Search Results (6)

The ineffectiveness and failing of chemotherapeutic treatments are often associated with multidrug resistance (MDR). MDR is primarily linked to the overexpression of ATP-binding cassette (ABC) transporter proteins in cancer cells. ABCG2 (ATP-binding cassette subfamily G member 2, also known as the breast cancer resistance protein (BCRP)) mediates MDR by an increased drug efflux from the cancer cells. Therefore, the inhibition of ABCG2 activity during chemotherapy ought to improve the efficacy of the administered anti-cancer agents by reversing MDR or by enhancing the agents’ pharmacokinetic properties. Significant efforts have been made to develop novel, powerful, selective, and non-toxic inhibitors of BCRP. However, thus far the clinical relevance of BCRP-selective MDR-reversal has been unsuccessful, due to either adverse drug reactions or significant toxicities in vivo. We here report a facile access towards carboranyl quinazoline-based inhibitors of ABCG2. We determined the influence of different methoxy-substitution patterns on the 2-phenylquinazoline scaffold in combination with the beneficial properties of an incorporated inorganic carborane moiety. A series of eight compounds was synthesized and their inhibitory effect on the ABCG2-mediated Hoechst transport was evaluated. Molecular docking studies were performed to better understand the structure-protein interactions of the novel inhibitors, exhibiting putative binding modes within the inner binding site. Further, the most potent, non-toxic compounds were investigated for their potential to reverse ABCG2-mediated mitoxantrone (MXN) resistance. Of these five evaluated compounds, N-(closo-1,7-dicarbadodecaboran(12)-9-yl)-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)-quinazolin-4-amine (DMQCd) exhibited the strongest inhibitory effect towards ABCG2 in the lower nanomolar ranges. Additionally, DMQCd was able to reverse BCRP-mediated MDR, making it a promising candidate for further research on hybrid inorganic-organic compounds. Full article

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. Full article

The extensive use of conventional antibiotics has led to the growing emergence of many resistant strains of pathogenic bacteria. Evidence suggests that cationic antimicrobial peptides (AMPs) have the greatest potential to serve as traditional antibiotic substitutes. Recent studies have also reported that certain AMPs have selective toxicity toward various types of cancer cells. The electrostatic attraction between the negatively charged membrane components and AMPs is believed to play a crucial role in the disruption of bacterial and cancer cell membranes. In the current study, we used a potent AMP called Pleurocidin (Ple) derived from winter flounder Pleuronectes americanus and its C-terminal-amidated derivative Pleurocidin-amide (Ple-a), and evaluated their antibacterial and anticancer activities. Our results indicated that both Ple and Ple-a exhibited significant antibacterial activity against a broad spectrum of Gram-positive and Gram-negative bacteria, especially marine pathogens, with MIC values ranging from 0.25 to 32 μg/mL. These peptides are also potent against several multidrug-resistant (MDR) bacterial strains, with MIC values ranging from 2 to 256 μg/mL. When used in combination with certain antibiotics, they exhibited a synergistic effect against MDR E. coli. Ple and Ple-a also showed notable cytotoxicity toward various cancer cell lines, with IC₅₀ values ranging from 11 to 340 μM, while normal mouse fibroblast 3T3 cells were less susceptible to these peptides. Ple-a was then selected to study its anticancer mechanism toward A549 human lung adenocarcinoma cells. Western blot analysis and confocal microscopy showed that Ple-a could inhibit autophagy of A549 cells, and induce apoptosis 48 h after treatment. Our findings provided support for the future application of Ple-a as potential therapeutic agent for bacterial infections and cancer treatment. Full article

