Synthesis of Tumor Selective Indole and 8-Hydroxyquinoline Skeleton Containing Di-, or Triarylmethanes with Improved Cytotoxic Activity.

The reaction between glycine-type aminonaphthol derivatives substituted with 2- or 1-naphthol and indole or 7-azaindole has been tested. Starting from 2-naphthol as a precursor, the reaction led to the formation of ring-closed products, while in the case of a 1-naphthol-type precursor, the desired biaryl ester was isolated. The synthesis of a bifunctional precursor starting from 5-chloro-8-hydroxyquinoline, morpholine, and ethyl glyoxylate via modified Mannich reaction is reported. The formed Mannich base 10 was subjected to give bioconjugates with indole and 7-azaindole. The effect of the aldehyde component and the amine part of the Mannich base on the synthetic pathway was also investigated. In favor of having a preliminary overview of the structure-activity relationships, the derivatives have been tested on cancer and normal cell lines. In the case of bioconjugate 16, as the most powerful scaffold in the series bearing indole and a 5-chloro-8-hydroxyquinoline skeleton, a potent toxic activity against the resistant Colo320 colon adenocarcinoma cell line was observed. Furthermore, this derivative was selective towards cancer cell lines showing no toxicity on non-tumor fibroblast cells.

Impact of V9302, a Competitive Antagonist of Transmembrane Glutamine Flux on Reversal of Resistance in Breast Cancer Cell Lines.

Chemotherapy is a known treatment modality that improves the long-term survival of breast cancer patients. However, due to the resistance to numerous anticancer drugs, alternative chemotherapeutic strategies are required. Regarding antimetabolic drugs, several compounds have proven anticancer properties, such as statins. The present study aimed to investigate the in vitro effects of V9302, a competitive antagonist of glutamine flux, on different subtypes of breast cancers (estrogen, progesterone, and HER2 receptor-positive or negative, and Pgp-negative and Pgp-overexpressing). The interactions of V9302 with standard chemotherapeutic drugs (doxorubicin and cisplatin) were also determined by MTT staining on breast cancer cell lines. Furthermore, the influence of V9302 on the cell cycle of MCF-7 and its Pgp-overexpressing counterpart KCR was monitored by flow cytometry. It was shown that V9302 exerted synergistic interactions with doxorubicin in all breast cancer cell lines. In cell cycle analysis, the KCR cell line was more sensitive to V9302. After 48 h, cell proliferation was completely blocked, and elevated G1, suppressed S, and decreased G2/M could be detected. Inhibition of glutamate transport can be assumed to block resistance related to Pgp.

pH-Triggered Hydrogel Nanoparticles for Efficient Anticancer Drug Delivery and Bioimaging Applications.

In this work, we developed multifunctional hydrogel nanoparticles (NPs) that can encapsulate anticancer drugs and imaging contrast agents as well. Mitomycin C (MMC) and rhodamine B (RB) were selected as models for anticancer drugs and imaging contrasting agents, respectively. Both MMC and RB were linked to the succinated polyvinyl alcohol polymer (PVA-SA). The selected labeled hydrogel NPs ((0.5% RB)-PVA-SA NPs and (1.5% RB)-PVA-SA NPs) improved the RB quantum yield from 29.8% to a minimum of 42.7%. Moreover, they showed higher emission stability compared to free RB when they were repeatedly excited at 554 nm for 2 h. Furthermore, the dye polymeric interactions significantly increased the RB fluorescence lifetime by approximately twofold. All these optical properties pave the way for our labeled hydrogel NPs to be used in imaging-guided therapy. For the labeled MMC-loaded NPs, the MMC-binding efficiency was found to be exceedingly high in all synthesized samples: a minimum of 92% was achieved. In addition, the obtained pH-dependent drug release profiles as well as the cytotoxicity evaluation demonstrated the high potential of releasing MMC under acidic cancerous conditions. Moreover, the in vitro cellular uptake experiment confirmed the accumulation of MMC NPs throughout the cytoplasm.

Evaluation of Novel Benzo-annelated 1,4-dihydropyridines as MDR Modulators in Cancer Cells.

