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Seixas, N.; Ravanello, B. B.; Morgan, I.; Kaluđerović, G. N.; Wessjohann, L. A. Chlorambucil Conjugated Ugi Dendrimers with PAMAM-NH2 Core and Evaluation of Their Anticancer Activity Pharmaceutics 11, 59, (2019) DOI: 10.3390/pharmaceutics11020059

Herein, a new Ugi multicomponent reaction strategy is described to enhance activity and solubility of the chemotherapeutic drug chlorambucil through its conjugation to poly(amidoamine) (PAMAM-NH2) dendrimers with the simultaneous introduction of lipidic (i-Pr) and cationic (–NH2) or anionic (–COOH) groups. Standard viability assays were used to evaluate the anticancer potential of the water-soluble dendrimers against PC-3 prostate and HT-29 colon cancer cell lines, as well as non-cancerous mouse NIH3T3 fibroblasts. It could be demonstrated that the anticancer activity against PC-3 cells was considerably improved when both chlorambucil and –NH2 (cationic) groups were present on the dendrimer surface (1b). Additionally, this dendrimer showed activity only against the prostate cancer cells (PC-3), while it did not affect colon cancer cells and fibroblasts significantly. The cationic chlorambucil-dendrimer 1b blocks PC-3 cells in the G2/M phase and induces caspase independent apoptosis.

Kufka, R.; Rennert, R.; Kaluđerović, G. N.; Weber, L.; Richter, W.; Wessjohann, L. A. Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells Beilstein J Org Chem 15, 96-105, (2019) DOI: 10.3762/bjoc.15.11

Tubugi-1 is a small cytotoxic peptide with picomolar cytotoxicity. To improve its cancer cell targeting, it was conjugated using a universal, modular disulfide derivative. This allowed conjugation to a neuropeptide-Y (NPY)-inspired peptide [K4(C-βA-),F7,L17,P34]-hNPY, acting as NPY Y1 receptor (hY1R)-targeting peptide, to form a tubugi-1–SS–NPY disulfide-linked conjugate. The cytotoxic impacts of the novel tubugi-1–NPY peptide–toxin conjugate, as well as of free tubugi-1, and tubugi-1 bearing the thiol spacer (liberated from tubugi-1–NPY conjugate), and native tubulysin A as reference were investigated by in vitro cell viability and proliferation screenings. The tumor cell lines HT-29, Colo320 (both colon cancer), PC-3 (prostate cancer), and in conjunction with RT-qPCR analyses of the hY1R expression, the cell lines SK-N-MC (Ewing`s sarcoma), MDA-MB-468, MDA-MB-231 (both breast cancer) and 184B5 (normal breast; chemically transformed) were investigated. As hoped, the toxicity of tubugi-1 was masked, with IC50 values decreased by ca. 1,000-fold compared to the free toxin. Due to intracellular linker cleavage, the cytotoxic potency of the liberated tubugi-1 that, however, still bears the thiol spacer (tubugi-1-SH) was restored and up to 10-fold higher compared to the entire peptide–toxin conjugate. The conjugate shows toxic selectivity to tumor cell lines overexpressing the hY1R receptor subtype like, e.g., the hard to treat triple-negative breast cancer MDA-MB-468 cells.

Drača, D.; Mijatović, S.; Krajnović, T.; Pristov, J. B.; Đukić, T.; Kaluđerović, G. N.; Wessjohann, L. A.; Maksimović-Ivanić, D. The synthetic tubulysin derivative, tubugi-1, improves the innate immune response by macrophage polarization in addition to its direct cytotoxic effects in a murine melanoma model Exp Cell Res 380, 159-170, (2019) DOI: 10.1016/j.yexcr.2019.04.028

Synthetic tubugis are equally potent but more stable than their natural forms. Their anticancer potential was estimated on a solid melanoma in vitro and in vivo. Tubugi-1 induced the apoptosis in B16 cells accompanied with strong intracellular production of reactive species, subsequently imposing glutathione and thiol group depletion. Paradoxically, membrane lipids were excluded from the cascade of intracellular oxidation, according to malondialdehyde decrease. Although morphologically apoptosis was typical, externalization of phosphatidylserine (PS) as an early apoptotic event was not detected. Even their exposition is pivotal for apoptotic cell eradication, primary macrophages successfully eliminated PS-deficient tubugi-1 induced apoptotic cells. The tumor volume in animals exposed to the drug in therapeutic mode was reduced in comparison to control as well as to paclitaxel-treated animals. Importantly, macrophages isolated from tubugi-1 treated animals possessed conserved phagocytic activity and were functionally and phenotypically recognized as M1. The cytotoxic effect of tubugi-1 is accomplished through its ability to polarize the macrophages toward M1, probably by PS independent apoptotic cell engulfment. The unique potential of tubugi-1 to prime the innate immune response through the induction of a specific pattern of tumor cell apoptosis can be of extraordinary importance from fundamental and applicable aspects.
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Pantelić, N. Đ.; Lerbs, M.; Wolf, K.; Wessjohann, L. A.; Kaluđerović, G. N. In vitro anticancer evaluation of novel triphenyltin(IV) compounds with some N-acetyl-S-(naphthoquinone)cysteine derivatives J Serb Chem Soc (2019) DOI: 10.2298/JSC190322032P

