Synthesis of small molecule bioactive compounds with potential anti–cancer activity

Date
2020-03
Journal Title
Journal ISSN
Volume Title
Publisher
Stellenbosch : Stellenbosch University
Abstract
ENGLISH ABSTRACT: Cancer is a major burden on human health and infrastructure as a leading cause of death worldwide. A collective name for a group of diseases characterised by uncontrolled cellular growth; cancer can be caused by a variety of factors including genetic factors and lifestyle choices. The approach to managing these diseases can be summarised into two broad categories, prevention and treatment. The pool of natural products (broadly chemicals derived from natural sources) has long been drawn upon for healing effect and a starting point for the development of pharmaceuticals. Humans have passed down knowledge of the healing properties of certain species plants, for example, for many generations. The paths to maximise the positive effect natural products have to offer against cancer, within the context of the studies herein, are twofold. Achieving a biological understanding of how these products gain their effect paving the way for new treatments and preventions to be developed; and improving access to, and quality of, the active compounds we have at our disposal already. This study is composed of three parts. Firstly, an investigation into the nutraceutical compounds of Flavokawain A and Fisetin, naturally occurring in the Kava plant of Fijian origin and strawberries respectively. These agents display prophylactic properties, and are proposed to reduce the occurrence of certain cancers in the populations that consume the plants these compounds occur in. The mechanism by which these compounds achieve their properties is not well understood. Fluorescent analogues of these compounds were achieved synthetically and imaged via confocal microscopy. Both compounds were found to collect in the endoplasmic reticulum of A549 lung cancer cells as well as displaying low micromolar toxicities to these cells. The second study arose as a short-term collaboration with researchers from Leipzig University, Germany. The researchers have developed synthetic strategies useful for forming 1-4 dihydroquinoline-3 carboxylate derivatives enantioselectively. This scaffold is similar to those of 4–aza–podophyllotoxins, a synthetic analogue to the natural product podophyllotoxin. Previous research reveals that a single enantiomer is responsible for the low nanomolar efficiencies this compound class displays. Thus, our study attempted to achieve an enantioselective synthesis of 4–aza–podophyllotoxin and succeeded in achieving enantioenriched samples using binaphthol phosphoric acid catalysts. Lastly, an investigation into the synthesis of a modified lung cancer drug combatting resistant, mutant epidermal growth factor receptor (EGFR) lung cancer was attempted. Within the investigation a synthetic scaffold was achieved based on WZ 4002 – an irreversible inhibitor currently undergoing clinical trials for resistant lung cancers. EGFR mediated resistance rejects the covalent modifiers currently in use; within this study sulfonyl fluorides have been proposed as replacements. Demonstrated within the study is a viable copper mediated triazole formation strategy which tolerates the sulfonyl fluoride electrophile. The scaffold is primed to achieve a variety of triazole linked probes containing sulfonyl fluorides which we proposed to investigate the chemical space around the EGFR binding site to combat resistance.
AFRIKAANSE OPSOMMING: Kanker is een van die hoofoorsake van sterftes wêreldwyd en plaas ‘n groot las op menslike gesondheid en infrastruktuur. Kanker is ‘n versamelnaam vir ‘n groep siektes wat deur onbeheerde sellulêre groei gekenmerk word. Die siekte kan deur ‘n verskeidenheid faktore veroorsaak word, insluitend genetiese faktore en slegte leefstyl keuses. Die benadering en bestuur van die siekte kan in twee breë kategorieë vervat word: voorkoming en behandling. Die versameling natuurlike produkte (chemikalieë van natuurlike bronne) is al lank vir genesende effek gebruik en as 'n beginpunt vir die ontwikkeling van farmaseutiese produkte. Hierdie studie ondersoek die moonltikhede waaronder die positiewe effek van natuurlike produkte die grootste uitwerking op die behandeling van kanker het. Die studie is tweeledige en vestig ‘n begrip van die werking van hierdie natuurlike produkte wat kan lei tot nuwe behandelinge en voorkoming, asook die verbetering van kwaliteit en toegangklikheid tot die natuurlike verbindings wat ons reeds tot ons beskikking het. Hierdie studie bestaan uit drie afdelings. (This part does not make sense as the word tweeledig means in two parts and now they are saying it comprises of three parts.)Hierdie studie bestaan uit drie dele. Die eerste studie ondersoek die voedingsverbindings van Flavokawain A en Fisetin wat natuurlik in die Kava-plant, van Fidjiaanse oorsprong, en aarbeie voorkom. Hierdie middels het profilaktiese eienskappe en word voorgestel om die voorkoms van sekere kanker in die bevolkingsgroepe wat hierdie plante verteer, te verminder. Die meganisme waardeur hierdie verbindings hul eienskappe voortbring, word nie volkome verstaan nie. Fluoresserende analoë van hierdie verbindings is sinteties bewerkstellig en deur middel van konfokale mikroskopie ondersoek. Daar is gevind dat albei verbindings in die endoplasmiese retikulum van A549 longkankerselle versamel en lae mikromolêre toksisiteite vir die selle vertoon. Die tweede studie het ontstaan as 'n korttermyn samewerking met navorsers van die Leipzig Universiteit in Duitsland. Die navorsers het sintetiese strategieë ontwikkel wat nuttig is vir die vorming van 1-4 dihidrokinolien-3 karboksilaatderivate enantioselektief. Hierdie steierwerk is soortgelyk aan dié van 4-aza-podofilotoksiene, 'n sintetiese analoog aan die natuurlike produk podofillotoksien. Vorige navorsing toon aan dat 'n enkele enantiomeer verantwoordelik is vir die lae nanomolêre doeltreffendheid wat hierdie saamgestelde klas vertoon. Dus het ons studie gepoog om 'n enantioselektiewe sintese van 4-aza-podofilotoksien te bewerkstellig en het daarin geslaag om enantioen-verrykte monsters met behulp van binaftol-fosforsuurkatalisators te verkry. Laastens is 'n ondersoek na die sintese van 'n gemodifiseerde longkankermiddel gebruik om weerstandige, mutante epidermale groeifaktorreseptor (EGFR) longkanker te bestry. Binne die ondersoek is 'n sintetiese steierwerk op grond van WZ 4002 bewerkstellig - 'n onomkeerbare inhibeerder wat tans kliniese ondersoeke ondergaan vir die gebruik teen weerstandbiedende longkanker. EGFR-gemedieerde weerstand verwerp die kovalente wysigers wat tans in gebruik is; binne hierdie studie word sulfonielfluoriede as vervanging voorgestel. Die studie demonstreer die lewensvatbaarheid van koperbemiddelde triasoolvormingstrategie wat die sulfonielfluoried-elektrofiel verdra. Die steier word voorberei om 'n verskeidenheid triasoolgekoppelde probe wat sulfonielfluoriede bevat te bewerkstellig, wat ons voorgestel het om die chemiese ruimte rondom die EGFR-bindingsplek te ondersoek om weerstandigheid teen te staan.
Description
Thesis (MSc)--Stellenbosch University, 2020.
Keywords
Fluorescence, Fluorescent -- Tagging, Bromo-fisetin, Synthesis, 4-azapodophylotoxin, Chiral catalysis, Enantioselective catalysis, Kinase inhibitors, Sulfonefluorescein
Citation