BACKGROUND: Multidrug resistance (MDR) is the main problem in anticancer therapy today. Causative transmembrane efflux pumps in cancer cells have been reconsidered as promising anticancer target structures to restore anticancer drug sensitivity by various strategies, including MDR modulators. MDR modulators interfere with the efflux pumps and improve the cellular efficiency of chemotherapeutics. So far, only a few candidates have gone through clinical trials with disappointing results because of low specificity and toxic properties. AIM: This study aimed to find novel MDR modulators to effectively combat multidrug resistance in cancer cells. OBJECTIVE: We synthesized various novel benzo-annelated 1,4-dihydropyridines to evaluate them as MDR modulators towards ABCB1 in cancer cells. METHODS: Synthesized compounds were purified by column chromatography. The MDR modulation of ABCB1 was determined in cellular efflux assays using the flow cytometry technique and cellular fluorescent measurements by the use of each fluorescent substrate. RESULTS: Compounds were yielded in a two-step reaction with structurally varied components. Further, substituent- dependent effects on the determined MDR inhibiting properties towards ABCB1 were discussed. Cellular studies prove that there is no toxicity and restoration of cancer cell sensitivity towards the used anticancer drug. CONCLUSION: Novel MDR modulators could be identified with favorable methoxy and ester group functions. Their use in both ABCB1 non-expressing and overexpressing cells proves a selective toxicity-increasing effect of the applied anticancer agent in the ABCB1 overexpressing cells, whereas the toxicity effect of the anticancer drug was almost unchanged in the non-expressing cells. These results qualify our novel compounds as perspective anticancer drugs compared to MDR modulators with nonselective toxicity properties.

Synthesis and Antibacterial Evaluation of Novel Small-Molecule Antibacterials of a Reduced Acridine Structure in S. aureus Strains Including MRSA.

BACKGROUND: The increasing antibacterial drug resistance remains a threat to global health with increasing mortality and morbidity. There is an urgent need to find novel antibacterials and develop alternative strategies to combat the increasing antibacterial drug resistance. OBJECTIVE: We aimed to synthesize novel small-molecule antibacterials to evaluate the structuredependent antibacterial compound activities against S. aureus and MRSA. METHODS: Compounds were synthesized by primary N-alkylation to form alkyl acridinium salts that were further functionalized with substituted phenyl residues and finally purified by column chromatography. The antibacterial growth inhibition activity was determined as MIC value. RESULTS: The substituent effects on the determined antibacterial growth inhibitory properties have been discussed. CONCLUSION: The best activities have been found for compounds with methoxy functions, exceeding the activities of reported novel antibacterial peptides. The compounds have also shown antibacterial drug-enhancing effects, which have been manifested as a reduction in the MIC values of the used antibiotics.

Nitrogen-containing andrographolide derivatives with multidrug resistance reversal effects in cancer cells.

Multidrug resistance (MDR) remains a challenging issue in cancer treatment. Aiming at finding anticancer agents to overcome MDR, the triacetyl derivative (2) of the labdane diterpenoid lactone andrographolide (1) underwent the Michael-type addition reaction followed by elimination, yielding twenty-three new derivatives, bearing nitrogen-containing substituents (3-25). Their structures were assigned, mainly, by 1D and 2D NMR experiments. The MDR reversal potential of compounds 1-25 was assessed, by functional and chemosensitivity assays, using resistant human ABCB1-gene transfected L5178Y mouse lymphoma cells as a model. Several derivatives exhibited remarkable P-glycoprotein (P-gp) inhibitory ability. Compounds 13 and 20, bearing thiosemicarbazide moieties, were the most active exhibiting a strong MDR reversal effect at 2 µM. Some compounds showed selectivity towards the resistant cells, with compound 5 exhibiting a collateral sensitivity effect associated with significant antiproliferative activity (IC50 = 5.47 ± 0.22 µM). Moreover, all selected compounds displayed synergistic interaction with doxorubicin, with compound 3 being the most active. In the ATPase assay, selected compounds exhibited characteristics of P-gp inhibitors.

