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Studies on Synthesis of (±)-Centrolobine and Dolastatin 10 Analogues

Title
Studies on Synthesis of (±)-Centrolobine and Dolastatin 10 Analogues
Authors
최윤실
Issue Date
2012
Department/Major
대학원 생명·약학부약학전공
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
유재상
Abstract
Part A : Synthesis of (±)–Centrolobine Centrolobine is a natural product isolated from the heartwood of centrolobium robustum and from the stem of Brosinum potabile in the Amazon forest. It exhibits activity against Leishmania amazonensis promastigotes, a parasite associated with leishmaniasis. 2, 6-Disubstituted tetrahydropyran scaffolds have gained prominence recently owing to their excellent biological properties. This unit is also present in several natural products with cis stereoconnectivity at the 2, 6-positions. Some recent examples, which fall into this class, include leucascandrolides, phorboxazoles, (+)-SCH 351448, (−)-centrolobine and others. Although several total syntheses have been reported previously, there is no instance reported that used intramolecular hydroalkoxylation as a key step in the construction of the tetrahydropyran skeleton. By using the Brønsted acidic ionic liquids, (±)-centrolobine has been successfully synthesized. Part B : Studies on Synthesis of Dolastatin 10 and Its Analogues The marine natural product dolastatin 10 originally isolated from the sea hare Dolabella auricularia and structurally defined in 1987 by Pettit and co-workers as a member of a whole family of cytotoxic antimitotic peptides and it has expected to combine with peptide site of β-tubulin. Although this natural product was dropped in phase II clinical trial, its close analog TZT-1027 is currently in phase II human cancer clinical trial. The common structural part, (S)-dolaphenine (Doe) synthesized with Ellman’s chiral sulfonamide. β-methoxy--amino acid dolaproine (Dap) comprises the most complex unit of the pentapeptide. In our ongoing research focused on the utilization of Baylis–Hillman adducts for the total synthesis of biologically active products, we herein reported Baylis–Hillman strategy for the preparation of dolaproine (Dap). However diastereomer appeared by the epimerization, changed scheme of using chiral auxiliary.;본 논문은 천연물의 전합성에 관한 것이며, part A와 part B 두 부분으로 구성되어 있다. Part A는 (±)-centrolobine, Part B는 dolastatin 10 analogue의 합성을 다루고 있다. Part A의 centrolobine은 아마존에 있는 centrolobium robustum 심재(heartwood)와 Brosinumpotabile 줄기로부터 분리된 천연물로, leishmaniasis의 원인 기생충인 Leishmania amazonensis promastigotes에 대한 antileishmanial activity를 나타낸다. Centrolobine의 구조를 보면 2,6-disubstituted tetrahydropyran scaffolds가 있는데, 이 구조는 우수한 생물학적 활성을 지니고 있으며, leucascandrolides, phorboxazoles, (+)-SCH 351448 등 많은 천연물 구조에서 2,6-position에 cis stereoconnectivity를 볼 수 있다. 비록 다양한 시도로 많은 연구실에서 centrolobine을 합성했지만, 친환경적이고, 재사용이 가능한 Brønsted acidic ionic liquid를 이용하여 alkenyl alcohol의 hydroalkoxylation을 합성하고자 했다. Part B의 해양 천연물인 dolastatin 10은 Indian Ocean sea hare인 Dolabella auricularia에서 분리된 linear pentapeptide로 1987년 George R. Pettit에 의해 cytotoxic antimitotic이 있다는 것이 밝혀졌다. β-tubulin의 peptide site와 결합하는 것으로 예상되며, microtubule의 polymerization을 억제함으로써 결과적으로 암세포 증식을 억제하는 효과를 나타낸다. Dolastatin 10이 독성에 의해 phase II 임상시험에서 중단 되었지만 analogue인 TZT-1027는 현재 phase II human cancer 임상시험이 진행 중이다. 따라서 Dolastatin 10의 analogue를 합성하여 생리학적 활성을 규명하고자 하는 것이 본 연구의 목적이며, (S)-Boc-dolaphenine은 Ellman’s chiral sulfonamide를 사용하여 sulfonyl imide를 만들고 DIBAL redution을 거쳐 chiral compound로 합성하였다. β-methoxy-g-amino acid인 (2R,3R,4S)-dolaproine (Dap)은 Dolastatin 10 구조에서 가장 복잡한 unit으로 Baylis–Hillman반응에 중점을 두고 연구를 진행했지만, epimerization에 의한 diastereomer의 생성으로 인해 반응 경로를 변경하였고 chiral auxiliary를 도입하여 dolaproine (Dap)를 합성하는 연구를 진행하였다.
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