A New Synthetic Curcuminoid Displays Antitumor Activities in Metastasized Melanoma.

AIM: The semisynthetic derivatives MePip-SF5 and isogarcinol, which are aligned with the natural products curcumin and garcinol, were tested for their antitumor effects in a preclinical model of pulmonary melanoma metastasis. METHODS AND RESULTS: MePip-SF5 was almost five times more effective in inhibiting B16F10 melanoma cell proliferation than its original substance of curcumin (IC50 MePip-SF5 2.8 vs. 13.8 µM). Similarly, the melanoma cytotoxicity of isogarcinol was increased by 40% compared to garcinol (IC50 3.1 vs. 2.1 µM). The in vivo toxicity of both drugs was assessed in healthy C57BL/6 mice challenged with escalating doses. Isogarcinol induced toxicity above a dose of 15 mg/kg, while MePip-SF5 showed no in vivo toxicity up to 60 mg/kg. Both drugs were tested in murine pulmonary metastatic melanoma. C57BL/6 mice (n = 10) received 500,000 B16F10 melanoma cells intravenously. After intraperitoneal injection of MePip-SF5 (60 mg/kg) or isorgarcinol (15 mg/kg) at days 8, 11 and 14 and sacrifice at day 16, the MePip-SF5-treated mice showed a significantly (p < 0.05) lower pulmonary macroscopic and microscopic tumor load than the vehicle-treated controls, whereas isogarcinol was ineffective. The pulmonary RNA levels of the mitosis marker Bub1 and the inflammatory markers TNFα and Ccl3 were significantly (p < 0.05) reduced in the MePip-SF5-treated mice. Both drugs were well tolerated, as shown by an organ inspection and normal liver- and kidney-related serum parameters. CONCLUSIONS: The novel curcuminoid MePip-SF5 showed a convincing antimetastatic effect and a lack of systemic toxicity in a relevant preclinical model of metastasized melanoma.

Fluorinated and N-Acryloyl-Modified 3,5-Di[(E)-benzylidene]piperidin-4-one Curcuminoids for the Treatment of Pancreatic Carcinoma.

Pancreatic carcinoma is a cancer disease with high mortality. Thus, new and efficient treatments for this disease are badly needed. Curcumin has previously shown promising effects in pancreatic cancer patients; however, this natural compound suffers from inadequate efficacy and bioavailability, preventing its clinical approval. The synthetic curcuminoid EF24 was developed with activities superior to curcumin against various cancer types. In this study, a series of analogs of EF24 were investigated for anticancer effects on pancreatic carcinoma models. A distinct activity boost was achieved by straightforward N-acrylation of EF24 analogs, in particular, of compounds bearing 3-fluoro-4-methoxybenzylidene, 3,4-difluorobenzylidene, and 4-trifluoromethylbenzylidene moieties, while no improvement was seen for N-acryloyl-modified EF24. Apoptosis induction and suppression of phospho-STAT3 levels were determined, the latter corroborated by docking of active curcuminoids into STAT3. Hence, promising new clues for the development of efficient and superior curcuminoids as valuable treatment options for one of the most lethal cancer diseases were discovered in this study.

Palladium and Platinum Complexes of the Antimetabolite Fludarabine with Vastly Enhanced Selectivity for Tumour over Non-Malignant Cells.

The purine derivative fludarabine is part of frontline therapy for chronic lymphocytic leukaemia (CLL). It has shown positive effects on solid tumours such as melanoma, breast, and colon carcinoma in clinical phase I studies. As the treatment of CLL cells with combinations of fludarabine and metal complexes of antitumoural natural products, e.g., illudin M ferrocene, has led to synergistically enhanced apoptosis, in this research study different complexes of fludarabine itself. Four complexes bearing a trans-[Br(PPh3)2]Pt/Pd fragment attached to atom C-8 via formal η1-sigma or η2-carbene bonds were synthesised in two or three steps without protecting polar groups on the arabinose or adenine. The platinum complexes were more cytotoxic than their palladium analogues, with low single-digit micromolar IC50 values against cells of various solid tumour entities, including cisplatin-resistant ones and certain B-cell lymphoma and CLL, presumably due to the ten-fold higher cellular uptake of the platinum complexes. However, the palladium complexes interacted more readily with isolated Calf thymus DNA. Interestingly, the platinum complexes showed vastly greater selectivity for cancer over non-malignant cells when compared with fludarabine.

