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Synthesis of Spiro-bicyclo[2.2.2]Octane Derivatives Towards the Development of Paclitaxel Mimetics

Thornqvist, Viveca LU (2006)
Abstract (Swedish)
Popular Abstract in Swedish

Många av de föreningar som utvecklas i den farmaceutiska industrin idag har sina rötter i naturprodukter. Paclitaxel, den aktiva substansen i läkemedlet Taxol, återfinns bland annat i idegranens bark. Detta upptäcktes i början av 1960-talet då ett nationellt sökprogram för att finna nya naturprodukter för användning mot cancer organiserades i Amerika. Den låga halten av paclitaxel i barken och faktumet att trädet dör utan sin bark, i samband med positiva rapporter om dess effekt på olika typer av tumörer, ledde till ett massivt arbete för att syntetiskt producera paclitaxel. Framställning via totalsyntes av den komplexa molekylen är både komplicerat och dyrt, men behovet kunde tillfredsställas... (More)
Popular Abstract in Swedish

Många av de föreningar som utvecklas i den farmaceutiska industrin idag har sina rötter i naturprodukter. Paclitaxel, den aktiva substansen i läkemedlet Taxol, återfinns bland annat i idegranens bark. Detta upptäcktes i början av 1960-talet då ett nationellt sökprogram för att finna nya naturprodukter för användning mot cancer organiserades i Amerika. Den låga halten av paclitaxel i barken och faktumet att trädet dör utan sin bark, i samband med positiva rapporter om dess effekt på olika typer av tumörer, ledde till ett massivt arbete för att syntetiskt producera paclitaxel. Framställning via totalsyntes av den komplexa molekylen är både komplicerat och dyrt, men behovet kunde tillfredsställas via en semisyntetisk väg från en närbesläktad förening som isolerades från idegranens barr. Idag framställs paclitaxel via växtcellsodlingar och används i behandling mot en rad olika cancertyper. Dock är dess användbarhet begränsad på grund av svåra bieffekter, låg vattenlöslighet och resistens.



Det huvudsakliga syftet med arbetet som beskrivs i denna avhandling var att syntetisera paclitaxelmimetikor, samt att testa dessa för biologisk aktivitet. Syntes av paclitaxelmimietika, det vill säga derivat av paclitaxel som visar samma typ av biologisk aktivitet, är viktigt av flera anledningar. Framförallt vill man åstadkomma en struktur som är lättare att syntetisera, som har bibehållen aktivitet och som ger färre bieffekter. Paclitaxels rigida skelett kunde tänkas ersättas med en förenklad tredimensionell struktur, i vilken det är viktigt att de farmakofora - de för aktiviteten viktiga - grupperna hamnar i samma positioner i rymden som i paclitaxel. Genom datorbaserade beräkningar drogs slutsatsen att en spiro-bicyklo[2.2.2]oktankärna skulle vara ett passande substitut. Det laborativa arbetet resulterade i en syntes av den bicykliska strukturen i racemisk form. Vidare modifierades denna syntes så att båda enantiomererna av bicyklostrukturen kunde framställas med hög optisk renhet. Avslutningsvis utvecklades även en metod för syntes av spirofunktionaliteten. För att åstadkomma en testbar paclitaxelmimetika krävs vidare funktionalisering av spiro-bicyklo[2.2.2]oktankärnan med paclitaxels nödvändiga farmakofora grupper. (Less)
Abstract
Many of the drugs that are developed in the pharmaceutical industry have their origin in natural products. Paclitaxel, the active substance of the medicine Taxol, was found in the bark of the Pacific yew tree (Taxus brevifolia). This was discovered in the early 1960's when a screening program was initiated by the National Cancer Institute (NCI) in the US, with the aim to find new natural products that could be of use in cancer treatment. The low yield of paclitaxel from the bark and the fact that the tree dies without its bark, together with the many positive reports on different types of tumors, lead to a massive effort to find new ways of producing paclitaxel. Production via total synthesis of this complex molecule is both complicated... (More)
Many of the drugs that are developed in the pharmaceutical industry have their origin in natural products. Paclitaxel, the active substance of the medicine Taxol, was found in the bark of the Pacific yew tree (Taxus brevifolia). This was discovered in the early 1960's when a screening program was initiated by the National Cancer Institute (NCI) in the US, with the aim to find new natural products that could be of use in cancer treatment. The low yield of paclitaxel from the bark and the fact that the tree dies without its bark, together with the many positive reports on different types of tumors, lead to a massive effort to find new ways of producing paclitaxel. Production via total synthesis of this complex molecule is both complicated and expensive. However, the need could be satisfied via a semi synthetic route starting from a closely related analogue, which can be isolated from the leaves of the European yew (Taxus baccata). Today, paclitaxel is produced by plant tissue cultures and is used in the treatment of a variety of cancers. However, its use is limited due to severe side effects, low water solubility and resistance.