Cyclic Amines Coupled to Indole Derivatives With Improved Efflux Pump Inhibiting Activity in Bacteria and Cancer Cells.

BACKGROUND/AIM: Indole skeleton has become a significant tool in the field of anticancer and antibacterial therapeutic strategies. The modified aza-Friedel-Crafts reaction by direct coupling of different cyclic imines and indole derivatives has been explored. To investigate the scope and limitations of the reaction and observe the effect of structural modifications, our aim was to resynthesize selected compounds as well as prepare new derivatives starting from 6,7-dimethoxy-3,4-dihydroisoquinoline, (4aR,8aR)-4a,5,6,7,8,8a-hexahydroquinoxalin-2(1H)-one and 7-azaindole. Our further aim was the systematic biological evaluation of selected C-3-coupled indole and azaindole derivatives in favour of having a preliminary overview about the structure-activity relationships. MATERIALS AND METHODS: The synthesis and resynthesis of selected compounds were accomplished by extension of aza-Friedel-Crafts reaction. The products have been tested on bacteria and cancer cells. RESULTS: The most significant efflux pump inhibiting (EPI) activity was observed in the case of 6,7-dihydrothieno[3,2-c]pyridine coupled indole derivative. The reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline with 7-azaindole resulted in the most potent biofilm inhibitor product. Applying indole and 4,9-dihydro-3H-ß-carboline, 6,7-dihydrothieno[3,2-c]pyridine led to the formation of a product with the highest anticancer activity. 6,7-Dimethoxy-3,4-dihydroisoquinoline skeleton and indole as an electron-rich aromatic compound have been found to be effective in the inhibition of ABCB1. CONCLUSION: The compounds presented in the study were investigated regarding different aspects of antibacterial and anticancer activities. Accordingly, some compounds were found to have antibacterial effect on Escherichia coli and Staphylococcus aureus strains, certain C-3-coupled derivatives showed toxicity on sensitive and ABCB1 efflux pump expressing colon adenocarcinoma and a normal, non-cancerous fibroblast cell lines.

Antibacterial Potential of Symmetrical Twin-Drug 3,6-Diaminoxanthones.

Global health faces a significant issue with the rise of infectious diseases caused by bacteria, fungi, viruses, and parasites. The increasing number of multi-drug resistant microbial pathogens severely threatens public health worldwide. Antibiotic-resistant pathogenic bacteria, in particular, present a significant challenge. Therefore, there is an urgent need to identify new potential antimicrobial targets and discover new chemical entities that can potentially reverse bacterial resistance. The main goal of this research work was to create and develop a library of 3,6-disubstituted xanthones based on twin drugs and molecular extension approaches to inhibit the activity of efflux pumps. The process involved synthesizing 3,6-diaminoxanthones through the reaction of 9-oxo-9H-xanthene-3,6-diyl bis(trifluoromethanesulfonate) with various primary and secondary amines. The resulting 3,6-disubstituted xanthone derivatives were then tested for their in vitro antimicrobial properties against a range of pathogenic strains and their efficacy in inhibiting the activity of efflux pumps, biofilm formation, and quorum-sensing. Several compounds have exhibited effective antibacterial properties against the Gram-positive bacterial species tested. Xanthone 16, in particular, has demonstrated exceptional efficacy with a remarkable MIC of 11 µM (4 µg/mL) against reference strains Staphylococcus aureus ATCC 25923 and Enterococcus faecalis ATCC 29212, and 25 µM (9 µg/mL) against methicillin-resistant S. aureus 272123. Furthermore, some derivatives have shown potential as antibiofilm agents in a crystal violet assay. The ethidium bromide accumulation assay pinpointed certain compounds inhibiting bacterial efflux pumps. The cytotoxic effect of the most promising compounds was examined in mouse fibroblast cell line NIH/3T3, and two monoamine substituted xanthone derivatives with a hydroxyl substituent did not exhibit any cytotoxicity. Overall, the nature of the substituent was critical in determining the antimicrobial spectra of aminated xanthones.

