Publikation
Bini Araba, A.; Ur Rehman, N.; Al-Araimi, A.; Al-Hashmi, S.; Al-Shidhani, S.; Csuk, R.; Hussain, H.; Al-Harrasi, A.; Zadjali, F.; New derivatives of 11-keto-β-boswellic acid (KBA) induce apoptosis in breast and prostate cancers cells Nat. Prod. Res. 35, 707-716, (2021) DOI: 10.1080/14786419.2019.1593165
A series of new 11-keto-β-boswellic acid were partially-synthesized by modifying the hydroxyl and carboxylic acid functional groups of ring A. The structures of the new analogs were confirmed by detailed spectral data analysis. Compounds 4, 5 and 9 exhibited potent anti-cancer results against two human tumor cancer cell lines having IC50 value of MCF-7 (breast) and LNCaP (prostate): 123.6, 9.6 and 88.94 μM and 9.6, 44.12 and 12.03 μM, respectively. Additionally, a maximum nuclear fragmentation was observed for 4 (78.44%) in AKBA treated cells after 24 hr followed by 5 and 9 with (74.25 and 66.9% respectively). This study suggests that the presence of hydrazone functionality (4 and 9) has effectively improved the potency of AKBA. Interestingly, compound 5 with a lost carboxylic acid group of ring A showed comparable potent activity. Highly selective AKBA requires further modification to improve its bioavailability and solubility inside the cancer cells.
Publikation
Hussain, H.; Ali, I.; Wang, D.; Mamadalieva, N. Z.; Hussain, W.; Csuk, R.; Loesche, A.; Fischer, L.; Staerk, D.; Anam, S.; AlZain, M. N.; Mushtaq, M.; Ul-Haq, Z.; Ullah, R.; Noman, O. M.; Abbas, G.; Green, I. R.; 4-Benzyloxylonchocarpin and Muracatanes A-C from Ranunculus muricatus L. and Their Biological Effects Biomolecules 10, 1562, (2020) DOI: 10.3390/biom10111562
Ranunculus muricatus L. is a spiny fruit buttercup that is used in various traditional medicinal systems. In the current investigation of R. muricatus, the new chalcone 4-benzyloxylonchocarpin (1), the new anthraquinone muracatanes A (2), the new-to-nature anthraquinone muracatanes B (3), and the new naphthalene analog muracatanes C (4) were isolated, in addition to the three previously reported compounds, 4-methoxylonchocarpin (5), β-sitosterol (6), and β-sitosterol β-D-glucopyranoside (7). Their structures were elucidated using 1D (1H and 13C) and 2D (COSY, HSQC, and HMBC) NMR spectroscopy and HR-ESI-MS. Chalcone 1 showed potent acetylcholinesterase inhibitory effects with Ki of 5.39 µM and Ki′ of 3.54 µM, but none of the isolated compounds showed inhibitory activity towards butyrylcholinesterase. Anthraquinone 3 illustrated α-glucosidase inhibitory effects with IC50-values of 164.46 ± 83.04 µM. Compound 5 displayed moderate cytotoxic activity towards ovarian carcinoma (A2780, IC50 = 25.4 µM), colorectal adenocarcinoma (HT29, IC50 = 20.2 µM), breast cancer (MCF7, IC50 = 23.7 µM), and thyroid carcinoma (SW1736, IC50 = 26.2 µM) while it was inactive towards pharynx carcinoma (FaDu: IC50 > 30 µM).