Analogs of the Catechol Derivative Dynasore Inhibit HIV-1 Ribonuclease H, SARS-CoV-2 nsp14 Exoribonuclease, and Virus Replication.

Viral replication often depends on RNA maturation and degradation processes catalyzed by viral ribonucleases, which are therefore candidate targets for antiviral drugs. Here, we synthesized and studied the antiviral properties of a novel nitrocatechol compound (1c) and other analogs that are structurally related to the catechol derivative dynasore. Interestingly, compound 1c strongly inhibited two DEDD box viral ribonucleases, HIV-1 RNase H and SARS-CoV-2 nsp14 3'-to-5' exoribonuclease (ExoN). While 1c inhibited SARS-CoV-2 ExoN activity, it did not interfere with the mRNA methyltransferase activity of nsp14. In silico molecular docking placed compound 1c in the catalytic pocket of the ExoN domain of nsp14. Finally, 1c inhibited SARS-CoV-2 replication but had no toxicity to human lung adenocarcinoma cells. Given its simple chemical synthesis from easily available starting materials, these results suggest that 1c might be a lead compound for the design of new antiviral compounds that target coronavirus nsp14 ExoN and other viral ribonucleases.

Targeting Colon Cancer Cells with Pyrazino-Imidazolinone Derivatives: Synthesis, Molecular Docking, and in Vitro Evaluation of Anti-Proliferative and Pro-Apoptotic Activities.

We report the synthesis, spectroscopic characterization, molecular docking and biological evaluation of nine pyrazino-imidazolinone derivatives. These derivatives were evaluated for their anticancer activity against three cancer cell lines: 518A2 melanoma, HCT-116, and HCT-116 p53 knockout mutant colon carcinoma. The MTT assay was employed to assess their effectiveness. Among the nine compounds tested, four compounds (5 a, 5 d, 5 g, and 5 h) exhibited promising antiproliferative activity specifically against HCT-116 p53-negative cells (IC50 0.23, 0.20, 2.07 and 58.75 µM, respectively). Interestingly, treatment with the 3,4-dimethoxyphenyl derivative 5a resulted in a significant increase (199 %) in caspase activity in HCT-116 p53-negative cells compared to untreated cells while the bromo-pyrazine derivative 5d demonstrated (190 %) increase. These findings suggest that compounds 5a and 5 d induce p53-independent apoptotic cell death. Additionally, in silico molecular docking studies with EGFR and tyrosinase proteins indicated that compounds 5 d and 5 e have the potential to bind to important anticancer drug targets.

Versatile anti-infective properties of pyrido- and dihydropyrido[2,3-d]pyrimidine-based compounds.

A series of 1H-indeno[2',1':5,6]dihydropyrido[2,3-d]pyrimidine and 1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine derivatives was prepared and screened for antiparasitic and viral RNase H inhibitory activity. Several compounds showed considerable activity against Toxoplasma gondii parasites and Leishmania major amastigotes, which warrants further investigation. Based on the structural similarities of certain derivatives with common viral RNase H inhibitors, a HIV-1 RNase H assay was used to study the RNase H inhibition by selected test compounds. Docking of active derivatives into the active site of the HIV-1 RNase H enzyme was carried out. The new compound 2a, inactive in the antiparasitic tests, showed distinct HIV-1 RNase H inhibition. Thus, ring substitution determines antiparasitic or HIV-1 RNase H inhibitory activity of this promising compound class.

Regiospecific Reduction of 4,6-Dinitrobenzimidazoles: Synthesis, Characterization, and Biological Evaluation.

The regiospecific reduction of 4,6-dinitrobenzimidazole derivatives leading to the corresponding 4-amino-6-nitrobenzimidazoles was studied. The identification of the formed product structures was accomplished by spectroscopic and X-ray diffraction data. The anticancer and antiparasitic activities of the synthesized compounds were examined, and promising activities against Toxoplasma gondii and Leishmania major parasites were discovered for certain 4,6-dinitrobenzimidazoles in addition to moderate anticancer activities of the 4-amino-6-nitrobenzimidazole derivatives against T. gondii cells. However, the tumor cell experiments revealed a promising sensitivity of p53-negative colon cancer cells to these compounds.

Anti-Tumoural [NHC(thiolato)] Gold(I) Complexes Derived from HIF-1α Inhibitor AC1-004 Target the Mitochondrial Redox System and Show Antiangiogenic Effects in vivo.

