ISOLATION AND IDENTIFICATION OF CYCLIC POLYKETIDES FROM ENDIANDRA KINGIANA GAMBLE (LAURACEAE), AS BCL-XL/BAK AND MCL-1/BID DUAL INHIBITORS, AND APPROACHES TOWARD THE SYNTHESIS OF KINGIANINS Mohamad Nurul Azmi Mohamad Taib, Yvan Six, Marc Litaudon, Khalijah Awang To cite this version: Mohamad Nurul Azmi Mohamad Taib, Yvan Six, Marc Litaudon, Khalijah Awang. ISOLATION AND IDENTIFICATION OF CYCLIC POLYKETIDES FROM ENDIANDRA KINGIANA GAMBLE (LAURACEAE), AS BCL-XL/BAK AND MCL-1/BID DUAL INHIBITORS, AND APPROACHES TOWARD THE SYNTHESIS OF KINGIANINS . Chemical Sciences. Ecole Doctorale Polytechnique; Laboratoires de Synthase Organique (LSO), 2015. English. tel-01260359 HAL Id: tel-01260359 https://pastel.archives-ouvertes.fr/tel-01260359 Submitted on 22 Jan 2016 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. ISOLATION AND IDENTIFICATION OF CYCLIC POLYKETIDES FROM ENDIANDRA KINGIANA GAMBLE (LAURACEAE), AS BCL-XL/BAK AND MCL-1/BID DUAL INHIBITORS, AND APPROACHES TOWARD THE SYNTHESIS OF KINGIANINS MOHAMAD NURUL AZMI BIN MOHAMAD TAIB FACULTY OF SCIENCE UNIVERSITY OF MALAYA KUALA LUMPUR, MALAYSIA AND ECOLE POLYTECHNIQUE PALAISEAU, FRANCE 2015 ISOLATION AND IDENTIFICATION OF CYCLIC POLYKETIDES FROM ENDIANDRA KINGIANA GAMBLE (LAURACEAE), AS BCL-XL/BAK AND MCL-1/BID DUAL INHIBITORS, AND APPROACHES TOWARD THE SYNTHESIS OF KINGIANINS MOHAMAD NURUL AZMI BIN MOHAMAD TAIB THESIS SUBMITTED IN FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY FACULTY OF SCIENCE UNIVERSITY OF MALAYA KUALA LUMPUR, MALAYSIA AND ECOLE POLYTECHNIQUE PALAISEAU, FRANCE 2015 Thesis submitted for the award of the degree of DOCTOR OF PHILOSOPHY In the field of CHEMISTRY by Mohamad Nurul Azmi MOHAMAD TAIB ISOLATION AND IDENTIFICATION OF CYCLIC POLYKETIDES FROM ENDIANDRA KINGIANA GAMBLE (LAURACEAE), AS BCL-XL/BAK AND MCL-1/BID DUAL INHIBITORS, AND APPROACHES TOWARD THE SYNTHESIS OF KINGIANINS Presented on 12th November 2015, to a committee composed of : Prof. Dr. Hasnah Mohd Sirat Referee Prof. Dr. Benoit Crousse Referee Prof. Dr. Sylvie Michel Referee Assoc. Prof. Dr. Rozana Othman Referee Prof. Dr. Khalijah Awang Examiner Dr. Yvan Six Examiner Dr. Marc Litaudon Examiner Dr. Fabien Gagosz President UNIVERSITY OF MALAYA ORIGINAL LITERARY WORK DECLARATION Name of Candidate: Mohamad Nurul Azmi MOHAMAD TAIB (I.C/Passport No: 851207-03-6031 ) Registration/Matric No: SHC110066 Name of Degree: Doctor of philosophy (PhD.) Title of Project Paper/Research Report/Dissertation/Thesis (“this Work”): Isolation and identification of cyclic polyketides from Endiandra kingiana Gamble (Lauraceae), as Bcl-xL/Bak and Mcl-1/Bid dual inhibitors, and approaches toward the synthesis of kingianins. Field of Study: Chemistry I do solemnly and sincerely declare that: (1) I am the sole author/writer of this Work; (2) This Work is original; (3) Any use of any work in which copyright exists was done by way of fair dealing and for permitted purposes and any excerpt or extract from, or reference to or reproduction of any copyright work has been disclosed expressly and sufficiently and the title of the Work and its authorship have been acknowledged in this Work; (4) I do not have any actual knowledge nor do I ought reasonably to know that the making of this work constitutes an infringement of any copyright work; (5) I hereby assign all and every rights in the copyright to this Work to the University of Malaya (“UM”), who henceforth shall be owner of the copyright in this Work and that any reproduction or use in any form or by any means whatsoever is prohibited without the written consent of UM having been first had and obtained; (6) I am fully aware that if in the course of making this Work I have infringed any copyright whether intentionally or otherwise, I may be subject to legal action or any other action as may be determined by UM. Candidate’s Signature Date: Subscribed and solemnly declared before, Witness’s Signature Date: Name: Dr. Khalijah Awang Designation: Professor iii ABSTRACT The preliminary screening showed that the bark of Endiandra kingiana Gamble exhibited potency as a modulating agent between Bcl-xL and Bak, which prompted its chemical investigation. Two groups of compounds were isolated and characterized; the endiandric acid series and the kingianin series. Eight new endiandric acid analogues (kingianic acids A-H [ 120 -127 ]) and three new kingianin analogues (kingianin O-Q [128 -130 ]) were isolated and structurally elucidated. The isolated compounds were evaluated for two bioassays; Bcl-xL/Bak and Mcl-1/Bid of