Publikation
Shamraiz, U.; Hussain, H.; Ur Rehman, N.; Al-Shidhani, S.; Saeed, A.; Khan, H. Y.; Khan, A.; Fischer, L.; Csuk, R.; Badshah, A.; Al-Rawahi, A.; Hussain, J.; Al-Harrasi, A.; Synthesis of new boswellic acid derivatives as potential antiproliferative agents Nat. Prod. Res. 34, 1845-1852, (2020) DOI: 10.1080/14786419.2018.1564295
In the current investigation, a series of heterocyclic derivatives of boswellic acids were prepared along with new monomers of 3-O-acetyl-11-keto-β-boswellic acid (AKBA, 1) 11-keto-β-boswellic acid (KBA, 2) and several new bis-AKBA and KBA homodimers and AKBA-KBA heterodimers. The effects of these compounds on the proliferation of different human cancer cell lines, viz., FaDu (pharynx carcinoma), A2780 (ovarian carcinoma), HT29 (colon adenocarcinoma), and A375 (malignant melanoma), have been evaluated. Thus, KBA homodimer 21 effectively inhibited the growth of FaDu, A2780, HT29, and A375 cells with EC50 values below 9 μM. In addition, compounds 7, 8, 11, 12, 15, 16, and 17 also exhibited cytotoxic effects for A2780, HT29, and A375 cancer cells. In particular, the pyrazine analog 8 was highly cytotoxic for A375 cancer cells with an EC50 value of 2.1 μM.
Bücher und Buchkapitel
Deising, H. B.; Amorim, R.; De Oliveira Silva, A.; Raschke, A.; Eisermann, I.; Wirsel, S. G. R.; Csuk, R.; Schmitz, L. M.; Arnold, N.; Antagonistic Microorganisms in Plant Protection: Consumers’ Friends or Foes? (Deising, H. B. et al., eds.). Modern Fungicides and Antifungal Compounds IX, 217-228, (2020)
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Publikation
Loesche, A.; Kahnt, M.; Serbian, I.; Brandt, W.; Csuk, R.; Triterpene-Based Carboxamides Act as Good Inhibitors of Butyrylcholinesterase Molecules 24, 948, (2019) DOI: 10.3390/molecules24050948
A set of overall 40 carboxamides was prepared from five different natural occurring triterpenoids including oleanolic, ursolic, maslinic, betulinic, and platanic acid. All of which were derived from ethylene diamine holding an additional substituent connected to the ethylene diamine group. These derivatives were evaluated regarding their inhibitory activity of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) employing Ellman’s assay. We further determined the type of inhibition and inhibition constants. Carboxamides derived from platanic acid have been shown to be potent and selective BChE inhibitors. Especially the mixed-type inhibitor (3β)-N-(2-pyrrolidin-1-ylethyl)-3-acetyloxy-20-oxo-30-norlupan-28-amide (35) showed a remarkably low Ki of 0.07 ± 0.01 µM (Ki′ = 2.38 ± 0.48 µM) for the inhibition of BChE.
Publikation
Loesche, A.; Wiemann, J.; Rohmer, M.; Brandt, W.; Csuk, R.; Novel 12-hydroxydehydroabietylamine derivatives act as potent and selective butyrylcholinesterase inhibitors Bioorg. Chem. 90, 103092, (2019) DOI: 10.1016/j.bioorg.2019.103092
The skeleton of the diterpene dehydroabietylamine was modified, and a set of 12-hydroxy-dehydroabietylamine derivatives was obtained. The compounds were screened in colorimetric Ellman’s assays to determine their ability to act as inhibitors for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum). Additional investigations concerning the enzyme kinetics were performed and showed 12-hydroxy-N-(4-nitro-benzoyl)dehydroabietylamine (13) and 12-hydroxy-N-(isonicotinoyl)dehydroabietylamine (17) as selective BChE inhibitors holding good inhibition constants Ki = 0.72 ± 0.06 μM and Ki = 0.86 ± 0.19 μM, respectively.
