Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 14, Issue 7, 2014

Patients with cancer are frequently exposed to risk of renal injuries associated with disease-related or iatrogenic causes. Nephrotoxicity is a potential adverse effect of anti-cancer agents and may result in a variety of functional abnormalities, including glomerular or tubular dysfunction, hypertension and disturbance of the renal endocrine function. In this review article, we comprehensively discuss the incidence, clinical presentation, prevention and management of anti-cancer agent-induced renal dysfunction. We focus on both relatively new anti-cancer agents (bevacizumab, gefitinib, gemcitabine, imatinib, rituximab and trastuzumab) and traditional agents (cisplatin, methotrexate, ifosfamide and taxanes) to cover a selection of the most frequently used anti-cancer agents. Increased understanding of the mechanism of renal injury by these agents is considered to be important for developing novel anti-cancer agents that have far fewer adverse effects on kidneys.

Background: Aberrant activity of epidermal growth factor receptor (EGFR) family proteins has been found to be associated with a number of human cancers including that of lung and breast. Consequently, the search for EGFR family inhibitors, a well established target of pharmacological and therapeutic value has been ongoing. Therefore, over the years several small molecules, which compete for ATP in the kinase domain have been synthesised and some of them have proved to be effective in attenuating EGFR mediated proliferation. Thus, there exists in literature a vast amount of experimental data on EGFR tyrosine kinase inhibitors. In this paper, we describe a comprehensive database EGFRIndb that contains details of the small molecular inhibitors of EGFR family. Description: EGFRIndb is a literature curated database of small synthetic molecular inhibitors of EGFR. It consists of 4581 compounds showing in vitro inhibitory activities (IC50, IC80, GI50, GI90, EC50, Ki, Kd and percentage inhibition) either against EGFR or its different isoforms i.e. Erbb2 (v-erb-b2 avian erythroblastic leukaemia viral oncogene homolog 2) and Erbb4 (v-erb-b2 avian erythroblastic leukaemia viral oncogene homolog 4) or various mutants. For each compound, database provides information on structure, experimentally determined inhibitory activity of compound against kinase as well as various cell lines, properties (physical, elemental and topological) and drug likeness. Additionally, it provides information on irreversible as well as dual inhibitors that have gained importance in recent years due to the emergence of clinical resistance to known drugs. As compound activity against similar kinases is a measure of its selectivity and specificity, the database also provides this information. It also provides simple search, advanced search, browse facility as well as a tool for structure based searching. Conclusion: EGFRIndb gathers biological and chemical information on EGFR inhibitors from the literature. It is hoped that it will serve as a useful resource in drug discovery and provide data for docking, virtual screening and Quantitative structure–activity relationship (QSAR) model development to the cancer researchers.

Betulinic acid (BA), a natural compound with a lupan skeleton, has been highly investigated in the past decade for a plethora of beneficial properties, including anti-cancer, anti-inflammatory, anti-angiogenic, immune-modulatory, and anti-HIV effects. In particular, BA has been reported to be effective in vitro against tumor cell lines of different origins, and also in vivo, in animal models of cancer. The best characterized mechanism of its antitumor effect consists of triggering apoptosis via the mitochondrial pathway. BA has also an anti-metastatic effect via the prevention of the epithelial-to-mesencymal transition in highly aggressive melanoma cells. Furthermore, in the same model, BA is able to counteract the pro-invasive potential of the pro-tumoral protein neutrophil gelatinaseassociated lipocalin. The present review addresses the current state of knowledge regarding the anti-tumor effects of betulinic acid, a potent chemotherapeutic agent.

Auranofin is a gold compound initially developed for the treatment of rheumatoid arthritis. Recent data suggest that auranofin has promise in the treatment of other inflammatory and proliferative diseases. However, the mechanisms of action of auranofin have not been well defined. In the present study, we identify vascular endothelial growth factor receptor-3 (VEGFR3), an endothelial cell (EC) surface receptor essential for angiogiogenesis and lymphangiogenesis, as a novel target of auranofin. In both primary EC and EC cell lines, auranofin induces downregulation of VEGFR3 in a dose-dependent manner. Auranofin at high doses (≥1 μM) decreases cellular survival protein thioredoxin reductase (TrxR2), TrxR2-dependent Trx2 and transcription factor NF-κB whereas increases stress signaling p38MAPK, leading to EC apoptosis. However, auranofin at low doses (≤0.5 μM) specifically induces downregulation of VEGFR3 and VEGFR3-mediated EC proliferation and migration, two critical steps required for in vivo lymphangiogenesis. Mechanistically, we show that auranofin-induced VEGFR3 downregulation is blocked by antioxidant N-acetyl-L-cysteine (NAC) and lysosome inhibitor chloroquine, but is promoted by proteasomal inhibitor MG132. These results suggest that auranofin induces VEGFR3 degradation through a lysosome-dependent pathway. Auranofin may be a potent therapeutic agent for the treatment of lymphangiogenesis-dependent diseases such as lymphedema and cancer metastasis.