Triphenyltin(IV) compounds with naphthoquinone derivatives containing N-acetylcysteine, N-acetyl-S-(1,2-dion-4-naphthyl)cysteine (1,2-NQC), 1, and N-acetyl-S-(1,4-dion-2-naphthyl)cysteine (1,4-NQC), 2, were synthesized and characterized by elemental microanalysis, IR, multinuclear (1H, 13C, 119Sn) NMR spectroscopy as well as HR-ESI mass spectrometry. With the aim of in vitro anticancer activity determination of ligand precursors and novel synthesized organotin(IV) compounds against human cervix adenocarcinoma (HeLa), human colon carcinoma (HT-29), and melanoma carcinoma cell line (B16F10), MTT colorimetric assay method was applied. The results indicate that synthesized compounds exhibited remarkable antiproliferative activity toward all tested cell lines with IC50 in the range of 0.17 to 0.87 μM. Complex 1 showed the greatest activity against HT-29 cells, with IC50 value of 0.21 ± 0.01 μM, 119 times better than cisplatin, while complex 2 demonstrated the highest activity toward HeLa cells, IC50 = 0.17 ± 0.01 μM, which is ~26 times better than cisplatin.

Shaaban, S.; Ashmawy, A. M.; Negm, A.; Wessjohann, L. A. Synthesis and biochemical studies of novel organic selenides with increased selectivity for hepatocellular carcinoma and breast adenocarcinoma Eur J Med Chem 179, 515-526, (2019) DOI: 10.1016/j.ejmech.2019.06.075

Nineteen organoselenides were synthesized and tested for their intrinsic cytotoxicity in hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines and their corresponding selective cytotoxicity (SI) was estimated using normal lung fibroblast (WI-38) cells. Most of the organic selenides exhibited good anticancer activity, and this was more pronounced in HepG2 cells. Interestingly, the naphthoquinone- (5), thiazol- (12), and the azo-based (13) organic selenides demonstrated promising SI (up to 76). Furthermore, the amine 4c, naphthoquinone 5, and azo-based 13 and 15 organic selenides were able to down-regulate the expression of Bcl-2 and up-regulate the expression levels of IL-2, IL-6 and CD40 in HepG2 cells compared to untreated cells. Moreover, most of the synthesized candidates manifested good free radical-scavenging and GPx-like activities comparable to vitamin C and ebselen. The obtained results suggested that some of the presented organoselenium candidates have promising anti-HepG2 and antioxidant activities.

Sakna, S. T.; Mocan, A.; Sultani, H. N.; El-fiky, N. M.; Wessjohann, L. A.; Farag, M. A. Metabolites profiling of Ziziphus leaf taxa via UHPLC/PDA/ESI-MS in relation to their biological activities Food Chem 293, 233-246, (2019) DOI: 10.1016/j.foodchem.2019.04.097

Ziziphus plants are well recognized for their nutritive and medicinal value worldwide, albeit their chemical profile has yet to be fully reported. The secondary metabolites profile of three traditionally used Ziziphus leaf accessions was investigated via ultra-high performance liquid chromatography coupled to photodiode array and electrospray ionization mass detectors (UHPLC/PDA/ESI-MS). A total of 102 metabolites were characterized revealing the first holistic approach onto Ziziphus leaf metabolome and to include the first report of several novel flavonoids and cyclopeptide alkaloids. Fragmentation pattern for cyclopeptide alkaloids was proposed via ESI-MS. Principal component analysis (PCA) revealed close metabolite resemblance among Z. spina-christi and Z. mauritiana leaf specimens found enriched in saponins and distinct from that of Z. jujuba in which quercetin-3-O-(2-pentosyl)-rhamnoside was most abundant. Further, in-vitro antioxidant, anti-inflammatory and antidiabetic assays revealed for Z. spina-christi and Z. mauritiana strong effects compared to Z. jujuba and in correlation with their metabolites repertoire.
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Makong, Y. S.; Fotso, G. W.; Mouthe, G. H.; Lenta, B.; Rennert, R.; Sewald, N.; Arnold, N.; Wansi, J. D.; Ngadjui, B. T. Bruceadysentoside A, a new pregnane glycoside and others secondary metabolites with cytotoxic activity from brucea antidysenterica J. F. Mill. (simaroubaceae) Nat Prod Res (2019) DOI: 10.1080/14786419.2019.1655024

