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Synthesis of Fluorocyclopentenyluracil and Fluorocyclopentenylcytosine and their cell growth inhibition

Title
Synthesis of Fluorocyclopentenyluracil and Fluorocyclopentenylcytosine and their cell growth inhibition
Authors
고영미
Issue Date
2004
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
鄭樂臣
Abstract
Fluorocyclopentenyluracil 5 and Fluorocyclopentenylcytosine 6 were designed as cell growth inhibitors. Synthesis of Fluorocyclopentenyluracil 5 and Fluorocyclopentenylcytosine 6 and their cell growth inhibition activities against various cancer cells are described. The key intermediate cyclopentenone was prepared from D-ribose. The final sugar was efficiently synthesized via an electrophilic vinyl fluorination reaction (n-BuLi, N-fluorobenzenesulfonimide at -78 ˚C). Coupling of 20a with N³-benzoyluracil via the Mitsunobu reaction followed by deprotection afforded Fluorocyclopentenyluracil and Fluorocyclopentenylcytosine. The synthesized compounds were evaluated for their cell growth inhibition against human glioblastoma cell line, human lung cancer cell line, human gastric cancer cell line, human cervix cancer cell line, human breast cancer cell line, human breast cancer cell line, human head and neck cancer cell line, human head and neck cancer cell line, human head and neck squamous carcinoma and human head and neck squamous carcinoma. Fluorocyclopentenyluracil did not show any significant cell growth inhibition. Fluorocyclopentenylcytosine exhibited potent cell growth inhibition (IC_(50) = 0.16μM) against human breast cancer cell line. And it exhibited potent cell growth inhibition (IC_(50) = 0.17μM and 0.22μM) against human head and neck squamous carcinoma and human breast cancer cell line. Fluorocyclopentenylcytosine exhibited potent cell growth inhibition against the other cancer cells.;우리는 Fluorocyclopentenyluracil 5 과 Fluorocyclopentenylcytosine 6을 세포 성장 저해 작용을 통한 항암제 후보물질로 고안하였다. 이 논문에서는 Fluorocyclopentenyluracil 5 와 Fluorocyclopentenylcytosine 6 의 합성 방법과 이 물질들의 여러 cancer cells 에 대한 암세포 성장 저해 시험 결과에 대하여 기술하였다. 우리가 목적으로 하는 물질의 중요 중간체인 cyclopentenone은 D-ribose로부터 시작하였다. Base와 축합 하기 전 Final sugar는 electrophilic vinyl fluorination reaction (n-BuLi, N-fluorobenzenesulfonimide at -78 ˚C) 을 이용하여 아주 효과적으로 만들어졌다. Mitsunobu reaction을 이용하여 Base와 Sugar 축합을 하였고, deprotection을 통하여 우리가 원하는 Fluorocyclopentenyluracil을 얻었다. 그리고 1,2,4-triazole을 이용하여 uracil울 cytosine으로 변화시켜 우리가 원하는 또 하나의 물질인 Fluorocyclopentenylcytosine을 얻어냈다. 만들어진 물질들은 암세포 성장 저해 작용을 가지고 있는지 없는지를 알기 위한 시험에 들어갔다. 이 시험에 사용된 cell을 다음과 같다: human glioblastoma cell line, human lung cancer cell line, human gastric cancer cell line, human cervix cancer cell line, human breast cancer cell line, human breast cancer cell line, human head and neck cancer cell line, human head and neck cancer cell line, human head and neck squamous carcinoma and human head and neck squamous carcinoma. 시험결과 Fluorocyclopentenyluracil 은 기술 할만한 암세포 성장 저해 작용을 나타내지 않았다. 그에 반해 Fluorocyclopentenylcytosine 은 human breast cancer cell line에 대해서는 IC_(50) = 0.16μM 그리고 human head and neck squamous carcinoma에 대해서는 IC_(50) = 0.17μM, human breast cancer cell line에 대해서는 IC_(50) = 0.22μM를 나타내는 등 다른 cancer cell에 대해서도 강력한 세포 성장 저해 작용을 보여 줬다. 이러한 결과로 보아 Fluorocyclopentenylcytosine은 좋은 효능을 가진 항암제로 기대되어진다.
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