Epithelial ovarian cancer (EOC) is a highly lethal gynecological malignancy since it could not be discovered until at late stage. Identifying the molecular phenotype alteration during the development and progression of ovarian cancer is an urgent demand for the targeted intervention therapy. Recently, inflammation and Integrin beta 1(ITGB1), a subunit of heterodimeric transmembrane receptors family, had been pointed out to be involved in promoting ovarian tumorigenesis and cancer progression, respectively. However, the relationship between ITGB1 and the inflammatory mediators in ovarian cancer progression remains obscure. In the present study, ITGB1 was observed to be frequently upregulated in ovarian cancer, overexpression of ITGB1 led to a more invasive and mesenchymal phenotype. Furthermore, our results also provided evidence concerning the role of inflammatory cytokines (IL-6, TGF-β1 and SDF-1) in ITGB1 expression as well as in the malignant potential of ovarian cancer cells. Consistently, sh-RNA mediated knocking down of ITGB1 evidently reduced tumor growth and peritoneal dissemination in in vivo Nod-scid SKOV3 orthotopic xenograft mice. Overall, the present data suggested that ITGB1 upregulation was involved in the regulation of tumorigenesis and disease exacerbation exerted by inflammatory cytokines as IL-6, TGF-β1 and SDF-1, and suggested that targeting ITGB1 and the underlying inflammatory modulator was an attractive strategy for therapeutic intervention during ovarian carcinogenesis.

Cancer cells display an overproduction of reactive oxygen species resulting from an exaggerated intrinsic oxidative stress. However, the concept of deleterious oxidants versus beneficial antioxidants has recently evolved. Indeed, molecules like natural coumarins have shown anti-oxidant or pro-oxidant properties depending on their intracellular concentration. Therefore, we have investigated the structure-activity relationship of a variety of coumarin derivatives in terms of cytotoxicity towards human and murine carcinoma cell lines (HT29, HepG2, A549, MCF7, OVCAR and CT26). Amongst those compounds, (E)-7-methoxy-4-(3-oxo-3- phenylprop-1-enyl)-2H-chromen-2-one and (E)-7-hydroxy-4-(3-(4-hydroxyphenyl)-3-oxoprop-1-enyl)-2H-chromen-2-one displayed the most potent cytotoxic effect on colon cancer cells, CT26, (IC50=4.9μM) linked to their pro-oxidant properties. Those compounds triggered the in vitro production of reactive oxygen species by tumor cells, leading to their death through a necrotic process. In vivo, molecules also slowed down tumor growth by 65.7% and 35.4%, respectively, without inducing significant side effects.

In current scenario of human health and diseases, drug-induced hepatic injury has been recognized as a serious and unresolved problem. Particularly, chemotherapeutic agents have been reported to induce organ toxicity. The aim of the present study is to evaluate organ toxicity and oxidative damage induced by cyclophosphamide (CP), a chemotherapeutic drug and its amelioration by sesamol, an antioxidant from sesame seeds. CP (150 mg/kg) is injected intraperitonially to experimental rats and from day 2 rats were orally treated with sesamol. Rats were sacrificed to evaluate non-enzymatic and enzymatic oxidative stress parameters in serum and tissue homogenates on day 8. Besides, liver function parameters and pro-inflammatory mediators were assessed. Histopathological studies of liver and kidney were also carried out. Elevated levels of endogenous reactive oxygen species, lipid peroxidation and decreased levels of glutathione, total thiols, along with the reduction in antioxidant enzymes including superoxide dismutase, catalase, glutathione-stransferase and glutathione peroxidase, were evident in CP-intoxicated animals. Pro-inflammatory mediators like tumor necrosis factor - α, interleukin (IL)-1β, IL-6 and cyclooxygenase-2 were also elevated. Moreover, the levels of liver function markers like serum alanine aminotransferase and aspartate aminotransferase were also altered. Histology of liver and kidney tissues further supported CP-induced organ damage. Altered parameters were significantly restored to normal by oral administration of sesamol (50 mg/kg) suggesting its antioxidative stress, anti-inflammatory and hepatoprotective abilities. The study clearly demonstrated the potentiality of sesamol against CPinduced organ toxicity and oxidative stress suggesting its applicability in treatment regime of cancer and other stress-associated disorders as a supportive/auxiliary therapy.

