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Synthesis of 18-Membered Cyclic Hexapeptide in Chloptosin Halfmer

Title
Synthesis of 18-Membered Cyclic Hexapeptide in Chloptosin Halfmer
Authors
주혜경
Issue Date
2007
Department/Major
대학원 나노과학부
Publisher
이화여자대학교 대학원
Degree
Master
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. Deprotection of the allyl and Troc groups afforded the linear hexapeptide which was ready for the crucial cyclization. Thus, the target 18-membered cyclic hexapeptide was successfully synthesized by using HOAt, HATU and DIEA as peptide coupling condition. In conclusion, the final macrocyclization was afforded in overall yield 4% in 14 steps. Study for the completion of the synthesis of chloptosin halfmer is under investigation in our laboratories.;대부분의 항암제는 암세포의 각종 대사경로에 개입하여 주로 핵산의 합성을 억제하거나 항암활성을 나타내는 약제이다. 기존에 잘 알려진 paclitaxel(taxol)¹, adriamycin², vinblastin 등은 cultured neoplastic cell에서 세포사멸을 유발한다. 그러나 이들 항암제는 암세포에만 선택적으로 작용하는 것이 아니라 정상세포, 특히 세포분열이 활발한 조직세포에도 손상을 입히기 때문에 골수기능저하, 위장장애, 탈모증 등의 여러 가지 부작용이 나타나게 된다. Umezawa group에 의해 Streptomyces strain MK498-98F의 배양액으로부터 추출된 세가지 물질(polyoxypeptin A, B, chloptosin) 중 하나인 chloptosin은 human carcinoma cell에서 세포사멸 효과를 선택적으로 유도하는 항암기전과 항균성을 갖고 있다.³ Chloptosin의 구조는 dimeric 18-membered cyclohexapeptide로 D-valine, (3R)- 과 (3S)-piperazic acid, O-methyl-L-serine, D-threonine, (2S,3aR,8aR)-6-chloro-3a-hydroxy-2,3,3a,8a-hexa-hydropyrrolo[2,3-b]indole-2-carboxylic acid 로 구성되어 있다. (3R)-, (3S)-piperazic acid는 다른 아미노산과의 결합을 위하여 다양한 protecting group을 사용하였다. (3R)-과 (3S)-piperazic acid의 N¹부분은 Cbz그룹으로 protection해 주었는데, 이때 N²부분까지 protection 되는 것을 막기 위해 condition 조절에 주의를 기울여야 했다. 또 (3S)-piperazic acid의 경우 N²부분까지 Fmoc 그룹으로 protection해 주어, 선택적으로 어느 하나의 보호기만 deprotection 함으로써 coupling 반응을 진행시킬 수 있었다. D-threonine와 O-methyl-L-serine의 결합은 DCC, HOBt를 이용하여 수행하였다. 이 dipeptide는 HATU를 coupling agent로, HOAt를 racemization suppressing agent로 사용하여 (3R)-piperazic acid 유도체와 coupling 해 주었다. 이후 (3S)-piperazic acid, D-valine 유도체가 순차적으로 결합되어 pentapeptide linear precursor를 총 10단계, 17% 수득률로 얻을 수 있었다. 이때 piperazic acid 유도체의 입체장애 및 N²부분의 낮은 친핵성 때문에 반응 조건을 조절하여 여러 차례 결합 반응을 시도하였고, 1-chloro-N,N,2-trimethylpropenylamine이라는 chlorinating reagent를 사용함으로써 결합을 성공적으로 수행할 수 있었다. 다음으로 HOAt와 HATU를 이용하여 pentapeptide에 6-chloropyrroloindoline moiety를 결합시켜 hexapeptide를 합성한 후, Pb/Cd couple을 이용하여 valine moiety의 amino group을 보호하고 있던 Troc 그룹을 제거하고 [Pd(Ph₃P)₄], PhSiH₃를 이용하여 6-chloropyrroloindoline moiety의 카르복시산을 보호하고 있던 allyl 그룹을 deprotection 시키고 난 후, HATU, HOAt를 이용하여 거대고리화 반응을 진행시켜 총 14단계 4%의 수득률로 18-membered cyclic hexapeptide 완성하였다.
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