Synthesis of novel Tetrahydroisoquinoline-related estrogen receptor modulators

Mabank, Tanya (2019-02)

Thesis (PhD)--Stellenbosch University, 2019.

Thesis

ENGLISH ABSTRACT: The tetrahydroisoquinoline (THIQ) core has displayed a rich history as a biologically active natural product and is an interesting scaffold to use in drug discovery. Its structural skeleton is present in a number of structurally diverse natural products exhibiting a wide range of biological, pharmaceutical and estrogen receptor (ER) activities.1-5 Estrogen is a steroid hormone which influences the functioning of many target tissues. However, the normal existence of estradiol in women affected with breast cancer may worsen the infection; and a deficiency may increase the risk of various hormone related diseases. Estradiol is the natural ligand responsible for modulating the expression and/or repression of specific estrogen gene transcriptions.6,7 In this project, we therefore considered the synthesis of four small sets of THIQ-based compounds with the potential ability to bind the ER with affinities competing with that of estradiol. The THIQ compounds generated included structures with or without linker groups, and a lactam core without a linker group. The compounds were structurally designed by making use of Schrodinger and Acclerys Discovery Studio software, to accommodate the receptors binding pocket and improve the potency and selectivity toward the ERβ. With the successful synthesis of the THIQ compounds generated, which included structures with or without linker groups, and a lactam core without a linker group, further biochemical studies were explored. During the synthesis of these final compounds, it was found that once demethylated, the final compounds showed some degree of decomposition and sedimentation upon preparation for bioevaluations. Whole cell testing however, only revealed that only one compound showed potential activity, with the rest showing quite poor activity. In terms of the cell proliferation, this compound (65%) compared well to the medicinal agent, Fulvestrant, which slowed growth to 63.5%.

AFRIKAANSE OPSOMMING: Die tetrahidroisokinolien (THIQ) kern het ‘n ryk geskiedenis as dit kom by natuurlike aktiewe tetrahidroisokinoliene en is ‘n struktuur wat dikwels gebruik word gedurende die ondekking van nuwe medisinale middels. Die struktuur kom in baie verskillinde natuurlike produkte voor en het biologiese, farmaseutiese en estrogeen reseptor (ER) aktiewiteite.1-5 Baie organe word beïnvloed deur die funksionering van die steroïde hormoon estrogeen. In vrouens wat aan borskanker ly kan estrogeen 'n nadelige uitwerking hê, hoewel te min estrogeen tot ander hormoonverwante siektes kan ly. Estradiool is die natuurlikethe bindingsmiddel wat verantwoordelik is vir die modulering van en/of die onderdrukking van spesifieke estrogeen gene transkripsies.6,7 In hierdie projek stel ons die sintese van vier stelsels voor wat die THIQ kern bevat. Die molekules het die potensiaal om in die binding met die ER, met estradiol te kompeteer. Die molekules wat gesintiseer is, het die volgende algemene strukture wat op trifluorometielsulfoniel THIQ – gebaseerd is: THIQ met bindings groepe, geen bindings groep en die laktam kern sonder die bindings groep. Die molekules was ontwerp deur gebruik te maak van die Schrodinger en Acclerys Discovery Studio sagteware, om sodoende interaksies met die ERβ, en dus selektiwiteit, te verbeter. Met die suksesvole sintese van die molekules, dws trifluorometielsulfoniel THIQ – gebaseerd, met bindings groepe, geen bindings groep en die laktam kern sonder die bindings groep, is verder biochemiese toetse gedoen. Gedeurende die sintese van hierdie finale molekules is dit bevind dat die demetieleerde weergawes degradasie en sedementasie ondergaan gedurende voorbereiding vir bio-evaluasie. Biochemiese en heel sel toetse het gewys dat van die molekules potensieel aktief is, terwyl die meeste minder aktief was. Een van die molekules het ‘n sel groei persentasie waarde van 65.0% getoon, teenoor die wel bekende Fulvestrant wat die groei tot 63.5% vertraag het.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/105676
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