AC1-004 is a potent inhibitor of the hypoxia-inducible factor alpha (HIF-1α) pathway, essential for tumour growth, angiogenesis and metastasis. We modelled a series of gold(I) complexes on AC1-004, retaining its 5-carboalkoxybenzimidazole as an NHC ligand while replacing its 2-aryloxymethyl residue with modified thiolato gold(I) fragments. The intention was to augment a potential HIF-1α inhibition by conducive effects typical of NHC gold complexes, such as an inhibition of tumoural thioredoxin reductase (TrxR), an increase in reactive oxygen species (ROS), and cytotoxic and antiangiogenic effects. We report on the synthesis and biological effects of twelve such N,N'-dialkylbenzimidazol-2-ylidene gold(I) complexes, obtained in average yields of 65 % for the thiophenolato and 45 % for the novel 4-(adamant-2-yl)benzenethiol complexes. The structure of one complex was validated via single-crystal X-ray diffraction. Structure-activity relationships (SAR) were derived by variation of the N-substituents (Me, Et, iPr, pentyl, Bn) and the thiolato ligand. Their cytotoxicity against various human cancer cell lines of different entities reached IC50 values in the single-digit micromolar range. The complexes were also assayed for the induction of tumour cell apoptosis (activation of caspase-3/7), TrxR inhibition and antiangiogenic effects in zebrafish. Cyclopropene-bearing congeners were employed in click reactions to examine the subcellular accumulation of the complexes.

Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities.

Aim: Efficient and readily available anticancer drugs are sought as treatment options. For this reason, chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties. Methods: 2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds (2A-R) were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol, various aryl aldehydes, and malononitrile. We performed assays to study the inhibition of tumor cell growth [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromid (MTT) assay], effects on microtubules (immunofluorescence), cell cycle (flow-activated cell sorting analysis), angiogenesis (zebrafish model), and MYB activity (luciferase reporter assay). Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative. Results: Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines (50% inhibitory concentrations in the low nanomolar range) and showed potent MYB inhibition. The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation. Substantial microtubule disruption and G2/M cell-cycle arrest were observed, where compound 2F stood out as a promising microtubule-disrupting agent. The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation in vivo. Conclusion: The close interplay of various mechanisms, including cell-cycle arrest, MYB inhibition, and anti-angiogenic activity, led to identifying promising multimodal anticancer drug candidates.

Formal synthesis of kibdelomycin and derivatisation of amycolose glycosides.

A convergent total synthesis of bacterial gyrase B/topoisomerase IV inhibitor kibdelomycin (a.k.a. amycolamicin) (1) was devised starting from inexpensive d-mannose and l-rhamnose, which were converted in new efficient ways to an N-acylated amycolose and an amykitanose derivative as late building blocks. For the former, we developed an expeditious, general method for the introduction of an α-aminoalkyl linkage into sugars via 3-Grignardation. The decalin core was built up in seven steps via an intramolecular Diels-Alder reaction. These building blocks could be assembled as published previously, making for a formal total synthesis of 1 in 2.8% overall yield. An alternative order of connecting the essential fragments was also made possible by the first protocol for the direct N-glycosylation of a 3-acyltetramic acid.

Evaluation of the Antiparasitic and Antifungal Activities of Synthetic Piperlongumine-Type Cinnamide Derivatives: Booster Effect by Halogen Substituents.

A series of synthetic N-acylpyrrolidone and -piperidone derivatives of the natural alkaloid piperlongumine were prepared and tested for their activities against Leishmania major and Toxoplasma gondii parasites. Replacement of one of the aryl meta-methoxy groups by halogens such as chlorine, bromine and iodine led to distinctly increased antiparasitic activities. For instance, the new bromo- and iodo-substituted compounds 3 b/c and 4 b/c showed strong activity against L. major promastigotes (IC50 =4.5-5.8 µM). Their activities against L. major amastigotes were moderate. In addition, the new compounds 3 b, 3 c, and 4 a-c exhibited high activity against T. gondii parasites (IC50 =2.0-3.5 µM) with considerable selectivities when taking their effects on non-malignant Vero cells into account. Notable antitrypanosomal activity against Trypanosoma brucei was also found for 4 b. Antifungal activity against Madurella mycetomatis was observed for compound 4 c at higher doses. Quantitative structure-activity relationship (QSAR) studies were carried out, and docking calculations of test compounds bound to tubulin revealed binding differences between the 2-pyrrolidone and 2-piperidone derivatives. Microtubules-destabilizing effects were observed for 4 b in T. b. brucei cells.

