pyrroQuin · Synthesis and Biological Evaluation of Pyrroquinoline Pseudo-Natural Products
„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“
- Период
- 2020-01-01 → 2021-12-31
- Финансиране от ЕС
- 162 806 €
- Участници
- 1
- Схема
- MSCA-IF
Линиите свързват координатора с партньорите.
Накратко на български
Пирохинолините са нови синтетични молекули, създадени чрез комбиниране на фрагменти от природни вещества по начин, който не се среща в природата. Те помагат за откриването на нови лекарствени кандидати чрез проследяване на промените в облика на клетките.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Synthesis and Biological Evaluation of Pyrroquinoline Pseudo-Natural Products
Natural products (NPs) and their structural scaffolds are a rich source of small molecule tools for chemical biology and drug candidates due to their inherent activity exploited by nature.[1] In the past, natural product scaffolds were modified through chemical synthesis or simplified for the discovery of novel biologically active molecules.[2] In a new approach, natural product fragments[3] are combined in a biosynthetically unrelated manner to afford novel chemotypes with unknown biological activity. These compounds are termed pseudo natural products (pseudo NPs)[4], and a proof of concept has been established by the Waldmann group in several examples.[2] The biological activities of the obtained compounds were completely unrelated to the natural products the fragments were sourced from. The purpose of this project was to explore the synthesis of members of the novel pseudo NP class pyrroquinoline (PQ) and investigating their biological activity with a target agnostic morphological profiling method called “cell painting”. PQs are a combination of tetrahydroquinoline and pyrrolidine fragments in manners not observed through biosynthesis. For this proposal, two scaffolds were designed where the fragments are combined to an edge-on fused as well as a bridged scaffold. Through the use of cell painting we are able to stream line the biological characterisation of the compounds without using a large number of primary assays. The morphological changes observed in cells upon compound treatment can give us direct indications on the involved cellular targets. References [1] G. M. Cragg, D. J. Newman, Biochim Biophys Acta 2013, 1830, 3670-3695. [2] a) G. Karageorgis, H. Waldmann, Synthesis 2018, 51, 55-66; b) G. S. Cremosnik, J. Liu, H. Waldmann, Nat Prod Rep 2020, 37, 1497-1510; c) M. Grigalunas, A. Burhop, A. Christoforow, H. Waldmann, Curr Opin Chem Biol 2020, 56, 111-118. [3] B. Over, S. Wetzel, C. Grutter, Y. Nakai, S. Renner, D. Rauh, H. Waldmann, Nat. Chem. 2013, 5, 21-28. [4] G. Karageorgis, D. J. Foley, L. Laraia, H. Waldmann, Nat. Chem. 2020, 12, 227-235.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Natural products (NPs) and their structural scaffolds are a rich source of small molecule tools for chemical biology and drug candidates. In a novel approach, this proposal will investigate the combination of natural product fragments to form pseudo-natural products (pseudo-NPs) with uncharted biological activity. The purpose of this project is to explore the diastereo- and enantioselective synthesis of two pyrroquinoline scaffolds, a combination of pyrrolidine and tetrahydroquinoline fragments, and submit the obtained compound collections (>100 compounds) to phenotypical screening assays to assess their biological activity. The obtained molecules could potentially serve as novel biological probes and lay the foundation for the discovery of novel targets or drugs. Highly active compounds will be used to establish structure activity relationships (SAR) and design affinity isolation probes for the identification of cellular targets.
Оригинален текст от CORDIS (на английски).
Участници
- MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV · MUNCHENКоординаторГермания
Връзки
Данни: CORDIS, © Европейски съюз