Hybrid Drugs-A Strategy for Overcoming Anticancer Drug Resistance?

Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers' molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance.

Cinnoline Scaffold-A Molecular Heart of Medicinal Chemistry?

The cinnoline nucleus is a very important bicyclic heterocycle that is used as the structural subunit of many compounds with interesting pharmaceutical properties. Cinnoline derivatives exhibit broad spectrum of pharmacological activities such as antibacterial, antifungal, antimalarial, anti-inflammatory, analgesic, anxiolytic and antitumor activities. Some of them are under evaluation in clinical trials. In the present review, we have compiled studies focused on the biological properties of cinnoline derivatives conducted by many research groups worldwide between 2005 and 2019. Comprehensive and target oriented information clearly indicate that the development of cinnoline based molecules constitute a significant contribution to the identification of lead compounds with optimized pharmacodynamic and pharmacokinetic properties.

Synthesis, Biological Activity and Preliminary in Silico ADMET Screening of Polyamine Conjugates with Bicyclic Systems.

Polyamine conjugates with bicyclic terminal groups including quinazoline, naphthalene, quinoline, coumarine and indole have been obtained and their cytotoxic activity against PC-3, DU-145 and MCF-7 cell lines was evaluated in vitro. Their antiproliferative potential differed markedly and depended on both their chemical structure and the type of cancer cell line. Noncovalent DNA-binding properties of the most active compounds have been examined using ds-DNA thermal melting studies and topo I activity assay. The promising biological activity, DNA intercalative binding mode and favorable drug-like properties of bis(naphthalene-2-carboxamides) make them a good lead for further development of potential anticancer drugs.

DNA Interaction Studies of Selected Polyamine Conjugates.

The interaction of polyamine conjugates with DNA double helix has been studied. Binding properties were examined by ethidium bromide (EtBr) displacement and DNA unwinding/topoisomerase I/II (Topo I/II) activity assays, as well as dsDNA thermal stability studies and circular dichroism spectroscopy. Genotoxicity of the compounds was estimated by a comet assay. It has been shown that only compound 2a can interact with dsDNA via an intercalative binding mode as it displaced EtBr from the dsDNA-dye complex, with Kapp = 4.26 × 106 M-1; caused an increase in melting temperature; changed the circular dichroism spectrum of dsDNA; converted relaxed plasmid DNA into a supercoiled molecule in the presence of Topo I and reduced the amount of short oligonucleotide fragments in the comet tail. Furthermore, preliminary theoretical study has shown that interaction of the discussed compounds with dsDNA depends on molecule linker length and charge distribution over terminal aromatic chromophores.

IN SILICO ADME STUDIES OF POLYAMINE CONJUGATES AS POTENTIAL ANTICANCER DRUGS.

The ADME properties and drug-likeness of several polyamine derivatives containing dimeric phthalimide, quinoline, cinnoline and chromone moieties with three different polyamines: 1,4-bis(3-aninopropyl)piperazine, 4,9-dioxa-1,12-dodecanediamine and 3,3-diamino-N-methyldipropylamine as linkers were presented. These compounds are structurally related to DNA bisintercalators, a group of agents with anti-cancer activity. Their biological properties were previously assessed in vitio in a highly aggressive melanoma cell line A375. Current studies evaluate their potential to be qualified as drugs by performing in silico ADME screening. The research is carried out using Discovery Studio 3.0 ADMET protocol obtained from Accelrys and might be useful for further developing and optimization of potential anticancer drugs.

Synthesis and biological evaluation of new bischromone derivatives with antiproliferative activity.

The synthesis of new bischromone derivatives (4a-c and 5a-c) as potential anticancer drugs is described. The difference in the reactivity between 4-oxo-4H-chromene-3-carboxylic acid 2 (or its methyl ester 3) and 4-oxo-4H-chromene-3-carbonyl chloride 1 with three different polyamines: 3,3'-diamino-N-methyldipropylamine (a), 1,4-bis(3-aminopropyl)piperazine (b), 4,9-dioxa-1,12-dodecanediamine (c) resulted in the formation of two different groups of products, compounds 4a-c and 5a-c, designed in agreement with the bisintercalators' structural requirements. The transformation of 4-oxo-4H-chromene-3-carboxylic acid into 2H-chromene-2,4(3H)-diones (5) was confirmed by the NMR and XRD experiments. Compounds 4a and 5a were evaluated in vitro in the highly aggressive melanoma cell line A375. An enhanced induction of apoptosis and cell cycle arrest clearly revealed that compound 5a was more potent than 4a. Compound 5a was also more active in diminishing the adhesive potential of melanoma cells. Current studies support the notion that small changes in the three-dimensional structure of molecules might have a substantial impact on their biological activity.

Anticancer activity of some polyamine derivatives on human prostate and breast cancer cell lines.

The aim of this study was to expand our knowledge about anticancer activity of some polyamine derivatives with quinoline or chromane as terminal moieties. Tested compounds were evaluated in vitro towards metastatic human prostate adenocarcinoma (PC3), human carcinoma (DU145) and mammary gland adenocarcinoma (MCF7) cell lines. Cell viability was estimated on the basis of mitochondrial metabolic activity using water-soluble tetrazolium WST1 to establish effective concentrations of the tested compounds under experimental conditions. Cytotoxic potential of polyamine derivatives was determined by the measurement of lactate dehydrogenase activity released from damaged cells, changes in mitochondrial membrane potential, the cell cycle distribution analysis and apoptosis assay. It was revealed that the tested polyamine derivatives differed markedly in their antiproliferative activity. Bischromane derivative 5a exhibited a rather cytostatic than cytotoxic effect on the tested cells, whereas quinoline derivative 3a caused changes in cell membrane integrity, inhibited cell cycle progression, as well as induced apoptosis of prostate and breast cancer cells which suggest its potential application in cancer therapy.

Synthesis and in vitro biological evaluation of new polyamine conjugates as potential anticancer drugs.

The synthesis of new polyamine derivatives containing dimeric quinoline (3a-c), cinnoline (4a-c) and phthalimide (7a-c and 8a-c) moieties is described. Three different polyamines: (1,4-bis(3-aminopropyl)piperazine (a), 4,9-dioxa-1,12-dodecanediamine (b), 3,3'-diamino-N-methyldipropylamine (c) were used as linkers. The new compounds were obtained according to known procedures. Their biological activity was assessed in vitro in a highly aggressive melanoma cell line A375. Polyamine diimides containing phthalimide moieties demonstrated no inhibitory activities against melanoma cells. Quinoline diamides were more efficient than cinnoline ones. Mainly cytostatic activity exerted as altered cell cycle profiles was observed at the concentrations causing about 50% reduction of adherent cell proliferation. Based on their structure as well as their biological activity, we assume that some of the newly synthesized compounds may act as DNA bisintercalators. This study might be useful for further designing and developing anticancer drugs with potent activities.