Globally, colon cancer is a major cause of deaths, being the fourth most common type of cancer in the world. The most common therapeutic choice in the early stages of colon cancer is surgical resection, but in some stages of the disease, adjuvant chemotherapy is recommended and is essential for the proper treatment of this pathology [¹]. Complex combinations based on metals play an important role in the treatment of cancer because of their cytotoxic properties against cancer cells. An organometallic compound that can be used clinically and that plays an important role in the treatment of patients with colon cancer is oxaliplatin. Following studies, chlorine-based derivatives of Au (I)-phosphate showed comparable values to cisplatin on HT-29 (colon cancer) cell lines. Further studies continued to determine absorption at the cellular level, showing that most lipophilic compounds demonstrated a higher colon cancer cell absorption, meaning that they could be correlated with high antiproliferative activity [²]. Copper-based complex combinations were studied, and an inhibitory effect in the nanomolar range on the Colo 205 and Colo 320 colon cancer cell lines was thus observed. Some complexes showed increased toxicity to cancer cells compared to the MRC-5 cell lines. The antiproliferative activity of these complex combinations is significantly low in normal cell lines, thus increasing selectivity towards neoplastic cells was observed. Complex combinations based on Cu (I) show cytotoxic effects against LoVo MDR cell lines that are five times higher compared to oxaliplatin, thus showing the ability to overcome oxaliplatin resistance [³]. Nanostructured drug delivery systems allow the incorporation of metal-based drugs, thus limiting some of their most common shortcomings, such as low selectivity, low solubility and permeability, and high toxicity, which limit he dosage and the emergence of resistance at the cellular level [⁴]. These drug delivery systems are able to carry the drug and to release it according to its requested dose, even in a targeted manner, thus improving therapeutic activity and limiting systemic toxicity. Full article

In recent years, hundreds of novel small molecular drugs used for different treatments have been studied in the three phases of clinical trials around the world. However, less than 10% of them are eventually used due to diverse problems. Even some traditional drugs that have been approved by the Food and Drug Administration (FDA) have faced similar dilemmas. For instance, many drugs have poor water solubility, are easily hydrolyzed, or possess undesirable toxicity, while a variety of cancer cells develop drug resistance (DR) or multiple drug resistance (MDR) towards chemotherapeutic agents after long-term therapy. In order to improve the efficacy and efficiency of drugs, research has been directed forward towards the creation of assemblies of peptide–drug conjugates (PDCs) which have proven to possess wide potential for overcoming such complications based on their excellent biocompatibility, controllable biodegradability, site-selective targeting, and comparably low cytotoxicity. In this review, we focus on the recent developments and advances made in the creation of self-assembled nanostructures of PDCs for cancer therapy, on the chemical and physical properties of such drugs and peptides, and how they are arranged together to form diverse supramolecular nanostructures. Additionally, we cover certain mechanisms regarding how peptides or their derivatives enhance the efficiency and efficacy of those selected drugs and provide a brief discussion regarding the perspectives and remaining challenges in this intriguing field. Full article

Heat Shock Protein 90 (Hsp90) chaperone interacts with a broad range of client proteins involved in cancerogenesis and cancer progression. However, Hsp90 inhibitors were unsuccessful as anticancer agents due to their high toxicity, lack of selectivity against cancer cells and extrusion by membrane transporters responsible for multidrug resistance (MDR) such as P-glycoprotein (P-gp). Recognizing the potential of new compounds to inhibit P-gp function and/or expression is essential in the search for effective anticancer drugs. Eleven Hsp90 inhibitors containing an isoxazolonaphtoquinone core were synthesized and evaluated in two MDR models comprised of sensitive and corresponding resistant cancer cells with P-gp overexpression (human non-small cell lung carcinoma and colorectal adenocarcinoma). We investigated the effect of Hsp90 inhibitors on cell growth inhibition, P-gp activity and P-gp expression. Structure–activity relationship analysis was performed in respect to cell growth and P-gp inhibition. Compounds 5, 7, and 9 directly interacted with P-gp and inhibited its ATPase activity. Their potential P-gp binding site was identified by molecular docking studies. In addition, these compounds downregulated P-gp expression in MDR colorectal carcinoma cells, showed good relative selectivity towards cancer cells, while compound 5 reversed resistance to doxorubicin and paclitaxel in concentration-dependent manner. Therefore, compounds 5, 7 and 9 could be promising candidates for treating cancers with P-gp overexpression. Full article