Anti-cancer agents in medicinal chemistry [journal]
- Pyrrolidino Analogues of Gefitinib with Improved EGFR Inhibition, Cancer Cell Cytotoxicity and Pharmacokinetic Properties. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2016 Jun 21.
The binding mode analysis of Gefitinib revealed that 6-propylmorpholino group (sidechain) shows no interactions due to its weak electron density. In order to modify the electron density of Gefitinib's sidechain, novel pyrrolidino analogues of Gefitinib where morpholino groups were replaced by substituted pyrrolidino groups were synthesized. Gefitinib derivatives with high electronegativity atoms or groups in the pyrrolidino moiety always exhibit high potent activity against EGFR and human cancer cell lines, A431, MDA-MB-231 and A549. Among these derivatives, 16 displayed the best pharmacokinetic properties that makes it to be a promising candidate for developing drugs to replace Gefitinib.
- Quinoxaline Nucleus: A Promising Scaffold in Anti-cancer Drug Discovery. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2016 Jun 21.
Heterocyclic compounds are a class of substances, which play a critical role in modern drug discovery being incorporated in the structure of a large variety of drugs used in many different types of diseases. Quinoxaline is an important heterocycle nucleus with a wide spectrum of biological activities, and recently much attention has been found on anticancer drug discovery based on this class. Owing to the importance of this system, the aim of this review is to provide an update on the synthesis and anticancer activity of quinoxaline derivatives covering articles published between 2010 and 2015.
- Statins and Alkylphospholipids as New Anticancer Agents Targeting Lipid Metabolism. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2016 Jun 23.
The partial efficacy and high toxicity of the current anticancer chemotherapeutics as well as the development of multiple drug resistance are major problems in cancer therapy. Therefore, there is an emergency need for the development of novel well-tolerated anticancer agents with different mode of action that could be successfully used in combination with other drugs as an adjuvant therapy. The inhibition of intracellular signaling pathways associated with cancer growth and invasiveness is a main therapeutic approach in cancer treatment. It is well known that lipid metabolism is involved in the regulation of key cellular processes such as proliferation, differentiation and apoptosis. Statins and alkylphospholipids are both relatively new synthetic agents with considerable anticancer properties that disturb lipid metabolism and subsequently modulate proliferation and cell survival signaling pathways, leading to apoptosis. Numerous in vitro and in vivo studies have shown promising results for the use of statins and alkylphospholipids as potential therapeutic agents in the treatment of various human malignancies. However, more investigations and clinical trials are needed to assess their optimal safe dose and maximal efficacy and better understand the molecular mechanisms underlying the antitumor effects of these drugs.
- Glycodendrimer PPI as a Potential Drug in Chronic Lymphocytic Leukemia. The Influence of Glycodendrimer on Apoptosis in in vitro B-CLL Cells Defined by Microarrays. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2016 Jun 21.
Chronic lymphocytic leukemia (CLL) cells are characterized by failures in the apoptosis pathway and increased proliferation, resulting in the progressive accumulation of B-lymphocytes in blood. Despite the wide range of antileukemic drugs, CLL remains an incurable disease. However, a breakthrough is expected which will allow more effective treatment. The study investigates the influence of poly(propylene)imine (PPI) dendrimer on peripheral amino groups, 30% of which were coated with maltotriose (PPI-G4-OS-Mal-III), on CLL cells, and demonstrates that it acts through the induction of the apoptotic mechanism. CLL and normal lymphocytes were treated with the dendrimer, either alone or in combination with fludarabine (FA). The results confirm that PPI-G4-OS-Mal-III influences the viability of CLL cells in vitro and does not exert any significant harmful effect on normal lymphocytes. It is important to note that the dendrimer was used as a drug itself and not as a drug carrier. The percentages of apoptotic and necrotic cells, and the protein expression, were checked using a flow cytometer. Gene expression was screened using a two-colour microarray with 60-mer probes. The dendrimer appears to significantly influence gene and protein expression in CLL cells. Since dendrimers can be specifically targeted, they may be very effective in CLL therapy, especially since in vitro PPI-G4-OS-Mal-III has been found to have stronger effect than fludarabine.
