 의한 Coated Conductor 제조)

  • Ko, Rock-Kil;Chung, Jun-Ki;Kim, Ho-Sup;Ha, Hong-Soo;Shi, Dongqi;Song, Kyu-Jeong;Park, Chan;Yoo, Sang-Im;Moon, Seung-Hyun;Kim, Young-Cheol
    • Journal of the Korean Institute of Electrical and Electronic Material Engineers
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    • v.17 no.11
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    • pp.1241-1245
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    • 2004
  • Continuous physical vapor deposition (PVD) method is one of many processes to fabricate long length coated conductor which is required for successful large-scale application of superconducting power devices. Three film deposition systems (pulsed laser deposition, sputtering, and evaporation) equipped with reel-to-reel(R2R) metal tape moving apparatus were installed and used to deposit multi-layer oxide thin films. Both RABiTS and IBAD texture templates are used. IBAD template consists of CeO$_2$(PLD)/YSZ(IBAD) on stainless steel(SS) metal tape, and RABiTS template has the structure of CeO$_2$/YSZ/Y$_2$O$_3$ which was continuously deposited on Ni-alloy tape using R$_2$R evaporation and DC reactive sputtering in a deposition system designed to do both processes. 0.4 m-long coated conductor with Ic(77 K) of 34 A/cm was fabricated using RABiTS template. 0.5 m and 1.1 m-long coated conductor with Ic(77 K) of 41 A/cm and 26 A/cm were fabricated using IBAD template.

Transition State Variation in the Anilinolysis of O-Aryl Phenyl Phosphonochloridothioates in Acetonitrile

  • Adhikary, Keshab Kumar;Lumbiny, Bilkis Jahan;Dey, Shuchismita;Lee, Hai-Whang
    • Bulletin of the Korean Chemical Society
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    • v.32 no.8
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    • pp.2628-2632
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    • 2011
  • The nucleophilic substitution reactions of Y-O-aryl phenyl phosphonochloridothioates with substituted anilines ($XC_6H_4NH_2$) and deuterated anilines ($XC_6H_4ND_2$) are kinetically investigated in acetonitrile at $55.0^{\circ}C$. The deuterium kinetic isotope effects (DKIEs) invariably increase from an extremely large secondary inverse ($k_H/k_D$ = 0.439; min) to a primary normal ($k_H/k_D$ = 1.34; max) as both substituents of nucleophile (X) and substrate (Y) change from electron-donating to electron-withdrawing. These results are opposite to the DKIEs on Y-O-aryl methyl phosphonochloridothioates, and can be rationalized by the gradual transition state (TS) variation from backside to frontside attack. The trigonal bipyramidal pentacoordinate TS is proposed for a backside attack, while the hydrogen-bonded, four-center-type TS is proposed for a frontside attack. The negative values of the cross-interaction constants (${\rho}_{XY(H)}$ = -0.38 for $XC_6H_4NH_2$ and ${\rho}_{XY(D)}$ = -0.29 for $XC_6H_4ND_2$) indicate that the reactions proceed by a concerted $S_N2$ mechanism.

Fabrication of coated conductor by continuous PVD methods (연속 공정 PVD 방법에 의한 coated conductor 제조)

  • Ko, Rock-Kil;Chung, Jun-Ki;Kim, Ho-Sup;Ha, Hong-Soo;Shi, Dongqi;Park, Yu-Mi;Choe, Su-Jeong;Song, Kyu-Jeong;Yoo, Sang-Im;Moon, Seung-Hyun;Park, Chan
    • Proceedings of the Korean Institute of Electrical and Electronic Material Engineers Conference
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    • 2004.07a
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    • pp.93-96
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    • 2004
  • 다층의 산화물 박막 구조를 갖는 coated conductor의 장선 제조를 위해서는 연속 증착 공정이 필요하다. 본 연구에서는 RABiTs와 IBAD 공정을 사용한 texture template을 사용하였으며, 금속 테잎을 연속적으로 이동하면서 증착할 수 있는 박막증착 장치(PLD, sputtering, evaporation)를 구축하여 PVD 방법으로 coated conductor를 제조하였다. $CeO_2/YSZ/Y_2O_3$의 완충층을 sputtering 과 evaporation을 이용하여 2축배향성을 가지는 NiW 위에 연속적으로 증착하였다. YBCO 초전도층은 연속 PLD 방법으로 증착하고, Tc, Ic, XRD, SEM을 통해 그 특성을 분석하였다. 그 결과 RABiTS template을 사용하여 Ic가 34A/cm(@77K)인 0.4m 길이의 coated conductor를 제조하였다. IBAD template를 사용하여 Ic가 34A/cm(@77K)인 0.5m길이의 coated conductor를 제조하였고, Jc는 $1.2MA/cm^2$ 이였다.

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