| 1. |
- Apprato, Giulia, et al.
(författare)
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Exploring the chemical space of orally bioavailable PROTACs
- 2024
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Ingår i: Drug Discovery Today. - : Elsevier. - 1359-6446 .- 1878-5832. ; 29:4
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Forskningsöversikt (refereegranskat)abstract
- A principal challenge in the discovery of proteolysis targeting chimeras (PROTACs) as oral medications is their bioavailability. To facilitate drug design, it is therefore essential to identify the chemical space where orally bioavailable PROTACs are more likely to be situated. To this aim, we extracted structure-bioavailability insights from published data using traditional 2D descriptors, thereby shedding light on their potential and limitations as drug design tools. Subsequently, we describe cuttingedge experimental, computational and hybrid design strategies based on 3D descriptors, which show promise for enhancing the probability of discovering PROTACs with high oral bioavailability.
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| 2. |
- Atilaw, Yoseph, et al.
(författare)
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Prenylated Flavonoids from the Roots of Tephrosia rhodesica
- 2020
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Ingår i: Journal of Natural Products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 83:8, s. 2390-2398
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Tidskriftsartikel (refereegranskat)abstract
- Five new compounds-rhodimer (1), rhodiflavan A (2), rhodiflavan B (3), rhodiflavan C (4), and rhodacarpin (5)-along with 16 known secondary metabolites, were isolated from the CH2Cl2-CH3OH (1:1) extract of the roots of Tephrosia rhodesica. They were identified by NMR spectroscopic, mass spectrometric, X-ray crystallographic, and ECD spectroscopic analyses. The crude extract and the isolated compounds 2-5, 9, 15, and 21 showed activity (100% at 10 mu g and IC50 = 5-15 mu M) against the chloroquine-sensitive (3D7) strain of Plasmodium falciparum.
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| 3. |
- Atilaw, Yoseph, et al.
(författare)
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Solution Conformations Shed Light on PROTAC Cell Permeability
- 2021
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 12:1, s. 107-114
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Tidskriftsartikel (refereegranskat)abstract
- Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies of a VHL-based PROTAC (1), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that 1 populates elongated and polar conformations in solutions that mimic extra- and intracellular compartments. Conformations were folded and had a smaller polar surface area in chloroform, mimicking a cell membrane interior. Formation of intramolecular and nonclassical hydrogen bonds, π–π interactions, and shielding of amide groups from solvent all facilitate cell permeability by minimization of size and polarity. We conclude that molecular chameleonicity appears to be of major importance for 1 to enter into target cells.
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| 4. |
- Begnini, Fabio, et al.
(författare)
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Cell Permeability of Isomeric Macrocycles : Predictions and NMR Studies
- 2021
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 12:6, s. 983-990
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Tidskriftsartikel (refereegranskat)abstract
- Conformation-dependent 3D descriptors have been shown to provide better predictions of the physicochemical properties of macrocycles than 2D descriptors. However, the computational identification of relevant conformations for macrocycles is nontrivial. Herein, we report that the Caco- 2 cell permeability difference between a pair of diastereomeric macrocycles correlated with their solvent accessible 3D polar surface area and radius of gyration. The descriptors were calculated from the macrocycles’ solution- phase conformational ensembles and independently from ensembles obtained by conformational sampling. Calculation of the two descriptors for three other stereo- and regioisomeric macrocycles also allowed the correct ranking of their cell permeability. Methods for conformational sampling may thus allow ranking of passive permeability for moderatelyflexible macrocycles, thereby contributing to the prioritization of macro- cycles for synthesis in lead optimization.
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| 5. |
- Bogaerts, Jonathan, et al.
(författare)
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Employing complementary spectroscopies to study the conformations of an epimeric pair of side-chain stapled peptides in aqueous solution
- 2021
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Ingår i: RSC Advances. - : Royal Society of Chemistry. - 2046-2069. ; 11:7, s. 4200-4208
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the conformational preferences of free ligands in solution is often necessary to rationalize structure–activity relationships in drug discovery. Herein, we examine the conformational behavior of an epimeric pair of side-chain stapled peptides that inhibit the FAD dependent amine oxidase lysine specific demethylase 1 (LSD1). The peptides differ only at a single stereocenter, but display a major difference in binding affinity. Their Raman optical activity (ROA) spectra are most likely dominated by the C-terminus, obscuring the analysis of the epimeric macrocycle. By employing NMR spectroscopy, we show a difference in conformational behavior between the two compounds and that the LSD1 bound conformation of the most potent compound is present to a measurable extent in aqueous solution. In addition, we illustrate that Molecular Dynamics (MD) simulations produce ensembles that include the most important solution conformations, but that it remains problematic to identify relevant conformations with no a priori knowledge from the large conformational pool. Furthermore, this work highlights the importance of understanding the scope and limitations of the available techniques for conducting conformational analyses. It also emphasizes the importance of conformational selection of a flexible ligand in molecular recognition.
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| 6. |
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| 7. |
- Kalenga, Thobias M, et al.