binding affinities and cytotoxic effects against various human tumour cells. The second part describes the progression towards the total synthesis of kingianin analogues. The pentacyclic kingianin skeleton was formed by Diels-Alder reaction between two monomers having a bicyclo[4.2.0]octadiene backbone formed by a stereospecific electrocyclization of polyenes. The research was focusing on construction of bicyclo[4.2.0]octadiene monomer using [2+2] ketene cycloaddition approach at the early stage of the synthesis. One of the main advantages of such a strategy is the rapid assembly of the carbon skeleton of kingianins, thus maximizing the chances for good overall yields of the final products. So far, an efficient synthesis of the bicyclo[4.2.0]octene backbone was successfully achieved. Five approaches to synthesize this backbone starting from [2+2] cycloaddition of the cyclohexadienes to functionalized ketenes followed by functionalization of substituent at C-7 and C-8 positions with the correct relative configuration were described. From these approaches, compounds 280 and 311 were identified as the key intermediates. This key step of the synthesis provided an access to the kingianins skeleton. iv ABSTRAK Pemeriksaan awal menunjukkan bahawa kulit pokok Endiandra kingiana Gamble mempunyai potensi sebagai ejen modulasi antara protein Bcl-xL dan Bak, yang mendorong kepada penyiasatan sebatian kimianya. Dua kumpulan sebatian telah diasingkan dan dikenalpasti iaitu; siri asid endiandrik dan siri kingianin. Lapan analog asid endiandrik baharu (asid kingianik A-H [ 120 -127 ]) dan tiga analog kingianin baharu (kingianin O-Q [128 -130 ]) telah diasingkan dan dikenalpasti. Sebatian tulen yang diasingkan telah dinilai terhadap dua bioassei; kebolehan untuk mengikat antara protein Bcl-xL/Bak dan Mcl-1/Bid dan kesan sitotoksik terhadap sel tumor manusia. Bahagian kedua menerangkan perkembangan sintesis analog kingianin. Rangka pentasiklik kingianin adalah terbentuk daripada tindak balas Diels-Alder antara dua monomer yang mempunyai struktur bisiklo[4.2.0]oktadiena yang dibentuk daripada elektrosiklik poliena. Kajian ini memberi tumpuan kepada pembinaan bisiklo[4.2.0]oktadiena monomer dengan menggunakan pendekatan sikloadisi [2+2] ketena pada peringkat awal sintesis. Salah satu kelebihan utama strategi ini adalah pembentukan pantas rangka karbon kingianin, sekaligus meningkatkan peluang pembentukan hasil yang maksimum. Setakat ini, sintesis bisiklo[4.2.0]oktana telah berjaya dicapai. Sebanyak lima pendekatan telah dilakukan bermula dari sikloadisi [2+2] antara sikloheksadiena dengan ketena diikuti dengan fungsionalisasi kumpulan berfungsi dikedudukan C-7 dan C-8 dengan konfigurasi yang betul. Daripada pendekatan ini, sebatian 280 dan 311 telah dikenalpasti sebagai sebatian perantara yang terbaik bagi menghasilkan analog kingianin. v RÉSUMÉ Un criblage biologique préliminaire a montré que l'extrait des écorces d'Endiandrakingiana possédait une forte affinité pour la protéine anti-apoptotique Bcl- xL, motivant ainsi la réalisationd’une étude chimique complète. Deux groupes de composés ont été isolés et caractérisés: d’une part, huit nouveaux dérivés de l'acide endiandrique (les acides kingianiques A à H [ 120 −127 ]) et d’autre part, trois nouvelleskingianines (les kingianines O à Q [ 128 −130 ]). Le potentiel inhibiteur des nouvelles molécules vis-à-vis des interactionsBcl-xL/Bak et Mcl-1/Bida ensuite été évalué, ainsi que leurs propriétés cytotoxiques sur diverses lignées cellulaires tumorales humaines. La seconde partie du manuscrit présente une approche vers la synthèse totale des kingianines et de composés analogues.Le squelette pentacyclique des produits naturels résulte formellement d’une réaction de Diels-Alder entre deux unités bicyclo[4.2.0]octadiène, elles-mêmes issues d’une cascade d’électrocyclisation de tétraènes entièrement conjugués. Une stratégie de construction directe de motifs bicyclo[4.2.0]octadiènespar une cycloaddition [2+2] entre des cycloalcènes et des cétènes convenablement choisisdoit assurer l’obtention des molécules cibles avec de bons rendements globaux. Au total, cinq approches ont été implémentées. Elles débutent par la cycloaddition [2+2] entre des cyclohexadiènes et des cétènes fonctionnalisés et se poursuivent par la fonctionnalisation des positions C7 et C8 en contrôlant la configuration relative de ces centres. Les résultats obtenus ont conduit à identifier les composés 280 et 311 comme des intermédiaires clefs à même d’être convertis en diènes