Indonesian Euphorbiaceae: Ethnobotanical Survey, In Vitro Antibacterial, Antitumour Screening and Phytochemical Analysis of Euphorbia atoto.

Indonesia is among the countries with the most significant biodiversity globally. Jamu, the traditional medicine of Indonesia, predominantly uses herbal materials and is an integral component of the Indonesian healthcare system. The present study reviewed the ethnobotanical data of seven Indonesian Euphorbiaceae species, namely Euphorbia atoto, E. hypericifolia, Homalanthus giganteus, Macaranga tanarius, Mallotus mollissimus, M. rufidulus, and Shirakiopsis indica, based on the RISTOJA database and other literature sources. An antimicrobial screening of the plant extracts was performed in 15 microorganisms using the disk diffusion and broth microdilution methods, and the antiproliferative effects were examined in drug-sensitive Colo 205 and resistant Colo 320 cells by the MTT assay. The antimicrobial testing showed a high potency of M. tanarius, H. giganteus, M. rufidulus, S. indica, and E. atoto extracts (MIC = 12.5-500 µg/mL) against different bacteria. In the antitumour screening, remarkable activities (IC50 0.23-2.60 µg/mL) were demonstrated for the extracts of H. giganteus, M. rufidulus, S. indica, and E. atoto against Colo 205 cells. The n-hexane extract of E. atoto, with an IC50 value of 0.24 ± 0.06 µg/mL (Colo 205), was subjected to multistep chromatographic separation, and 24-methylene-cycloartan-3ß-ol, jolkinolide E, tetra-tert-butyl-diphenyl ether, α-tocopherol, and ß-sitosterol were isolated.

Furanonaphthoquinones, Diterpenes, and Flavonoids from Sweet Marjoram and Investigation of Antimicrobial, Bacterial Efflux, and Biofilm Formation Inhibitory Activities.

The chloroform extract of Origanum majorana exhibited high antibacterial and antifungal activities against 12 bacterial and 4 fungal strains; therefore, it was subjected to bioassay-guided isolation to afford six compounds (1-6). The structures were determined via one- and two-dimensional nuclear magnetic spectroscopy and high-resolution electrospray ionization mass spectrometry experiments. The compounds were identified as furanonaphthoquinones [majoranaquinone (1), 2,3-dimethylnaphtho[2,3-b]furan-4,9-dione (2)], diterpenes [19-hydroxyabieta-8,11,13-trien-7-one (3), 13,14-seco-13-oxo-19-hydroxyabieta-8-en-14-al (4)], and flavonoids [sterubin (5) and majoranin (6)]. Compounds 1 and 2 were first obtained from a natural source and compounds 3 and 4 were previously undescribed. Majoranaquinone (1) exhibited a high antibacterial effect against 4 Staphylococcus, 1 Moraxella, and 1 Enterococcus strains (MIC values between 7.8 µM and 1 mM). In the efflux pump inhibition assay, majoranaquinone (1) showed substantial activity in Escherichia coli ATCC 25922 strain. Furthermore, 1 was found to be an effective biofilm formation inhibitor on E. coli ATCC 25922 and E. coli K-12 AG100 bacteria. Our findings proved that bioactivities of majoranaquinone (1) significantly exceed those of the essential oil constituents; therefore, it should also be considered when assessing the antimicrobial effects of O. majorana.

Effect of Indole-Containing Pyrazino[2,1-b]quinazoline-3,6-diones in the Virulence of Resistant Bacteria.

Drug resistance is rising to alarming levels, constituting one of the major threats to global health. The overexpression of efflux pumps and the formation of biofilms constitute two of the most common resistance mechanisms, favoring the virulence of bacteria. Therefore, the research and development of effective antimicrobial agents that can also counteract resistance mechanisms are extremely important. Pyrazino[2,1-b]quinazoline-3,6-diones, from marine and terrestrial organisms and simpler synthetic analogues, were recently disclosed by us as having relevant antimicrobial properties. In this study, using a multi-step approach, it was possible to synthesize new pyrazino[2,1-b]quinazoline-3,6-diones focusing on compounds with fluorine substituents since, to the best of our knowledge, the synthesis of fluorinated fumiquinazoline derivatives had not been attempted before. The new synthesized derivatives were screened for antibacterial activity and, along with previously synthetized pyrazino[2,1-b]quinazoline-3,6-diones, were characterized for their antibiofilm and efflux-pump-inhibiting effects against representative bacterial species and relevant resistant clinical strains. Several compounds showed relevant antibacterial activity against the tested Gram-positive bacterial species with MIC values in the range of 12.5-77 µM. Furthermore, some derivatives showed promising results as antibiofilm agents in a crystal violet assay. The results of the ethidium bromide accumulation assay suggested that some compounds could potentially inhibit bacterial efflux pumps.

