Current Medicinal Chemistry - Volume 21, Issue 5, 2014

Since Human CYP1 enzymes catalyze the metabolic activation of procarcinogens and deactivation of certain anticancer drugs, the inhibition of these enzymes has been considered as an effective approach for chemoprevention and treatment of CYP1-mediated drug resistance. Recent knowledge relating to the enhanced expression of CYP1B1 in tumors also provided certain advantages in cancer therapy by the activation of prodrugs only in tumor cells. This review concentrates on the characterized CYP1 inhibitors and CYP1-activatied anticancer prodrugs. The mechanism for enzyme inhibition and activation of prodrugs, the cancer preventive/therapeutic potential of these chemicals and their related SARs are highlighted. According to their structural features, CYP1 inhibitors are divided into the following categories: flavonoids, trans-stilbenes, coumarins, terpenoids, alkaloids, quinones, isothiocyanates and synthetic aromatics. In the same way, CYP1-activatied prodrugs are categorized into four groups: benzothiazoles, flavonoids, stilbenes and alkylating agents. Almost all of these inhibitors and prodrugs are planar molecules with one aromatic ring and some have similarity with identified CYP1 substrates. CYP1 inhibitors could effectively block the procarcinogen-induced tumor initiation in animal models and benefit us with chemoprevention. The advent of Phortress and aminoflavone as clinical candidates shows promising perspectives in developing CYP1-mediated prodrugs as chemotherapeutic drugs that are specifically activated in tumors. All of these preclinical and clinical studies indicate that inhibitors and prodrugs target CYP1 are promising anticancer strategies.

Inactivation of the tumor suppressor p53 and/or overexpression of the oncogene MDM2 frequently occur in human cancers, and are associated with poor prognosis, advanced forms of the disease, and chemoresistance. MDM2, the major negative regulator of p53, induces p53 degradation and inactivates its tumor suppressing activity. In turn, p53 regulates MDM2 expression. This MDM2-p53 negative feedback loop has been widely studied and presents an attractive target for cancer therapy, with a few of the inhibitors of this interaction already having advanced into clinical trials. Additionally, there is an increasing interest in understanding MDM2’s p53-independent activities in carcinogenesis and cancer progression, which may also have implications for cancer therapy. This review aims to highlight the various roles that the MDM2-p53 interaction plays in cancer, the p53 independent oncogenic activities of MDM2 and the various strategies that may be used to target MDM2 and the MDM2-p53 interaction. We will summarize the major preclinical and clinical evidences of MDM2 inhibitors for human cancer treatment and make suggestions to further improve efficacy and safety of this interesting class of cancer therapeutics.

The anti-tumor therapeutic ellipticine and its derivatives act as potent anticancer agents via a combined mechanism involving cell cycle arrest and induction of apoptosis. Cell death induced by ellipticine has been shown to engage a p53-dependent pathway, cell cycle arrest, interaction with several kinases and induction of the mitochondrial pathway of apoptotic cell death. Cell cycle arrest was shown to result from DNA damage caused by a variety of tumor chemotherapeutic agents; this is also the case for ellipticines. The prevalent DNA-mediated mechanisms of anti-tumor, mutagenic and cytotoxic activities of ellipticine are (i) intercalation into DNA, (ii) inhibition of DNA topoisomerase II activity, and (iii) covalent binding to DNA in vitro and in vivo after enzymatic activation by cytochrome P450 and/or peroxidase enzymes The mechanism leading to apoptosis by ellipticine is thought to also be associated with DNA damage, by inhibition of topoisomerase II and the covalent modification of DNA. In addition, the formation of ellipticine-DNA adducts ultimately can mutate cancer cells or initiate cell death. The aim of this review is to summarize our knowledge on the molecular mechanisms with the aim to explain the effectiveness of ellipticines as DNA-targeted chemotherapeutics in cancer cells.