New 4,5-Diarylimidazol-2-ylidene-iodidogold(I) Complexes with High Activity against Esophageal Adenocarcinoma Cells.

Inspired by the vascular-disrupting agent combretastatin A-4 and recently published anticancer active N-heterocyclic carbene (NHC) complexes of Au(I), a series of new iodidogold(I)-NHC complexes was synthesized and characterized. The iodidogold(I) complexes were synthesized by a route involving van Leusen imidazole formation and N-alkylation, followed by complexation with Ag2O, transmetalation with chloro(dimethylsulfide)gold(I) [Au(DMS)Cl], and anion exchange with KI. The target complexes were characterized by IR spectroscopy, 1H and 13C NMR spectroscopy, and mass spectrometry. The structure of 6c was validated via single-crystal X-ray diffraction. A preliminary anticancer screening of the complexes using two esophageal adenocarcinoma cell lines showed promising nanomolar activities for certain iodidogold(I) complexes accompanied with apoptosis induction, as well as c-Myc and cyclin D1 suppression in esophageal adenocarcinoma cells treated with the most promising derivative 6b.

New Functional Polymer Materials via Click Chemistry-Based Modification of Cellulose Acetate.

Cellulose acetate (CA) was partially acrylated, and the resulting cellulose acetate acrylate (acryl-substitution degree of 0.2) underwent quantitative thio-Michael click reactions with various thiols. A toolbox of functional CA polymers was obtained in this way, and their properties were studied. The modification with fatty alkyl thiols led to hydrophobic materials with large water drop contact angles. Octadecylthio-, butoxycarbonylpropylthio-, and furanylthio-modifications formed highly transparent materials. The new derivative CAASFur disintegrated completely under industrial composting conditions. Films of modified CA polymers were cast and investigated in terms of barrier properties. The nanocomposite of CAAS18 compounded with a synthetic layered silicate (hectorite) of a large aspect ratio showed permeabilities as low as 0.09 g mm m-2 day-1 for water vapor and 0.16 cm3 mm m-2 day-1 atm-1 for oxygen. This portfolio of functional CA polymers opens the door to new applications.

Syntheses and Antibacterial Evaluation of New Penicillium Metabolites Gregatins G and Thiocarboxylics C.

Two pairs of side-chain epimeric 3-methoxycarbonyl-dihydrofuran-4-ones with structures purported for thiocarboxylics C1/2 and gregatins G1/2 , isolated from Penicillium sp. Sb62, were synthesised for the first time in five steps and 17-25 % yield. Key steps were a Suzuki cross-coupling, a Yamaguchi esterification, and a base-induced Knoevenagel-type condensation. The optimum protecting group for the 10-OH group in the dienyl side-chain, orthogonal to necessary protecting groups on O-10 of the furanone, was found to be t-butyldiphenylsilyl (TBDPS). The specific rotations of our synthetic products deviated markedly from those reported for the natural isolates. In contrast to the isolates, the synthetic products were not active against Escherichia coli and Staphylococcus aureus bacteria.

Divergent Synthesis of Six Recent Berkeleylactones.

The six recently isolated berkeleylactones E, J, K, M, N, and O were synthesized for the first time by a divergent strategy starting from a common intermediate in our synthesis of berkeleylactone A. Key features were the stereoselective formation of the γ,δ-dihydroxy-α,ß-unsaturated ester moiety and the development of a general protection group strategy. Along the way we also established a short high-yielding formal synthesis of the often-synthesized antibiotic A26771B.

Synthesis and Anticancer Evaluation of New Indole-Based Tyrphostin Derivatives and Their (p-Cymene)dichloridoruthenium(II) Complexes.

New N-alkylindole-substituted 2-(pyrid-3-yl)-acrylonitriles with putative kinase inhibitory activity and their (p-cymene)Ru(II) piano-stool complexes were prepared and tested for their antiproliferative efficacy in various cancer models. Some of the indole-based derivatives inhibited tumor cell proliferation at (sub-)micromolar concentrations with IC50 values below those of the clinically relevant multikinase inhibitors gefitinib and sorafenib, which served as positive controls. A focus was set on the investigation of drug mechanisms in HCT-116 p53-knockout colon cancer cells in order to evaluate the dependence of the test compounds on p53. Colony formation assays as well as experiments with tumor spheroids confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic caspase-3/7 activity and ROS formation, as well as anti-angiogenic properties. Docking calculations with EGFR and VEGFR-2 identified the two 3-aryl-2-(pyrid-3-yl)acrylonitrile derivatives 2a and 2b as potential kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in cancer treatment.