(författare)
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Antibacterial and cytotoxic biflavonoids from the root bark of Ochna kirkii
- 2021
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Ingår i: Fitoterapia. - : Elsevier BV. - 1873-6971 .- 0367-326X. ; 151
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Tidskriftsartikel (refereegranskat)abstract
- The new isoflavonoid kirkinone A (1) and biflavonoid kirkinone B (2) along with six known compounds (3-8) were isolated from the methanolic extract of the root bark of Ochna kirkii. The compounds were identified by NMR spectroscopic and mass spectrometric analyses. Out of the eight isolated natural products, calodenin B (4) and lophirone A (6) showed significant antibacterial activity against the Gram-positive bacterium Bacillus subtilis with MIC values of 2.2 and 28μM, and cytotoxicity against the MCF-7 human breast cancer cell line with EC50 values of 219.3 and 19.2μM, respectively. The methanolic crude extract of the root bark exhibited cytotoxicity at EC50 8.4μg/mL. The isolated secondary metabolites and the crude extract were generally inactive against the Gram-negative Escherichia coli (MIC ≥400μg/mL). Isolation of biflavonoids and related secondary metabolites from O. kirkii demonstrates their chemotaxonomic significance to the genus Ochna and to other members of the family Ochnaceae.
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| 8. |
- Kalenga, Thobias M, et al.
(författare)
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Biflavanones, Chalconoids, and Flavonoid Analogues from the Stem Bark of Ochna holstii.
- 2021
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Ingår i: Journal of Natural Products. - : American Chemical Society (ACS). - 1520-6025 .- 0163-3864. ; 84:2, s. 364-372
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Tidskriftsartikel (refereegranskat)abstract
- Two new biflavanones (1 and 2), three new bichalconoids (3-5), and 11 known flavonoid analogues (6-16) were isolated from the stem bark extract (CH3OH-CH2Cl2, 7:3, v/v) of Ochna holstii. The structures of the isolated metabolites were elucidated by NMR spectroscopic and mass spectrometric analyses. The crude extract and the isolated metabolites were evaluated for antibacterial activity against Bacillus subtilis (Gram-positive) and Escherichia coli (Gram-negative) as well as for cytotoxicity against the MCF-7 human breast cancer cell line. The crude extract and holstiinone A (1) exhibited moderate antibacterial activity against B. subtilis with MIC values of 9.1 μg/mL and 14 μM, respectively. The crude extract and lophirone F (14) showed cytotoxicity against MCF-7 with EC50 values of 11 μg/mL and 24 μM, respectively. The other isolated metabolites showed no significant antibacterial activities (MIC > 250 μM) and cytotoxicities (EC50 ≥ 350 μM).
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| 9. |
- Kalenga, T. M., et al.
(författare)
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Modified ent-Abietane Diterpenoids from the Leaves of Suregada zanzibariensis
- 2022
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Ingår i: Journal of Natural Products. - : American Chemical Society (ACS). - 0163-3864 .- 1520-6025. ; 85:9, s. 2135-2141
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Tidskriftsartikel (refereegranskat)abstract
- The leaf extract of Suregada zanzibariensis gave two new modified ent-abietane diterpenoids, zanzibariolides A (1) and B (2), and two known triterpenoids, simiarenol (3) and fi-amyrin (4). The structures of the isolated compounds were elucidated based on NMR and MS data analysis. Single-crystal X-ray diffraction was used to establish the absolute configurations of compounds 1 and 2. The crude leaf extract inhibited the infectivity of herpes simplex virus 2 (HSV-2, IC50 11.5 mu g/mL) and showed toxicity on African green monkey kidney (GMK AH1) cells at CC50 52 mu g/ mL. The isolated compounds 1-3 showed no anti-HSV-2 activity and exhibited insignificant toxicity against GMK AH1 cells at >= 100 mu M.
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| 10. |
- Kiganda, Ivan, et al.
(författare)
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Antiviral Rotenoids and Isoflavones Isolated from Millettia oblata ssp. teitensis
- 2023
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Ingår i: Journal of Natural Products. - 0163-3864 .- 1520-6025. ; 87:4, s. 1003-1012
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Tidskriftsartikel (refereegranskat)abstract
- Three new (1-3) and six known rotenoids (5-10), along with three known isoflavones (11-13), were isolated from the leaves of Millettia oblata ssp. teitensis. A new glycosylated isoflavone (4), four known isoflavones (14-18), and one known chalcone (19) were isolated from the root wood extract of the same plant. The structures were elucidated by NMR and mass spectrometric analyses. The absolute configuration of the chiral compounds was established by a comparison of experimental ECD and VCD data with those calculated for the possible stereoisomers. This is the first report on the use of VCD to assign the absolute configuration of rotenoids. The crude leaves and root wood extracts displayed anti-RSV (human respiratory syncytial virus) activity with IC50 values of 0.7 and 3.4 μg/mL, respectively. Compounds 6, 8, 10, 11, and 14 showed anti-RSV activity with IC50 values of 0.4-10 μM, while compound 3 exhibited anti-HRV-2 (human rhinovirus 2) activity with an IC50 of 4.2 μM. Most of the compounds showed low cytotoxicity for laryngeal carcinoma (HEp-2) cells; however compounds 3, 11, and 14 exhibited low cytotoxicity also in primary lung fibroblasts. This is the first report on rotenoids showing antiviral activity against RSV and HRV viruses.
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