- A Facile and Microwave-assisted Rapid Synthesis of 2-Arylamino-4-(3c-indolyl)-thiazoles as Apoptosis Inducing Cytotoxic Agents. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2016 Jun 21.
A new series of novel 2-arylamino-4-(3¢-indolyl)thiazoles have been designed as potent cytotoxic agents. One-pot microwave-assisted rapid and high yielding synthesis of 2-arylamino-4-(3¢-indolyl)thiazoles involve the reaction of easily available α-tosyloxyketones with N-arylthioureas in polyethylene glycol-400 (PEG-400). In-vitro cytotoxicity study of 2-arylamino-4-(3¢-indolyl)thiazoles against a panel of human cancer cell lines revealed IC50 values in the low micromolar range. Of the fifteen synthesized arylaminothiazoles, compounds 17b, 17d, 17g and 17i-l showed significant anti-proliferative activity against the selected cancer cell lines with IC50 < 10 µM. The lead compound 17b in this series exhibited good cytotoxic activity against MCF-7 breast cancer cells with an IC50 value of 1.86 µM, which was better in comparison to doxorubicin. Furthermore, it was found that the potent compound 17b induces ROS-mediated apoptosis in MCF-7 cells in a dose-dependent manner as indicated by upregulation of Bax and caspase-3 and down-regulation of Bcl-2 through the mitochondrial apoptosis pathway.
- Physico-chemical and biological evaluation of flavonols: fisetin, quercetin and kaempferol alone and incorporated in beta cyclodextrins. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2016 Jun 20.
Incorporation of fisetin, quercetin and kaempferol in beta cyclodextrins was proved by scanning electron microscopy (SEM), differencial scanning calorimetry (DSC) and X-ray powder diffraction (XRPD). Pure compounds and their complexes where tested for antiproliferative and pro-apoptotic activity on the B164A5 murine melanoma cell line and for the antimicrobial properties on the selected strains. The phytocompounds present in a different manner in vitro chemopreventive and weak antimicrobial activity. Incorporation in beta cyclodextrins had a mixt effect on the biological activity conducing to decrease, increase or consistent effect compared to pure phytocompound depending on the screened process and on the chosen combination.
- Synthesis, in vitro antiproliferative and antiinflammatory activities, and kinase inhibitory effects of a new series of 1,3,4-triarylpyrazole derivatives. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2016 Jun 19.
In the present study, a series of new 1,3,4-triarylpyrazole derivatives were synthesized. Their in vitro antiproliferative activity was tested against a panel of 58 cancer cell lines of nine different cancer types at the NCI. Compounds 1a, 1c, and 1g showed the highest activities against the cancer cell line panel, with more inhibitory effects against leukemia and breast cancer subpanels. The highest activity was exerted by compound 1a possessing methoxy group and mono-substituted pyridyl ring. It exerted 77.83%, 72.90%, and 76.47% inhibitions at 10 µM concentration against RPMI-8226, K-562 leukemia cell lines, and MDA-MB-468 breast cancer cell line, respectively. Its IC50 values against those most three cell lines were 0.174 µM, 1.19 µM, and 4.08 µM, respectively. Compound 1a was further tested against a panel of 16 kinases, many of them are known to be over-expressed in leukemia and breast cancer. The most sensitive kinases were V600E-B-RAF, C-RAF, FLT3, and P38α/MAPK14. The highest potency was exerted against P38α/MAPK14, IC50 was 0.515 µM. Moreover, the ability of compounds 1a, 1b, and 1g to inhibit NO and PGE2 production in LPS-induced RAW 264.7 macrophages was also examined. The hydroxyl analogue 1b was the most active as antiinflammatory agent. At 50 µM concentration, it inhibited 80.26% and 95.31% of NO and PGE2 productions, respectively, in the LPS-induced RAW 264.7 macrophages. Compound 1a was more selective against cancer cells than non-cancerous cells.
- Retinoic acid Signaling in P19 Stem Cell Differentiation. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2016 Jun 14.