Valproic acid (VPA) is extensively used as an anticonvulsive agent and as a treatment for other neurological disorders. It has been shown that VPA exerts an anti-proliferative effect on several types of cancer cells by inhibiting the activity of histone deacetylases (HDACs), which are involved in replication and differentiation processes. However, VPA has some disadvantages, among which are poor water solubility and hepatotoxicity. Therefore, the aim of the present study was to design and synthesize three derivatives of VPA to improve its physicochemical properties and anti-proliferative effects. For this purpose, the amino acids aspartic acid, glutamic acid and proline were added to the molecular structure of VPA. Docking and molecular dynamics simulations were used to determine the mode of recognition of these three derivatives by different conformations of HDAC8. This receptor was used as the specific target because of its high affinity for this type of substrate. The results demonstrate that, compared to VPA, the test compounds bind to different sites on the enzyme and that hydrogen bonds and hydrophobic interactions play key roles in this difference. The IC50 values of the VPA derivatives, experimentally determined using HeLa cells, were in the mM range. This result indicates that the derivatives have greater antiproliferative effects than the parent compound. Hence, these results suggest that these amino acid derivatives may represent a good alternative for anticancer treatment.

A novel series of 3-substituted-4-(4-methylthio phenyl)-1H-pyrrole derivatives were synthesized via Van Leusen pyrrole synthesis. The in vitro anticancer activity against a panel of 16 cancer cell lines and 2 normal cell lines was investigated by MTT assay. It was found that some of the pyrrole compounds showed similar antiproliferative activity against cancer cells compared with Paclitaxel, but little impact on normal cell lines, which indicated that the novel pyrrole derivatives could be used as potential anticancer candidates for possessing both selectivity and good therapeutic efficacy. Structure-activity relationship analysis found that 3-phenylacetyl-4- (4-methylthio phenyl)-1H-pyrrole derivatives displayed the most strong anticancer activity, among which [4-(4-methylthio phenyl)-1Hpyrrol- 3-yl] (4-methoxy phenyl) methanone (3j) was employed to investigate the effect of these pyrrole analogues on cell cycle by propidium iodide (PI) staining on cell flow cytometry. Cell necrotic effect of 10.0 μM 3j against MGC80-3 cells were also observed under fluorescence microscope and transmission electron microscope by ultrathin sections observation.

The design and synthesis of substituted 1-(1-ethy-1H-benzimidazol-2-yl) ethanone (3a-f) and substituted 1-(2-bromoethyl)-2- (1-hydrazinylidene or ethylidene)-1H-benzimidazole (3g-j) have been successfully achieved under microwave irradiation with an aim for finding promising anticancer agents. Among the synthetic compounds, those with potential activity were selected and evaluated in-vitro for anticancer activity at the National Cancer Institute (NCI), USA, against 60 cancer cell lines from nine types of human cancer. The title compound 3e (NSC: 765733/1) exhibited notable growth inhibition that satisfies threshold criteria at single dose (10 μM) on all human cell lines of NCI. This compound was considered for further study at five dose levels (0.01, 0.1, 1, 10 and 100 μM) with GI50 values ranging from 0.19 to 92.7 μM. Compound 3e was found superior for Non-small cell lung cancer cell lines (HOP-92) and calculated end points (GI50 0.19, TGI 1.45, LC50 >100 and Log10GI50 -6.70, Log10TGI -5.84, Log10LC50 >-4.00). Docking study was performed using Maestro 9.0 to provide binding mode into binding sites of topoisomerase enzyme (PDB ID: 1SC7). Hopefully in the future, compound 3e could be used as novel template for the development of potential anticancer agents.

