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Synthesis Towards Biologically Active Natural Products

Larsson, Rikard LU (2012)
Abstract (Swedish)
Popular Abstract in Swedish

Moder natur har i tusentals år varit en fantastisk källa till biologiskt aktiva substanser mänskligheten utnyttjat för att bota och förebygga sjukdomar. Från början användes olika beredningar och avkok från växter funna i närområdet som erfarenheten visat hade effekt mot åkomman man ville behandla. Detta har i modern tid utvecklats till att vi idag på ett systematiskt sätt undersöker naturen, tar reda på exakt vilken substans i det biologiska materialet som står för den biologiska aktiviteten och försöker sedan på syntetisk väg tillverka denna substans i laboratoriet. Med detta angreppssätt kan vi även, genom att studera de substanser vi hittar, förstå hur naturen bygger upp dessa fantastiska... (More)
Popular Abstract in Swedish

Moder natur har i tusentals år varit en fantastisk källa till biologiskt aktiva substanser mänskligheten utnyttjat för att bota och förebygga sjukdomar. Från början användes olika beredningar och avkok från växter funna i närområdet som erfarenheten visat hade effekt mot åkomman man ville behandla. Detta har i modern tid utvecklats till att vi idag på ett systematiskt sätt undersöker naturen, tar reda på exakt vilken substans i det biologiska materialet som står för den biologiska aktiviteten och försöker sedan på syntetisk väg tillverka denna substans i laboratoriet. Med detta angreppssätt kan vi även, genom att studera de substanser vi hittar, förstå hur naturen bygger upp dessa fantastiska substanser via allt mer komplicerade intermediärer samt även vidareutveckla de aktiva substanserna med avseende på potens och biverkningar.

Mitt bidrag till detta har varit att utveckla en syntesmetod, som bygger på ett förslag på hur naturen tillverkar dessa substanser, för att syntetisera de två naturprodukterna transtaganolide C och transtaganolide D. I denna process har jag syntetiserat de föreslagna biosyntetiska intermediärerna (även dessa naturprodukter funna i naturen), dock återstår det ett steg för att slutföra syntesen av transtaganolide C och D.

I avhandlingen har jag även studerat den, inom läkemedelskemin, viktiga substansklassen kallad tetrahydroisokinoliner, där jag utvecklat en metod för att introducera en grupp som kallas indol. Dessa substanser har utvärderats för deras inhiberande effekt på prostatacancer celler. (Less)
Abstract
In 2005 two research groups independently reported the isolation of a series of structurally intriguing C-19 terpenolides from the plants Thapsia transtagana and Thapsia garganica. The compounds were shown to be potent inhibitors of the sarco/endoplasmic reticulum Ca2+-ATPases. The interesting biological properties and the unique structural characteristics of the transtaganolides/basiliolides (the names transtaganolides/basiliolides were suggested in parallel in 2005) led to a great response from the synthetic community, with four groups presenting synthetic strategies towards this novel class of natural products.

Herein, an approach towards transtaganolides C and D, utilizing an Ireland-Claisen rearrangement/Diels-Alder... (More)
In 2005 two research groups independently reported the isolation of a series of structurally intriguing C-19 terpenolides from the plants Thapsia transtagana and Thapsia garganica. The compounds were shown to be potent inhibitors of the sarco/endoplasmic reticulum Ca2+-ATPases. The interesting biological properties and the unique structural characteristics of the transtaganolides/basiliolides (the names transtaganolides/basiliolides were suggested in parallel in 2005) led to a great response from the synthetic community, with four groups presenting synthetic strategies towards this novel class of natural products.

Herein, an approach towards transtaganolides C and D, utilizing an Ireland-Claisen rearrangement/Diels-Alder cycloaddition reaction sequence from an achiral 5-halo-activated prenylated pyran-2-one, is presented. In addition, the biomimetic total synthesis of transtaganolides E and F, synthesized via an Ireland-Claisen/high-pressure Diels-Alder reaction sequence from an unactivated geranylated pyran-2-one reported from T. transtagana, and efforts in transforming these into transtaganolides C and D are disclosed.

Furthermore, a protocol for the synthesis of C-1 indolyl substituted tetrahydroisoquinolines (THIQs) via the classical Pictet-Spengler reaction has been developed. This protocol has been used for the synthesis of several diketopiperazine fused C-1 indolyl substituted THIQs which have been assayed for their inhibitory activity on hormone-independent and metastatic PC-3 prostate cancer cell lines. The inhibitory effects of the assayed compounds were compared to that of etoposide and several of the assayed compounds showed comparable or even better inhibitory effect at higher concentrations. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Prof. Almqvist, Fredrik, Kemiska institutionen, Umeå universitet, Umeå, Sverige
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Transtaganolide, basiliolide, natural product, total synthesis, biomimetic, Thapsia, Diels-Alder, Ireland-Claisen, Pictet-Spengler, tetrahydroisoquinoline, indole
pages
97 pages
publisher
Department of Chemistry, Lund University
defense location
Hörsal C; Kemicentrum, Getingevägen 60, Lunds Tekniska Högskola
defense date
2012-05-31 09:30
ISBN
978-91-7422-300-2
language
English
LU publication?
yes
id
bbca82e2-b84f-40be-95d2-bb46d3378d71 (old id 2521087)
date added to LUP
2012-05-04 10:55:32
date last changed
2016-09-19 08:45:14
@misc{bbca82e2-b84f-40be-95d2-bb46d3378d71,
  abstract     = {In 2005 two research groups independently reported the isolation of a series of structurally intriguing C-19 terpenolides from the plants Thapsia transtagana and Thapsia garganica. The compounds were shown to be potent inhibitors of the sarco/endoplasmic reticulum Ca2+-ATPases. The interesting biological properties and the unique structural characteristics of the transtaganolides/basiliolides (the names transtaganolides/basiliolides were suggested in parallel in 2005) led to a great response from the synthetic community, with four groups presenting synthetic strategies towards this novel class of natural products. <br/><br>
Herein, an approach towards transtaganolides C and D, utilizing an Ireland-Claisen rearrangement/Diels-Alder cycloaddition reaction sequence from an achiral 5-halo-activated prenylated pyran-2-one, is presented. In addition, the biomimetic total synthesis of transtaganolides E and F, synthesized via an Ireland-Claisen/high-pressure Diels-Alder reaction sequence from an unactivated geranylated pyran-2-one reported from T. transtagana, and efforts in transforming these into transtaganolides C and D are disclosed. <br/><br>
Furthermore, a protocol for the synthesis of C-1 indolyl substituted tetrahydroisoquinolines (THIQs) via the classical Pictet-Spengler reaction has been developed. This protocol has been used for the synthesis of several diketopiperazine fused C-1 indolyl substituted THIQs which have been assayed for their inhibitory activity on hormone-independent and metastatic PC-3 prostate cancer cell lines. The inhibitory effects of the assayed compounds were compared to that of etoposide and several of the assayed compounds showed comparable or even better inhibitory effect at higher concentrations.},
  author       = {Larsson, Rikard},
  isbn         = {978-91-7422-300-2},
  keyword      = {Transtaganolide,basiliolide,natural product,total synthesis,biomimetic,Thapsia,Diels-Alder,Ireland-Claisen,Pictet-Spengler,tetrahydroisoquinoline,indole},
  language     = {eng},
  pages        = {97},
  publisher    = {ARRAY(0x77f3b58)},
  title        = {Synthesis Towards Biologically Active Natural Products},
  year         = {2012},
}