Synthesis, Reactivity and Biological Activity of 17β-HSD1 Inhibitors Based on a Thieno[2,3-d]pryrimidin-4(3H)-one Core

Breast cancer is the most common cancer in women in Western countries. In the early stages of development most breast cancers are hormone-dependent, and estrogens, especially estradiol, have a pivotal role in their development and progression. One approach to the treatment of hormone-dependent breast cancers is to block the formation of the active estrogens by inhibiting the action of the steroid metabolising enzymes. 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is a key enzyme in the biosynthesis of estradiol, the most potent female sex hormone. The 17beta-HSD1 enzyme catalyses the final step and converts estrone into the biologically active estradiol. Blocking 17beta-HSD1 activity with a specific enzyme inhibitor could provide a means to reduce circulating and tumour estradiol levels and thus promote tumour regression. In recent years 17beta-HSD1 has been recognised as an important drug target. Some inhibitors of 17beta-HSD1 have been reported, however, there are no inhibitors on the market nor have clinical trials been announced. The majority of known 17beta-HSD1 inhibitors are based on steroidal structures, while relatively little has been reported on non-steroidal inhibitors. As compared with 17beta-HSD1 inhibitors based on steroidal structures, non-steroidal compounds could have advantages of synthetic accessibility, drug-likeness, selectivity and non-estrogenicity. This study describes the synthesis of large group of novel 17beta-HSD1 inhibitors based on a non-steroidal thieno[2,3-d]pyrimidin-4(3H)-one core. An efficient synthesis route was developed for the lead compound and subsequently employed in the synthesis of thieno[2,3-d]pyrimidin-4(3H)-one based molecule library. The biological activities and binding of these inhibitors to 17beta-HSD1 and, finally, the quantitative structure activity relationship (QSAR) model are also reported. In this study, several potent and selective 17beta-HSD1 inhibitors without estrogenic activity were identified. This establishment of a novel class of inhibitors is a progressive achievement in 17beta-HSD1 inhibitor development. Furthermore, the 3D-QSAR model, constructed on the basis of this study, offers a powerful tool for future 17beta-HSD1 inhibitor development. As part of the fundamental science underpinning this research, the chemical reactivity of fused (di)cycloalkeno thieno[2,3-d]pyrimidin-4(3H)-ones with electrophilic reagents, i.e. Vilsmeier reagent and dimethylformamide dimethylacetal, was investigated. These findings resulted in a revision of the reaction mechanism of Vilsmeier haloformylation and further contributed to understanding the chemical reactivity of this compound class. This study revealed that the reactivity is dependent upon a stereoelectronic effect arising from different ring conformations.Rintasyöpä on länsimaissa yleisin naisilla esiintyvä syöpäsairaus. Alkuvaiheessa useimpien rintasyöpäkasvainten kehitys ja kasvu on riippuvainen steroidihormoneista, erityisesti voimakkaimmasta naissukupuolihormonista estradiolista. Yksi lähestymistapa hormoniriippuvaisen rintasyövän hoitoon on estää hormoneja valmistavien entsyymien toimintaa ns. entsyymi-inhibiittoreilla, jotka sitoutuvat entsyymeihin ja estävät niiden toiminnan. 17beta-HSD1-entsyymi katalysoi biologisesti aktiivisen estradiolin muodostumista. Useiden rintasyöpäsolulinjojen on havaittu sisältävän 17beta-HSD1-entsyymiä ja syöpäkasvainten pystyvän näin tuottamaan tarvitsemaansa hormonia. 17beta-HSD1-entsyymin toiminnan estämisellä voidaan rajoittaa estradiolin muodostumista ja näin mahdollisesti rajoittaa rintasyöpäkasvainten kasvua. 17beta-HSD1 on tunnistettu lupaavaksi kohteeksi lääkekehitykselle, mutta toistaiseksi lääkkeeksi sopivaa inhibiittoria ei ole löydetty. Väitöstutkimuksessa tunnistettiin uusi yhdisteryhmä, joka pystyy tehokkaasti estämään 17beta-HSD1-entsyymin toimintaa. Uudet inhibiittorimolekyylit pohjautuvat heterosykliseen tienopyrimidoni-runkoon ja niiden valmistukselle kehitettiin menetelmä. Tutkimuksen aikana valmistettiin noin 100 erilaista tienopyrimidoni-runkoista molekyyliä. Tutkimuksessa selvitettiin myös eräiden tienopyrimidoni-yhdisteiden rakennetta ja kemiallista reaktiivisuutta, sekä tutkittiin Vilsmeier-haloformylaation reaktiomekanismia. Tutkimuksessa valmistettujen yhdisteiden perusteella kehitettiin myös 3D-QSAR malli, jonka avulla pystytään virtuaalisesti ennustamaan molekyylien kykyä estää 17beta-HSD1-entsyymin toimintaa. Mallia voidaan lisäksi tulevaisuudessa käyttää apuna uusien 17beta-HSD1-inhibiittorien suunnittelussa

Approved and investigational fluorescent optical imaging agents for disease detection in surgery

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