Multidrug resistance (MDR) is a phenomenon whereby cancer cells experience intrinsic or acquired resistance to a broad spectrum of structurally and functionally distinct chemotherapeutic agents. Permeability glycoprotein (P-gp) is the key protein responsible for the development of MDR in cancer cells, as it exports chemotherapeutic agents from cells. In the present study, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram quantitative structure activity relationship (HQSAR) techniques were used to derive predictive models for phenylsulfonylfuroxan derivatives as P-gp inhibitors. Cross-validated correlation coefficients (q2) of 0.811, 0.855, and 0.907 and non-cross-validated correlation coefficients (r2) of 0.87, 0.985, and 0.973 were obtained for CoMFA, CoMSIA, and HQSAR derived models, respectively. The predictive power of the models were assessed using an external test set of five compounds and showed reasonable external predictabilities (r2 pred) of 0.704, 0.517, and 0.713, respectively. Contour and atomic contribution maps were generated to investigate physicochemical requirements of ligands for better receptor binding affinity. 3D Contour maps suggested molecular interactions such as steric and electrostatic effects and hydrogen bond formation. However, atomic contribution maps indicated that ortho and para positions of the R1 phenylsulfonyl ring are the most desirable regions to modulate P-gp antagonism. The 3rd and 4th positions of the central five-membered ring were also found to be important. Our results are in line with previous reports. Information obtained from the contour and atomic contribution maps were utilized to design more potent compounds containing different R1 fragments. In addition, the activities of these more potent compounds were predicted using derived models.

Background: α-Methylacyl-CoA racemase (AMACR) participates in the oxidation of branched chain fatty acids and is highly expressed in prostate cancer (PCa). The aims of this study were to verify if the AMACR inhibitor trifluoroibuprofen (TFIP) had anticancer effects and to determine the best route for in vivo administration. Materials and Methods: In vitro effects of TFIP were verified by using three non-tumour prostate epithelial cell lines, a series of eight PCa cell lines and six cell derivatives. In vivo experiments were performed using PC3 and 22rv1 xenografts grown in nude mice with TFIP administered intraperitoneally or by oral gavage. Results: AMACR was expressed in PCa cell lines but was absent in normal and BPH cells. Although androgen-independent (AI) cell lines originating from androgen-dependent (AD) LnCaP cells displayed increased AMACR expression, the levels of this enzyme were higher in AI with respect to AD cell lines. TFIP induced: (1) down-modulation of AMACR expression; (2) suppression of the survival Akt/mTOR signalling pathway and (3) down-modulation of cyclin D1 and survivin with G2/M arrest and apoptosis. TFIP exhibited antitumour effects independently of the administration method. Nevertheless, oral administration was associated with acute toxicity at doses >75 mg/Kg/day. A dose of 75 mg/Kg administered biweekly reduced the toxicity whereas limited toxic effects were observed at 50 mg/Kg/day. Intraperitoneal administration of 75-100 mg/Kg/day was not toxic. Conclusions: AMACR is a good pharmacological target for treatment of PCa and TFIP is a suitable anticancer compound with parenteral administration being the preferred route.

The aurora kinases are serine/threonine kinases that are essential for mitosis and contribute to tumorigenesis. Therefore, aurora kinases hold promise for molecularly targeted therapy. In the present study, we demonstrated that aurora B kinase (AURKB) is overexpressed in both cisplatin- and oxaliplatin-resistant cells. Downregulation of AURKB sensitized cells to both cisplatin and oxaliplatin, but not to paclitaxel, 5-FU or hydrogen peroxide. Interestingly, we found that both cisplatin- and oxaliplatin-resistant cells were hypersensitive to the AURKB specific inhibitors, AZD1152 HQPA and ZM447439, suggesting that both cisplatin- and oxaliplatinresistant cells develop an addiction to AURKB. These data provide evidence that aurora kinase inhibitors can overcome both cisplatin and oxaliplatin resistance. Therefore, AURKB inhibitors could offer potential benefits if used after first-line platinum-based chemotherapy.

To search for new chemotherapeutic agents to treat colorectal cancer, we isolated a number of natural ent-kaurane diterpenoids from the plant Croton tonkinensis. Among them, only CeKDs with the 15-oxo-16-ene moiety induced the apoptosis of colorectal cancer cell lines Caco-2 and LS180. The active CeKD induced the activation of ERK and JNK, but the inactive ones induced that of ERK, but not that of JNK. It thus appears that JNK seemed to play an important role in the apoptotic activity of the active compounds. The dualspecificity JNK kinase MKK4 was activated in both colorectal cancer cells treated with the active CeKD, but MKK7 was not activated. Further, the active CeKD, but not the inactive one, enhanced the generation of intracellular reactive oxygen species (ROS) in both cells. CeKD-induced cell apoptosis and ROS generation, as well as JNK activation, were inhibited by the antioxidant N-acetyl-L-cysteine. These findings suggest that ROS stimulated the phosphorylation of JNK mediated by MKK4 and played a critical role in CeKD-induced apoptosis in colorectal cancer cells.