The primary intention with the work presented in this thesis was to synthesize paclitaxel mimetics and to test them for biological activity. Paclitaxel mimetics can be described as synthetic, structurally simplified compounds which share paclitaxel's mechanism of action and that ideally show the same or improved activity. Compounds of this kind might become valuable tools for further investigations aimed at addressing the various concerns of paclitaxel. For the design of our paclitaxel mimetic, we searched for simple rigid skeletons that could replace paclitaxel's complex core structure. The geometry of the new structure had to be such, that when decorated with the pharmacophores (structural parts that are of importance for activity) of paclitaxel, they should have proper spatial arrangements. By molecular modelling we identified a spiro-bicyclo[2.2.2]octane framework to be a suitable core structure. In the course of our study, we successfully developed a synthesis of novel racemic bridgehead hydroxyl bicyclo[2.2.2]octane derivatives. This methodology was subsequently modified so as to allow the synthesis of both enantiomers of the bicyclic structures in high enantiomeric excess. In addition, a methodology for the spiro-annulation was developed. Functionalisation of the spiro-bicyclic core structure with the necessary paclitaxel pharmacophores, in order to obtain a testable mimetic, still remains to be completed. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Somfai, Peter, Organic Chemistry, Teknikringen 30, S-100 44 Stockholm, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Kemi, Organic chemistry, Organisk kemi, Chemistry, Natural science, paclitaxel, spiro, indium, Naturvetenskap, bicyclo[2.2.2]octane, allylation, paclitaxel mimetic
pages
85 pages
publisher
Organic Chemistry, Lund University
defense location
Kemicentrum Getingevägen 60 221 00 Lund
defense date
2006-06-09 10:30
ISBN
91-7422-117-5
language
English
LU publication?
yes
id
35b5b70f-3585-445a-b50a-05c3e2588a53 (old id 546908)
date added to LUP
2007-10-13 11:36:31
date last changed
2016-09-19 08:45:09
@phdthesis{35b5b70f-3585-445a-b50a-05c3e2588a53,
  abstract     = {Many of the drugs that are developed in the pharmaceutical industry have their origin in natural products. Paclitaxel, the active substance of the medicine Taxol, was found in the bark of the Pacific yew tree (Taxus brevifolia). This was discovered in the early 1960's when a screening program was initiated by the National Cancer Institute (NCI) in the US, with the aim to find new natural products that could be of use in cancer treatment. The low yield of paclitaxel from the bark and the fact that the tree dies without its bark, together with the many positive reports on different types of tumors, lead to a massive effort to find new ways of producing paclitaxel. Production via total synthesis of this complex molecule is both complicated and expensive. However, the need could be satisfied via a semi synthetic route starting from a closely related analogue, which can be isolated from the leaves of the European yew (Taxus baccata). Today, paclitaxel is produced by plant tissue cultures and is used in the treatment of a variety of cancers. However, its use is limited due to severe side effects, low water solubility and resistance.<br/><br>
<br/><br>
The primary intention with the work presented in this thesis was to synthesize paclitaxel mimetics and to test them for biological activity. Paclitaxel mimetics can be described as synthetic, structurally simplified compounds which share paclitaxel's mechanism of action and that ideally show the same or improved activity. Compounds of this kind might become valuable tools for further investigations aimed at addressing the various concerns of paclitaxel. For the design of our paclitaxel mimetic, we searched for simple rigid skeletons that could replace paclitaxel's complex core structure. The geometry of the new structure had to be such, that when decorated with the pharmacophores (structural parts that are of importance for activity) of paclitaxel, they should have proper spatial arrangements. By molecular modelling we identified a spiro-bicyclo[2.2.2]octane framework to be a suitable core structure. In the course of our study, we successfully developed a synthesis of novel racemic bridgehead hydroxyl bicyclo[2.2.2]octane derivatives. This methodology was subsequently modified so as to allow the synthesis of both enantiomers of the bicyclic structures in high enantiomeric excess. In addition, a methodology for the spiro-annulation was developed. Functionalisation of the spiro-bicyclic core structure with the necessary paclitaxel pharmacophores, in order to obtain a testable mimetic, still remains to be completed.},
  author       = {Thornqvist, Viveca},
  isbn         = {91-7422-117-5},
  keyword      = {Kemi,Organic chemistry,Organisk kemi,Chemistry,Natural science,paclitaxel,spiro,indium,Naturvetenskap,bicyclo[2.2.2]octane,allylation,paclitaxel mimetic},
  language     = {eng},
  pages        = {85},
  publisher    = {Organic Chemistry, Lund University},
  school       = {Lund University},
  title        = {Synthesis of Spiro-bicyclo[2.2.2]Octane Derivatives Towards the Development of Paclitaxel Mimetics},
  year         = {2006},
}