Modulation of the bacterial virulence and resistance by well-known European medicinal herbs.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia officinalis L., Sambucus nigra L., Matricaria chamomilla L., Agrimonia eupatoria L., Fragaria vesca L. and Malva sylvestris L. are plants that have a long tradition in European folk medicine. To this day, they are part of medicinal teas or creams that help with the healing of skin wounds and the treatment of respiratory or intestinal infections. However, so far these plants have not been investigated more deeply than in their direct antibacterial effect. AIM OF THE STUDY: Our research is focused on adjuvants that inhibit the mechanism of antibiotic resistance or modulate bacterial virulence. Based on a preliminary screening of 52 European herbs, which commonly appear as part of tea blends or poultice. Six of them were selected for their ability to revert the resistant phenotype of nosocomial bacterial strains. METHODS: Herbs selected for this study were obtained from commercially available sources. For the extraction of active compounds ethanol was used. Modulation of virulence was observed as an ability to inhibit bacterial cell-to-cell communication using two mutant sensor strains of Vibrio campbellii. Biofilm formation, and planktonic cell adhesion was measured using a static antibiofilm test. Ethidium bromide assay was used to checked the potential of inhibition bacterial efflux pumps. The antibacterial activities of the herbs were evaluated against resistant bacterial strains using macro dilution methods. RESULTS: Alcohol extracts had antibacterial properties mainly against Gram-positive bacteria. Of all of them, the highest antimicrobial activity demonstrated Malva sylvestris, killing both antibiotic resistant bacteria; Staphylococcus aureus with MIC of 0.8 g/L and Pseudomonas aeruginosa 0.7 g/L, respectively. Fragaria vesca extract (0.08 g/L) demonstrated strong synergism with colistin (4 mg/L) in modulating the resistant phenotype to colistin of Pseudomonas aeruginosa. Similarly, the extract of S. officinalis (0.21 g/L) reverted resistance to gentamicin (1 mg/L) in S. aureus. However, Sambucus nigra and Matricaria chamomilla seem to be a very promising source of bacterial efflux pump inhibitors. CONCLUSION: The extract of F. vesca was the most active. It was able to reduce biofilm formation probably due to the ability to decrease bacterial quorum sensing. On the other hand, the activity of S. nigra or M. chamomilla in reducing bacterial virulence may be explained by the ability to inhibit bacterial efflux systems. All these plants have potential as an adjuvant for the antibiotic treatment.

Lycorine Carbamate Derivatives for Reversing P-glycoprotein-Mediated Multidrug Resistance in Human Colon Adenocarcinoma Cells.

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Aiming at generating a small library of anticancer compounds for overcoming MDR, lycorine (1), a major Amaryllidaceae alkaloid isolated from Pancratium maritimum, was derivatized. Thirty-one new compounds (2-32) were obtained by chemical transformation of the hydroxyl groups of lycorine into mono- and di-carbamates. Compounds 1-32 were evaluated as MDR reversers, through the rhodamine-123 accumulation assay by flow cytometry and chemosensitivity assays, in resistant human colon adenocarcinoma cancer cells (Colo 320), overexpressing P-glycoprotein (P-gp, ABCB1). Significant inhibition of P-gp efflux activity was observed for the di-carbamate derivatives, mainly those containing aromatic substituents, at non-cytotoxic concentrations. Compound 5, bearing a benzyl substituent, and compounds 9 and 25, with phenethyl moieties, were among the most active, exhibiting strong inhibition at 2 µM, being more active than verapamil at 10-fold higher concentration. In drug combination assays, most compounds were able to synergize doxorubicin. Moreover, some derivatives showed a selective antiproliferative effect toward resistant cells, having a collateral sensitivity effect. In the ATPase assay, selected compounds (2, 5, 9, 19, 25, and 26) were shown to behave as inhibitors.

