| 1. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 2. |
- Carlström, Karl E., et al.
(författare)
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Characterization of More Selective Central Nervous System Nrf2-Activating Novel Vinyl Sulfoximine Compounds Compared to Dimethyl Fumarate
- 2020
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Ingår i: NEUROTHERAPEUTICS. - : SPRINGER. - 1933-7213 .- 1878-7479. ; 17, s. 1142-1152
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Tidskriftsartikel (refereegranskat)abstract
- The Nrf2 transcription factor is a key regulator of redox reactions and considered the main target for the multiple sclerosis (MS) drug dimethyl fumarate (DMF). However, exploration of additional Nrf2-activating compounds is motivated, since DMF displays significant off-target effects and has a relatively poor penetrance to the central nervous system (CNS). We de novo synthesized eight vinyl sulfone and sulfoximine compounds (CH-1-CH-8) and evaluated their capacity to activate the transcription factors Nrf2, NF kappa B, and HIF1 in comparison with DMF using the pTRAF platform. The novel sulfoximine CH-3 was the most promising candidate and selected for further comparison in vivo and later an experimental model for traumatic brain injury (TBI). CH-3 and DMF displayed comparable capacity to activate Nrf2 and downstream transcripts in vitro, but with less off-target effects on HIF1 from CH-3. This was verified in cultured microglia and oligodendrocytes (OLs) and subsequently in vivo in rats. Following TBI, DMF lowered the number of leukocytes in blood and also decreased axonal degeneration. CH-3 preserved or increased the number of pre-myelinating OL. While both CH-3 and DMF activated Nrf2, CH-3 showed less off-target effects and displayed more selective OL associated effects. Further studies with Nrf2-acting compounds are promising candidates to explore potential myelin protective or regenerative effects in demyelinating disorders.
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| 3. |
- Chinthakindi, Praveen K., et al.
(författare)
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Solid Phase Synthesis of Sulfonimidamide Pseudopeptides and Library Generation
- 2020
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Ingår i: European Journal of Organic Chemistry. - : Wiley-VCH Verlagsgesellschaft. - 1434-193X .- 1099-0690. ; 2020:25, s. 3796-3807
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Tidskriftsartikel (refereegranskat)abstract
- Many synthetic routes have been explored to make small molecule sulfonimidamides (SIAs), however, its introduction into larger molecules such as oligopeptides has not been studied before. We herein demonstrate three alternative and complementary methods for synthesis of SIA based pseudopeptides, on solid phase, using both on and off‐resin SIA‐synthesis, via sulfonimidoyl chlorides from sulfonamides, in high conversion. Beside evaluation of various resins such as 2‐CTC, Wang, and Rink amide‐ChemMatrix, the possibilities to further N‐functionalize and cyclize the SIA functionality on solid support are shown. The diastereomers of SIA containing pseudopeptides could in most cases be separated using normal reverse phase preparative HPLC. The solid phase SIA methodology has many advantages when it comes to handling and purification as compared to in solution, and will therefore enable exploration of the SIA group as isosteric substitutions and peptidomimetic building blocks in the development of drug‐like pseudopeptides in many ways. Of particular note these approaches facilitate combinatorial library synthesis as demonstrated herein.
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| 4. |
- Proietti, Giampiero
(författare)
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Organic Azides : Functional Molecules and Materials
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The work presented in this thesis stems from the chemistry of the azido group, and more specifically from the unique reactivity of perfluorinated aromatic azides and how to use this reactivity to access new types of molecules to enable new applications in asymmetric synthesis and materials.In the first section of this thesis, a photoactivatable fluorescence probe is presented, where the non-luminescent azide was activated via a UV-light-promoted intramolecular N–H insertion reaction forming a fluorescence emitter. Furthermore, ciprofloxacin was reacted with perfluorinated aromatic azide (PFAA) and phenylacetaldehyde, to form a drug derivative with a propeller-shaped architecture. The drug derivatization enabled the self-aggregation of the molecules into nanoparticles and the consequent aggregation-induced fluorescence emission (AIE). The second section of the thesis focuses on the development of a reaction between the photogenerated perfluorinated phenylnitrene and sulfoxides or sulfinamides to obtain sulfoximines and sulfonimidamides. One of these compounds, an enantiopure sulfonimidamide with an unprotected amino group, was employed as a novel chiral auxiliary for the synthesis of an enantioenriched amine via addition of Grignard reagents to the formed imines. In addition to the use as chiral auxiliary, the same sulfonimidamide containing a pyridine group was studied as an organogelator. The supramolecular aggregation led to the formation of the gel, which showed a microscopic chirality controlled by the stereocenter of the sulfur atom in the low-molecular weight gelator molecule. The last section illustrates a general method for the reduction of aromatic and aliphatic azides. The reduction is catalyzed by a nickel boride (Ni-B) catalyst that is prepared in situ from a Ni(II) salt and sodium borohydride in methanol allowing catalyst loading as low as 0.5 mol%. Moreover, bacterial nanocellulose (BNC) was used as solid support for the Ni-B catalyst enabling easy recovery of the catalyst and recyclability.
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