ATP: shikimate 3-phosphotransferase catalyzes the fifth chemical reaction of shikimate pathway. This metabolic route is responsible for the production of chorismate, a precursor of aromatic amino acids. This especially interesting enzymatic step is indispensable for the survival of the etiological agent of tuberculosis and not found in animals. Therefore the enzyme ATP: shikimate 3-phosphotransferase has been classified as a target for chemotherapeutic development of antitubercular drugs. The ATP:shikimate 3-phosphotransferase has also the denomination of shikimate kinase. This review highlights the available crystallographic studies of shikimate kinases that have been used to identify structural features for ligand-biding affinity. We also describe molecular docking studies focused on shikimate kinase. These computational studies were performed in order to identify the new generation of antitubercular drugs and several potential inhibitors have been described. In addition, a structural comparison of shikimate kinase ATP-binding pocket with human cyclin-dependent kinase 2 (CDK2) is described. This analysis shows the structural similarities between both enzymes, and the potential beneficial aspects of abundant structural studies of CDK2 and their inhibitors to bring further understanding of the ligand-binding specificity for shikimate kinase.

Malaria is arguably one of the main medical concerns worldwide because of the numbers of people affected, the severity of the disease and the complexity of the life cycle of its causative agent, the protist Plasmodium sp. The clinical, social and economic burden of malaria has led for the last 100 years to several waves of serious efforts to reach its control and eventual eradication, without success to this day. With the advent of nanoscience, renewed hopes have appeared of finally obtaining the long sought-after magic bullet against malaria in the form of a nanovector for the targeted delivery of antimalarial drugs exclusively to Plasmodium-infected cells. Different types of encapsulating structure, targeting molecule, and antimalarial compound will be discussed for the assembly of Trojan horse nanocapsules capable of targeting with complete specificity diseased cells and of delivering inside them their antimalarial cargo with the objective of eliminating the parasite with a single dose. Nanotechnology can also be applied to the discovery of new antimalarials through single-molecule manipulation approaches for the identification of novel drugs targeting essential molecular components of the parasite. Finally, methods for the diagnosis of malaria can benefit from nanotools applied to the design of microfluidic-based devices for the accurate identification of the parasite’s strain, its precise infective load, and the relative content of the different stages of its life cycle, whose knowledge is essential for the administration of adequate therapies. The benefits and drawbacks of these nanosystems will be considered in different possible scenarios, including cost-related issues that might be hampering the development of nanotechnology-based medicines against malaria with the dubious argument that they are too expensive to be used in developing areas.

Several substances widely dispersed in the environment including hormones, industrial by-products and pollutants exert hormone like activity affecting steroid-responsive physiological systems. These compounds, named endocrine disruptors, are suspected to affect the mammalian reproductive system. However it is still unclear whether these substances are able to elicit estrogen like activity at the low concentrations encountered in the environment. Here we compare the effects of the endocrine disruptor nonylphenol with the effects elicited by 17-β-estradiol on gene transcription in the human breast cancer cell line MCF7. The correlation of the nonylphenol induced gene expression alterations with a reference profile of estradiol treated cells shows that nonylphenol at a concentration of 100 nM exerts a significant effect on estrogen responsive gene transcription in MCF7 cells. Most of the genes regulated by 17-β-estradiol respond to the nonylphenol in the same direction though to a much lesser extent. Molecular modeling of the potential interaction of nonylphenol with the estrogen receptor α shows that nonylphenol is likely to bind to the estrogen receptor α.

Osteoclasts are one of the key therapeutic targets for a variety of orthopedic diseases such as osteoporosis and osteoarthritis. In this study, we synthesized a novel compound N-(3-(cyclohexylcarbamoyl) phenyl)-1H-indole-2- carboxamide (termed as OA-4) and investigated the effects of OA-4 on the differentiation and function of osteoclasts. OA-4 markedly diminished osteoclast differentiation and osteoclast specific gene expression in a dose-dependent manner. In addition, OA-4 dose-dependently suppressed osteoclastic bone resorption. Furthermore, we found OA-4 attenuated RANKL-induced p38 phosphorylation without affecting JNK or NF-κB signaling pathways. Collectively, we synthesized a novel compound OA-4 which can inhibit osteoclast formation and functions via the suppression of p38 signaling pathway.