New Chalcone-Triazole Hybrids with Promising Antimicrobial Activity in Multidrug Resistance Strains.

Resistance to antibiotics is an emerging problem worldwide, which leads to an increase in morbidity and mortality rates. Several mechanisms are attributed to bacterial resistance, overexpression of efflux pumps being one of the most prominent. As an attempt to develop new effective antimicrobial drugs, which could be able to act against resistant bacterial strains and considering the antimicrobial potential of flavonoids and triazolyl flavonoid derivatives, in particular chalcones, a small library of chalcone derivatives was synthesized and evaluated for its potential to act as antimicrobials and/or adjuvants in combination with antibiotics towards resistant bacteria. Although only compound 7 was able to act as antibacterial, compounds 1, 2, 4, 5, 7, and 9 revealed to be able to potentiate the activity of antibiotics in resistant bacteria. Moreover, five compounds (3, 5-8) demonstrated to be effective inhibitors of efflux pumps in Salmonella enterica serovar Typhimurium SL1344, and four compounds (1, 3, 7, and 10) showed higher ability than reserpine to inhibit biofilm formation of resistant Staphylococcus aureus 272123. Together, our results showed the potential of these compounds regarding reversion of bacterial resistance.

Derivatives of Trimethoxybenzoic Acid and Gallic Acid as Potential Efflux Pump Inhibitors: In Silico and In Vitro Studies.

The overexpression of efflux pumps is one of the strategies used by bacteria to resist antibiotics and could be targeted to circumvent the antibiotic crisis. In this work, a series of trimethoxybenzoic acid derivatives previously described as antifouling compounds was explored for potential antimicrobial activity and efflux pump (EP) inhibition. First, docking studies on the acridine resistance proteins A and B coupled to the outer membrane channel TolC (AcrAB-TolC) efflux system and a homology model of the quinolone resistance protein NorA EP were performed on 11 potential bioactive trimethoxybenzoic acid and gallic acid derivatives. The synthesis of one new trimethoxybenzoic acid derivative (derivative 13) was accomplished. To investigate the potential of this series of 11 derivatives as antimicrobial agents, and in reverting drug resistance, the minimum inhibitory concentration was determined on several strains (bacteria and fungi), and synergy with antibiotics and EP inhibition were investigated. Derivative 10 showed antibacterial activity against the studied strains, derivatives 5 and 6 showed the ability to inhibit EPs in the acrA gene inactivated mutant Salmonella enterica serovar Typhimurium SL1344, and 6 also inhibited EPs in Staphylococcus aureus 272123. Structure-activity relationships highlighted trimethoxybenzoic acid as important for EP inhibitory activity. Although further studies are necessary, these results show the potential of simple trimethoxybenzoic acid derivatives as a source of feasible EP inhibitors.

Coumarins, furocoumarins and limonoids of Citrus trifoliata and their effects on human colon adenocarcinoma cell lines.