Publikation
Hussain, H.; Csuk, R.; Green, I. R.; Ur Rehman, N.; Abbas, G.; Hussain, W.; Journey Describing the Cytotoxic Potential of Withanolides: A Patent Review Recent Pat. Anti-Canc. Drug Discov. 13, 411-421, (2018) DOI: 10.2174/1574892813666180808154928
Withanolides are C-28 ergostane steroids known to demonstrate some very interesting therapeutic properties. Numerous withanolides have been isolated from a variety of different plant species and can be employed to treat various types of cancers. Withanolides are indeed capable of demonstrating excellent anticancer, anti-inflammatory, and neuroprotective activities. Additionally, libraries of prepared withaferin A analogs incorporating an acyl, sulphate, amide and aldehyde functionality have demonstrated the most potential response. It is of particular interest to note that an acetyl group at either C-4, C-19 or C-27 enhances the anticancer effects. Since the majority of natural withanolides reported in patents are classified as “Type-A”, it is our opinion that there should now be a focus on developing “Type-B” withanolides and an investigation into their various therapeutic applications. Moreover, very little real innovation in synthetic methodologies has been reported which opens up huge possibilities for novel synthetic methodologies to be developed for the production of larger libraries new withanolides and their analogs to incorporate chemical diversity. In addition, since withanolides have the capability to conjugate with other anticancer compounds, this should encourage scientists to prepare lead compounds in cancer drug discovery.
Publikation
Wiemann, J.; Karasch, J.; Loesche, A.; Heller, L.; Brandt, W.; Csuk, R.; Piperlongumine B and analogs are promising and selective inhibitors for acetylcholinesterase Eur. J. Med. Chem. 139, 222-231, (2017) DOI: 10.1016/j.ejmech.2017.07.081
Piperlongumine B (19), an alkaloid previously isolated from long pepper (Piper longum) has been synthesized for the first time in a short sequence and in good yield together with 19 analogs. Screening of these compounds in Ellman's assays showed several of them to be good inhibitors of acetylcholinesterase while being less active for butyrylcholinesterase. Activity of the compounds increased with the ring size of the heterocycle, and a maximum of activity was observed for an analog holding 12 methylene groups in the aliphatic side chain. These compounds may be regarded as promising candidates for the development of efficient inhibitors of acetylcholinesterase being useful for the treatment of Alzheimer's disease.
Publikation
Heller, L.; Kahnt, M.; Loesche, A.; Grabandt, P.; Schwarz, S.; Brandt, W.; Csuk, R.; Amino derivatives of platanic acid act as selective and potent inhibitors of butyrylcholinesterase Eur. J. Med. Chem. 126, 652-668, (2017) DOI: 10.1016/j.ejmech.2016.11.056
A set of thirtyfive 30-norlupan derivatives (2–36) was prepared from the natural triterpenoid platanic acid (PA), and the hydroxyl group at C-3, the carboxyl group at C-17 and the carbonyl group at C-20 were modified. These derivatives were tested for their inhibitory activity for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum) using Ellman's assay. Extra enzyme kinetic studies were performed. The most active compound was (3β, 20R)-3-acetyloxy-20-amino-30-norlupan-28-oate (32) showing a Ki value of 0.01 ± 0.003 μM for BChE. This compound proved to be a selective (FB = 851), mixed-type inhibitor for BChE.
Publikation
Loesche, A.; Wiese, J.; Sommerwerk, S.; Simon, V.; Brandt, W.; Csuk, R.; Repurposing N,N'-bis-(arylamidino)-1,4-piperazinedicarboxamidines: An unexpected class of potent inhibitors of cholinesterases Eur. J. Med. Chem. 125, 430-434, (2017) DOI: 10.1016/j.ejmech.2016.09.051
Drug repurposing (=drug repositioning) is an effective way to cut costs for the development of new therapeutics and to reduce the time-to-market time-span. Following this concept a small library of compounds was screened for their ability to act as inhibitors of acetyl- and butyrylcholinesterase. Picloxydine, an established antiseptic, was shown to be an inhibitor for both enzymes. Systematic variation of the aryl substituents led to analogs possessing almost the same good properties as gold standard galantamine hydrobromide.