Retinoic acid, especially all-trans retinoic acid (RA) is the most potent natural form of vitamin A. RA is involved in a variety of biological functions including embryogenesis, cell differentiation and apoptosis. RA acts through its nuclear receptors by inducing transcription of specific target genes. Mouse P19 embryonic carcinoma (EC) stem cells (ES) are one of the most studied in vitro systems for RA-induced differentiation. P19 stem cells can be induced to differentiate into endodermal-like, mesodermal-like, and neuronal-like phenotypes in response to specific morphogens including RA. At low concentrations, RA directs P19 stem cells to differentiate to cells displaying an endodermal phenotype, whereas at higher concentrations it induces differentiation to neuroectoderm. In the past, many RA-regulated genes have been discovered in EC and ES cells and efforts are ongoing to elucidate the exact mechanisms of RA-induced ES cell differentiation and death. In the RA-induced differentiation process of the P19 stem cells, several proteins belonging to different families participate, some being obligatory while others, dispensable. Revealing the mechanisms behind RA-induced effects on ES cells has a bearing on understanding how cells proliferate and undergo apoptosis that can provide greater insight into cancer biology and therapy. In addition to summarizing the reports on gene/protein targets of RA in stem cells, the signaling pathways driven by some of the specific class of proteins in presence or absence of RA in P19 stem cells are the focus of this review.
- Regulatory Approaches to Non-clinical Reproductive Toxicity Testing of Anti-Cancer Drugs. [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2016 Jun 13.
This paper reviews the non-clinical reproductive toxicity testing of 15 drugs currently approved in the USA or Europe for the treatment of cancer. The list includes cytotoxic anti-tumour agents, small molecule inhibitors of pathways involved in neoplastic proliferation, monoclonal antibodies that target specific antigens expressed by neoplastic cells and supportive therapies used to counter the effects of chemotherapy. Most, but not all, drugs were tested for developmental or reproductive toxicity in animals prior to marketing and most were found to be embryotoxic or teratogenic. Because of the unmet need for comparative safety data on available cancer therapies for use by physicians when treating pregnant patients, at least embryo-fetal toxicity studies are now usually requested prior to marketing of new anti-cancer drugs, even when the pharmacological profile suggests likely side-effects on the embryo or fetus. A fertility study, and possibly a pre- and post-natal development study, is required for drugs intended to treat neoplastic conditions for which there is a good prognosis of long-term survival. Rats and rabbits are the preferred experimental species, but non-human primates are the only relevant models for some biopharmaceuticals. Non-clinical studies for anti-cancer drugs should be designed to allow the possibility of terminating the study once adverse effects have been adequately characterised, without using the full number of animals specified in regulatory guidelines. All 15 drugs are currently labelled as being harmful to pregnancy, either on the basis of animal data or documented hazards in humans. The recent revision of the FDA drug labelling.
- Hydroxy Cinnamic Acid Derivatives as Partial PPARγ agonists: In Silico Studies, Synthesis and Biological Characterization Against Chronic Myeloid Leukemia Cell Line (K562). [JOURNAL ARTICLE]
- Anticancer Agents Med Chem 2016 Jun 6.
Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that regulates the expression of many genes relevant to carcinogenesis. By analogy to selective estrogen receptor modulator for treatment of cancer, selective or partial PPARγ agonists are considered clinically important for chemotherapy of cancer. A series of p-coumaric (3a-3y) and ferulic acid (4a-4y) derivatives were designed and docked and virtually studied for their molecular properties. Synthesized derivatives were assessed to check their effect on non-transformed hepatocytes and further evaluated for their anti-proliferative potential on K562. Molecules 3c, 3m, 4c and 4m were found to have GI50 value less than 50μM. These molecules were found to block G0/G1 phase of cell cycle in dose dependent manner. Western blot analysis revealed that these molecules inhibit proliferating cell nuclear antigen (PCNA) and cyclin D1 expression. Collectively, these results suggest that these molecules could play a role as a novel therapeutic strategy for chronic myeloid leukemia.