Citrus trifoliata L. (Chinese or Japanese bitter orange) is a medicinal plant with furocoumarins and limonoids as characteristic secondary metabolites. The bitter taste of the fruit limits its use as food, however, it is applied in Asian traditional medicine for its antiphlogistic effect, to treat digestive ulcers and different gastrointestinal disorders and cancer. The phytochemical composition and pharmacological characteristics of this species have not been fully discovered, nevertheless its potential antiproliferative or cytotoxic effects might be related to furocoumarins or limonoids. Our aim was to isolate and identify secondary metabolites from C. trifoliata peel and seeds and to investigate their bioactivities that might be related to the supposed anticancer effect of the plant. By using different chromatographic methods, six pure compounds (phellopterin (2), scoparone (3), myrsellin (4), triphasiol (6), umbelliferone (7) and citropten (5,7-dimethoxycoumarin (8)) were isolated from the peel and four (imperatorin (1), auraptene (5), limonin (9) and deacetyl nomilin (10)) from the seeds of C. trifoliata fruits. These compounds are furocoumarin (1, 2), coumarin (3-8), and limonoid derivatives (9, 10). Scoparone (3) has been detected in this species for the first time. The furocoumarins (1-2) showed moderate activity on the human colorectal adenocarcinona tumor cell line COLO 320 in antiproliferative assays and 2 also had remarkable P-glycoprotein inhibitory activity and synergistic effect with doxorubicin. The coumarin 5 showed significant activity on the COLO 320 cell line in antiproliferative assays and P-glycoprotein inhibitory activity in the FACS (fluorescence activated cell sorting) assay.

Synthesis of 4-Hydroxyquinolines as Potential Cytotoxic Agents.

The synthesis of alkyl 2-(4-hydroxyquinolin-2-yl) acetates and 1-phenyl-4-(phenylamino)pyridine-2,6(1H,3H)-dione was optimised. Starting from 4-hydroxyquinolines (4HQs), aminomethylation was carried out via the modified Mannich reaction (mMr) applying formaldehyde and piperidine, but a second paraformaldehyde molecule was incorporated into the Mannich product. The reaction also afforded the formation of bisquinoline derivatives. A new 1H-azeto [1,2-a]quinoline derivative was synthesised in two different ways; namely starting from the aminomethylated product or from the ester-hydrolysed 4HQ. When the aldehyde component was replaced with aromatic aldehydes, Knoevenagel condensation took place affording the formation of the corresponding benzylidene derivatives, with the concomitant generation of bisquinolines. The reactivity of salicylaldehyde and hydroxynaphthaldehydes was tested; under these conditions, partially saturated lactones were formed through spontaneous ring closure. The activity of the derivatives was assessed using doxorubicin-sensitive and -resistant colon adenocarcinoma cell lines and normal human fibroblasts. Some derivatives possessed selective toxicity towards resistant cancer cells compared to doxorubicin-sensitive cancer cells and normal fibroblasts. Cytotoxic activity of the benzylidene derivatives and the corresponding Hammett-Brown substituent were correlated.

Antiproliferative and cytotoxic effects of sesquiterpene lactones isolated from Ambrosia artemisiifolia on human adenocarcinoma and normal cell lines.

CONTEXT: Ambrosia artemisiifolia L. (Asteraceae) contains sesquiterpene lactones as characteristic secondary metabolites. Many of these compounds exert antiproliferative and cytotoxic effects. OBJECTIVE: To isolate the sesquiterpene lactones from the aerial part of A. artemisiifolia and to elucidate their cytotoxic, antiproliferative and antibacterial effects. MATERIALS AND METHODS: The compounds were identified by one-dimensional (1D) and 2D NMR, HR-MS spectroscopy from the methanol extract. Isolated compounds were investigated for their cytotoxic and antiproliferative effects on human colonic adenocarcinoma cell lines and human embryonal lung fibroblast cell line using MTT assay. The selectivity of the sesquiterpenes was calculated towards the normal cell line. To check the effect of drug interactions between compounds and doxorubicin, multidrug-resistant Colo 320 cells were used. RESULTS: A new seco-psilostachyinolide derivative, 1,10-dihydro-1'-noraltamisin, and seven known compounds were isolated from the methanol extract. Acetoxydihydrodamsin had the most potent cytotoxic effect on sensitive (Colo205) cell line (IC50 = 7.64 µM), also the strongest antiproliferative effect on Colo205 (IC50 = 5.14 µM) and Colo320 (IC50 = 3.67 µM) cell lines. 1'-Noraltamisin (IC50 = 8.78 µM) and psilostachyin (IC50 = 5.29 µM) showed significant antiproliferative effects on the multidrug-resistant Colo320 cell line and had moderate selectivity against human embryonal lung fibroblast cell line. Psilostachyin C exhibited cytotoxic effects on Colo205 cells (IC50 = 26.60 µM). None of the isolated compounds inhibited ABCB1 efflux pump (EP; P-glycoprotein) or the bacterial EPs. DISCUSSION AND CONCLUSIONS: Acetoxydihydrodamsin, 1'-noraltamisin, and psilostachyin showed the most remarkable cytotoxic and antiproliferative activity on tumour cell lines and exerted selectivity towards MRC-5 cell line.

