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Synthetic Studies toward the Total Synthesis of Chloptosin Halfmer

Title
Synthetic Studies toward the Total Synthesis of Chloptosin Halfmer
Authors
한정희
Issue Date
2009
Department/Major
대학원 화학·나노과학과
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
한소엽
Abstract
Chloptosin was isolated from the culture broth Streptomyces strain MK498-98F in a screen for apoptosis-inducing agents. Many Anticancer agents such as paclitaxel(taxol), adriamycin, vinblastin are known to induce apoptosis in cultured neoplastic cells. However human carcinoma cells are often resistant to apoptosis when treated with these drugs. This phenotype may partly explain the poor therapeutic effect of cancer chemotherapy on most solid tumor. Chloptosin can overcome the limit as presenting anticancer acitivities on human carcinoma cells. The structure of chloptosin is dimeric cyclohexapeptide consisting of D-valine, (3S)-, (3R)-piperazic acid, O-methyl-L-serine, D-threonine, (2S,3aR,8aR)-6-chloro-3a-hydroxy-2,3,3a,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid. We tried to synthesize piperazic acid derivatives with various protecting groups to couple with other amino acids. N1 Moieties of (3R)- and (3S)-piperazic acids were protected by Cbz(benzyloxycarbonyl) group and N2 moiety of (3S)-piperazic acid derivative was protected by Fmoc(9-fluorenylmethylcarbonyl) group. Coupling between D-threonine and O-methyl-L-serine was carried out using DCC and HOBt. This dipeptide was then coupled with (3R)-piperazic acid derivative in the presence of HATU as a coupling agent, and HOAt as a racemization suppressing agent. (3S)-Piperazic acid derivative and D-valine derivative were coupled with the tripeptide sequentially using a chlorinating agent, 1-chloro-N,N,2-trimethylpropenylamine, to provide the pentapeptide. The linear hexapeptide was synthesized by combining L-6-chloropyrroloindoline derivative to the pentapeptide. We focused on the synthesis of the key chiral synthon of chloptosin, L-6-chloropyrroloindoline. L-6-Chlorotryptophan, an intermediate of L-6-chloropyrroloindoline, was prepared from 3-chloroaniline by a modified procedure of Cook utilizing Fischer indole/Schollkopt protocol. The Schollkopf chiral auxiliary, which was available from D-valine, was chosen for the preparation of L-6-chlorotryptophan. The conversion of N-trityl-L-6-chlorotryptophan tert-butyl ester to hydroxypyrroloindoline tert-butyl ester was achieved by oxidative cyclization with DMDO as an oxidizing agent. Both trityl and tert-butyl group were required to synthesize the cis and trans pyrroloindoline system stereospecifically. The Fmoc, TES, and allyl groups were introduced to protect amine, hydroxy, and carboxylic acid groups independently for the coupling reaction of the pyrroloindoline moiety and the linear pentapeptide. The linear hexapeptide was synthesized by combining L-6-chloropyrroloindoline derivative to the pentapeptide with HATU and HOAt. In conclusion, L-6-chloropyrroloindoline moiety was synthesized in 20 steps from 3-chloroaniline and 15% overall yield and linear hexapeptide of the chloptosin halfmer was afforded in overall 4% in 14 steps.;자연계에 존재하는 항균성 펩타이드는 질병을 유발하는 미생물로부터 자신들이 속한 다세포 기관을 방어하기 위해 미생물의 세포막을 표적으로 공격한다. 그러므로 동식물계에 있는 항균성 펩타이드는 천연의 방어체계를 이해하는 실마리가 된다. 그 중 고리형 펩타이드는 일반적으로 선형 펩타이드에 비해 생체 내에서 안정하고 구조의 유동성을 줄일 수 있는 이점 때문에 유망한 선도 물질로 알려져 있다. Chloptosin 은 이러한 고리형 펩타이드 물질 중 하나이며, Kauzo Umezawa group 에 의해 Streptomyces strain MK489-98F 의 배양액으로부터 추출된 물질 (polyoxypeptin A, B, chloptosin) 중 하나이며, 췌장선 암에 대해 두드러진 세포사멸 활성을 보인다. Chloptosin 은 두 개의 동일한 subunit biaryl linkage 로 연결되어있는 구조를 지니고 있다. 각각의 subunit 은 D-valine, (3S)- and (3R)-piperazic acids, O-methyl-L-serine, D-threonine, (2S,3aR,8aR)-6-chloro-3a-hydroxy-2,3,3a,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid 를 포함하는 18-membered cyclohexapeptide 구조를 이루고 있다. Chloptosin 의 합성은 크게 두 부분으로 나누어 진행된다. 먼저 D-valine, (3S)- and (3R)-piperazic acids, O-methyl-L-serine, D-threonine 이 순차적으로 결합된 선형 pentapeptide 의 합성을 진행하였다. 이 때 coupling reagent 로는 HATU, DCC 등이 사용되었고, racemization suppressing reagent 로는 HOAt, HOBt 등이 사용되었다. Chlotosin halfmer 의 머리 부분에 해당하는 L-6-chloropyrroloindoline moiety 의 합성은 D-valine 으로부터 합성된 chiral auxiliary 와 3-chloroaniline 을 출발물질로 하여 합성된 6-chloroindole 과의 couling 반응으로 L-6-chlorotryptophan 을 합성할 수 있었으며, 산화적 고리화반응을 통해 완성할 수 있었다. 각각 합성된 선형 pentapeptide 와 L-6-chloropyrroloindoline moiety 의 결합반응을 통해 선형 hexapeptide 를 합성할 수 있었다.
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