Syntheses and Biofilm Reducing Effects of l-Dopa-Derived Analogues of the Fungal Macrocidins A and Z.

Four analogues of the fungal metabolites macrocidin A and Z, featuring [13]para- or [13]metacyclophanes, were synthesised from fully and orthogonally protected l-dopa instead of l-tyrosine. They were tested for antibiotic activities and for effects on the growth and persistence of microbial biofilms. Tentative structure-activity relationships and distinct differences when compared with the natural lead compounds were identified.

Antiparasitic Activity of Fluorophenyl-Substituted Pyrimido[1,2-a]benzimidazoles.

A series of fourteen pyrimido[1,2-a]benzimidazole compounds was prepared by straightforward heterocyclic chemistry and oxidation methods. The new pyrimidobenzimidazole derivative 2a with a 3-fluorophenyl substituent was identified as a new antiparasitic compound showing excellent activities against Leishmania major parasites. 2a was highly active against L. major promastigotes and amastigotes with EC50 values in the nanomolar concentration range. Compound 3b was less active than 2a against L. major, but more active against Toxoplasma gondii with considerable selectivity. Hence, two promising and selective antiparasitic drug candidates 2a and 3b for the treatment of two parasitic diseases were identified, which can be prepared by green chemistry methods using simple one-pot reactions and oxidation procedures, respectively.

New chimeric HDAC inhibitors for the treatment of colorectal cancer.

Colorectal cancer is the third most common cause of cancer-associated deaths due to a high recurrence rate and an increasing occurrence of resistance to established therapies. This highlights the importance of developing new chemotherapeutic agents. The current study focuses on cancer-specific targets such as apoptosis-inhibiting survivin, which distinguishes cancer cells from healthy tissue. A combination of pharmacophores of established anticancer agents to afford chimeric pleiotropic chemotherapeutic agents was tested on this cancer entity. We analysed the effects of the dual mode anticancer agents, animthioxam, brimbam, troxbam, and troxham, as well as their structural congeners suberoylanilide hydroxamic acid and combretastatin A-4 on human cancer cell lines. Their cytotoxicity was determined using the MTT assay, further techniques for detecting apoptotic events, cell cycle analyses, clonogenic and wound healing assays, immunostaining, histone deacetylase (HDAC) activity measurements, and Western blot analysis for the detection of survivin expression in HCT116 colon cancer cells. Molecular docking studies were conducted to assess potential molecular targets of the test compounds. The test compounds were found selectively cytotoxic toward cancer cells by inducing apoptosis. The metastatic potential was effectively reduced by disruption of the microtubular cytoskeleton. The test compounds were also proven to be general HDAC inhibitors and to lead to reduced survivin expression.

Trans-[bis(benzimidazol-2-ylidene)dichlorido]platinum(II) complexes with peculiar modes of action and activity against cisplatin-resistant cancer cells.

Three series of cis- and trans-[bis(benzimidazol-2-ylidene)dichlorido]platinum(II) and cis-[(benzimidazol-2-ylidene)(DMSO)dichlorido]platinum(II) complexes were synthesised and screened for cytotoxicity against six human cancer cell lines. Depending on their N-alkyl and 5-alkoxycarbonyl substituents, two-digit nanomolar to single-digit micromolar IC50 values against cancer cell lines intrinsically resistant to or ill-responding to cisplatin were reached by both cis- and trans-configured complexes. The stability of the complexes under aqueous biotest conditions was shown via 1H and 195Pt NMR monitoring to be dependent on their configuration and their N-substituents. Localisation studies employing click reactions with 1-alkyne- or cyclopropene-tagged derivatives revealed that the cis-complexes accumulated in the cell nuclei and the trans-complexes in the mitochondria. While the most active cis-complexes showed modes of action akin to those of cisplatin, the most active trans-complexes differed from cisplatin by much lower rates of cellular uptake and ROS production, and by their non-interaction with the cell cycle and the DNA of cancer cells. Thus, we identified structural key elements for the synthesis of optimised trans-configured NHC platinum(II) complexes with high activity also against cisplatin-refractory cancer cells.