Antimicrobial, Multidrug Resistance Reversal and Biofilm Formation Inhibitory Effect of Origanum majorana Extracts, Essential Oil and Monoterpenes.

Origanum majorana L. is a widely used medicinal plant; its distilled oil and preparations are extensively utilised in the phytotherapy and food industries. The objective of this study is to evaluate the extracts and the essential oil (EO) of Origanum majorana L, and its monoterpenes for antimicrobial, bacterial multidrug resistance reversing, and biofilm formation inhibitory potency. The composition of EO and n-hexane extract was characterized by GC-MS. In the essential oil terpinen-4-ol (24.92%), trans-sabinene hydrate (25.18%), γ-terpinene (6.48%), cis-sabinene hydrate (5.44%), p-cymene (4.72%), sabinene (4.53%), α-terpineol (4.43%), and α-terpinene (3.00%) were found as the main constituents while trans-sabinene hydrate (1.43%), and terpinen-4-ol (0.19%) were detected in the n-hexane extract besides a series of hydrocarbons. The antibacterial activity of EO and terpinen-4-ol, α-terpinene, and linalool was also assessed against sensitive and drug-resistant S. aureus, and E. coli strains with MIC values of 0.125-0.250% and 30-61 µM, respectively. In the efflux pump (EP) inhibitory assay, made by the ethidium bromide accumulation method in E. coli ATCC 25922, and AG100 and S. aureus ATCC 25923, and MRSA ATCC 43300 strains, EO exhibited substantial activity, especially in the E. coli ATCC 25922 strain. Among the EO constituents, only sabinene was an EP inhibitor in sensitive Escherichia strain. In the case of S. aureus strains, EO and sabinene hydrate exhibited moderate potency on the drug-resistant phenotype. The antibiofilm effects of the samples were tested by crystal violet staining at sub-MIC concentration. γ-Terpinene, terpinen-4-ol, sabinene, sabinene hydrate and linalool were found to be effective inhibitors of biofilm formation (inhibition 36-86%) on E. coli ATCC 25922 and S. aureus MRSA ATCC 43300, while EO was ineffective on these strains. In contrast to this, biofilms formed by E. coli AG100 and S. aureus ATCC 25923 were significantly inhibited by the EO; however, it was not affected by any of the monoterpenes. This observation suggests that the antibiofilm effect might be altered by the synergism between the components of the essential oil.

Selenium and tellurium in the development of novel small molecules and nanoparticles as cancer multidrug resistance reversal agents.

Selenium is an essential trace element that is crucial for cellular antioxidant defense against reactive oxygen species (ROS). Recently, many selenium-containing compounds have exhibited a wide spectrum of biological activities that make them promising scaffolds in Medicinal Chemistry, and, in particular, in the search for novel compounds with anticancer activity. Similarly, certain tellurium-containing compounds have also exhibited substantial biological activities. Here we provide an overview of the biological activities of seleno- and tellurocompounds including chemopreventive activity, antioxidant or pro-oxidant activity, modulation of the inflammatory processes, induction of apoptosis, modulation of autophagy, inhibition of multidrug efflux pumps such as P-gp, inhibition of cancer metastasis, selective targeting of tumors and enhancement of the cytotoxic activity of chemotherapeutic drugs, as well as overcoming tumor drug resistance. A review of the chemistry of the most relevant seleno- or tellurocompounds with activity against resistant cancers is also presented, paying attention to the synthesis of these compounds and to the preparation of bioactive selenium or tellurium nanoparticles. Based on these data, the use of these seleno- and tellurocompounds is a promising approach in the development of strategies that can drive forward the search for novel therapies or adjuvants of current therapies against drug-resistant cancers.