The chemical investigation of the root barks leaves and stem barks of Brucea antidysenterica J. F. Mill. (Simaroubaceae) led to the isolation of a new pregnane glycoside, named Bruceadysentoside A or 3-O-β-L-arabinopyranosyl-pregn-5-en-20-one (1) together with seventeen known compounds. Their structures were established from spectral data, mainly HRESIMS, 1 D and 2 D NMR and by comparison with literature data. Compounds 1, 2, 5, 6, 8, 10, 12 and 13 were tested in vitro for their effects on the viability of two different human cancer cell lines, namely prostate PC-3 adenocarcinoma cells and colorectal HT-29 adenocarcinoma cells. No substantial activities were recorded for 2, 10, 12 and 13 (up to 10 μM concentration). 1, 5 and 8 did not show strong anti-proliferative effects up to 100 μM, however, 6 exhibited a stronger anti-proliferative effect with IC50 values of ∼ 100 μM against PC-3 and ∼ 200 μM against HT-29.

da Silva, I. C. V.; Kaluderovic, G.; de Oliveira, P. F.; Guimaraes, D. O.; Quaresma, C. H.; Porzel, A.; Muzitano, M. F.; Wessjohann, L. A.; Leal, I. C. R. Apoptosis caused by triterpenes and phytosterols and antioxidant activity of an enriched flavonoid extract and from Passiflora mucronata Anti-Cancer Agents Med Chem 18, 1405-1416, (2018) DOI: 10.2174/1871520618666180315090949

Background: P. mucronata (Pm) comes from South America, Brazil and is characterized as “Maracujá de Restinga”. It is used in folk medicine for its soothing properties and in treating insomnia. Objective: The present study for the first time analyzed the antioxidant and cytotoxicity of the hydroalcoholic leaves extract and fractions from Pm. Method: The cytotoxicity test will be evaluated by different assays (MTT and CV) against human prostate cancer (PC3) and mouse malignant melanoma (B16F10) cell lines, and the antioxidant test by DPPH method. Results: β-Amyrin, oleanolic acid, β-sitosterol and stigmasterol were isolated of the most active, hexane fraction. These substances were tested against the tumor cell lines: β-sitosterol and stigmasterol showed the most relevant activity to PC3 in CV assay and, oleanolic acid to B16F10 by the MTT assay. In addition, it was possible to indicate that the mode of cell death for stigmasterol, presumably is apoptosis. In terms of antioxidant activity, the hydroalcoholic leaves extract presented higher activity (EC50 133.3 μg/mL) compared to the flower (EC50 152.3 μg/mL) and fruit (EC50 207.9 μg/mL) extracts. By the HPLC-MS, it was possible to identify the presence of flavones in the leaf extract (isoschaftoside, schaftoside, isovitexin, vitexin, isoorientin, orientin). Conclusions: P. mucronata hexane fraction showed promising cytotoxic effect against cancer cell lines, and stigmasterol contributes to this activity, inducing apoptosis of these cells. Furthermore, as other Passiflora species, Pm extract showed antioxidant activity and flavones are its major phenolic compounds.

Mijatović, S.; Bramanti, A.; Nicoletti, F.; Fagone, P.; Kaluđerović, G. N.; Maksimović-Ivanić, D. Naturally occurring compounds in differentiation based therapy of cancer Biotechnol Adv 36, 1622-1632, (2018) DOI: 10.1016/j.biotechadv.2018.04.001

Differentiation of cancer cells entails the reversion of phenotype from malignant to the original. The conversion to cell type characteristic for another tissue is named transdifferentiation. Differentiation/transdifferentiation of malignant cells in high grade tumor mass could serve as a nonaggressive approach that potentially limits tumor progression and augments chemosensitivity. While this therapeutic strategy is already being used for treatment of hematological cancers, its feasibility for solid malignancies is still debated. We will presently discuss the natural compounds that show these properties, with focus on anthraquinones from Aloe vera, Senna, Rheum sp. and hop derived prenylflavonoids.

Frolov, A.; Bilova, T.; Paudel, G.; Berger, R.; Balcke, G. U.; Birkemeyer, C.; Wessjohann, L. A. Early responses of mature Arabidopsis thaliana plants to reduced water potential in the agar-based polyethylene glycol infusion drought model J Plant Physiol 208, 70-83, (2017) DOI: 10.1016/j.jplph.2016.09.013

Drought is one of the most important environmental stressors resulting in increasing losses of crop plant productivity all over the world. Therefore, development of new approaches to increase the stress tolerance of crop plants is strongly desired. This requires precise and adequate modeling of drought stress. As this type of stress manifests itself as a steady decrease in the substrate water potential (ψw), agar plates infused with polyethylene glycol (PEG) are the perfect experimental tool: they are easy in preparation and provide a constantly reduced ψw, which is not possible in soil models. However, currently, this model is applicable only to seedlings and cannot be used for evaluation of stress responses in mature plants, which are obviously the most appropriate objects for drought tolerance research. To overcome this limitation, here we introduce a PEG-based agar infusion model suitable for 6–8-week-old A. thaliana plants, and characterize, to the best of our knowledge for the first time, the early drought stress responses of adult plants grown on PEG-infused agar. We describe essential alterations in the primary metabolome (sugars and related compounds, amino acids and polyamines) accompanied by qualitative and quantitative changes in protein patterns: up to 87 unique stress-related proteins were annotated under drought stress conditions, whereas further 84 proteins showed a change in abundance. The obtained proteome patterns differed slightly from those reported for seedlings and soil-based models.

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