Anti-Cancer Agents in Medicinal Chemistry (v.12, #3)
Editorial [ Special Board Members Issue (Edior-in-Chief: Michelle Prudhomme)] by Michelle Prudhomme (176-176).
Apart from review articles, research articles are now also published in Anti-Cancer Agents in Medicinal Chemistry (ACA-MC). This special Editorial Board Issue gathers articles written by ACA-MC Editorial Board Members on the latest developments in various topics and contains both research and review articles. In the first paper, V. Murray and N. Kandasamy report their studies on the sequence specificity of the anti-tumour drug, cisplatin, in telomeric DNA sequences compared with consecutive guanine DNA sequences.The authors concluded that cisplatin preferentially damaged the ten consecutive guanine sequence although the telomeric DNA sequences were also a major site of cisplatin adduct formation. During the past two decades, a great interest has been devoted to histone deacetylases (HDACs), a family of metalloproteases which play a key role in the development of cancer. Small molecule histone deacetylase inhibitors (HDACIs) have been synthesized and form a newly emerging class of anti-cancer agents. In this issue, two articles deal with histone deacetylase inhibitors. The first one by Zeng Wenbin et al., entitled
The Sequence Specificity of the Anti-tumour Drug, Cisplatin, in Telomeric DNA Sequences Compared with Consecutive Guanine DNA Sequences by Vincent Murray (177-181).
The sequence specificity of the anti-tumour drug, cisplatin, was determined in a DNA sequence that contained seven telomeric repeats and a run of ten consecutive guanine bases. Cisplatin preferentially forms DNA adducts at consecutive guanine sequences. Hence these DNA sequences were examined in order to gain an insight into the important human genomic regions that are damaged by cisplatin. A polymerase stop/linear amplification assay was employed with an automated DNA capillary sequencer and laser-induced fluorescence detection to quantitatively determine the DNA sequence specificity of cisplatin in a plasmid clone containing seven telomeric repeats and a sequence of ten consecutive guanine bases. It was found that cisplatin preferentially damaged the ten consecutive guanine sequence although the telomeric DNA sequences were also a major site of cisplatin adduct formation.
Molecular Probing and Imaging of Histone Deacetylase Inhibitors in Cancer Treatment by Huang Jiaguo (182-186).
Molecules that inhibit histone deacetylases (HDACs) activity have shown a great promise as anticancer agents since they interfere with cell proliferation and angiogenesis, induce cell differentiation and promote apoptosis. A number of HDACIs (for example: SAHA) have been approved by FDA for the treatment of cancer in different stages of clinical trials. HDAC inhibition proves to be a worthy strategy for cancer therapy. Thus, the distribution and metabolism of HDACIs in vivo are of significant clinical value for diagnosis and assessment of therapeutic efficacy. Molecular imaging is one of the primary tools used to noninvasively evaluate biological processes at the cellular and molecular level in living subjects. Various imaging modalities, including optical bioluminescence/ fluorescence, PET, SPECT, MRI, CT and US are all successfully used to assess the anatomic or functional dissemination of tissues and specific molecular targets, such as imaging molecular interactions, tumor vitality, apoptosis, angiogenesis and response to cancer treatment in the body. The utility of molecular imaging for monitoring HDACIs provides a perfect strategy for deeper understanding about cancer. In this article, the recent progresses of molecular imaging for assessing HDACIs are reviewed. In addition, how imaging can be used, at least experimentally, to assess specific molecular targets is also discussed.
The Stem Cell Niche as a Pharmaceutical Target for Prevention of Skeletal Metastases by John M. Chirgwin (187-193).
Advanced cancers of the prostate and breast commonly progress by metastasizing to the skeleton, where they are incurable but cause serious morbidity and contribute to mortality. Growth of tumor in bone takes several years, opening a large window for pharmaceutical prevention of metastatic progression. Bone provides a unique microenvironment for tumor growth, including niches occupied by hematopoietic and mesenchymal stem cells. Recent data suggest that circulating tumor cells usurp these niches and compete with the normal stem cell occupants. Agents that encourage normal hematopoiesis or bone formation could inhibit colonization of bone by tumor stem cells and prevent or delay metastatic progression. It may be possible to develop high-throughput assays to test compounds for their ability to suppress tumor stem cell occupation of skeletal niches, thus decreasing metastatic progression in at-risk patients.
Synthesis of Cis-Fused Pyran Indolocarbazole Derivatives that Inhibit FLT3 Kinase and the DNA Damage Kinase, Checkpoint Kinase 1 by Francoise M. Perron-Sierra (194-201).
Protein kinases are important enzymes in solid tumour and leukaemia pathologies. Their structures are well understood at the atomic level and their key role in the progression of certain cancers makes them valuable targets for anti-cancer therapy. Through medicinal chemical approaches, we developed an efficient preparative stereospecific synthesis of N12, N13 pyran-bridged indolocarbazoles that opens access to functional diversity within this previously challenging series. We focused upon the indolocarbazole class of chemical inhibitors, which includes S27888, an inhibitor we previously identified. We used biochemical and cell-based assays to identify small molecule inhibitors of Checkpoint kinase 1 (Chk1), a serine/threonine protein kinase that is activated when cancer cells are treated with genotoxic agents. These compounds show a promising inhibitory profile on Chk1. Furthermore, these compounds are active against FLT3, which is a tyrosine kinase that is frequently activated in human leukaemias. These data suggest that this chemical class may provide a source of therapeutic compounds for a broad range of human cancers.
Melanoma and Epigenetic Treatment: Past and Future by Caterina AM La Porta (202-209).
Melanoma is the most aggressive form of skin cancer and advanced stages are inevitably resistant to conventional therapeutic agents. In particular, epigenetic strategies might open interesting new perspectives in combination with conventional ones. Current therapeutic strategies, in particular for metastatic melanoma, do not give great results in terms of survival. Herein, I review HDACis and microRNAs for melanoma. A critical discussion of all the recent findings on this topic is also included. In my view, further studies are needed to understand the toxicity of these treatments in order to improve survival of melanoma patients.
Curcumin and its Formulations: Potential Anti-Cancer Agents by Jun-Ling Ji (210-218).
Curcumin, one of the most studied chemopreventive agents, is a natural compound extracted from Curcuma longa L. Extensive research over the last half century has revealed that curcumin can inhibit the proliferation of various tumor cells in culture, prevent carcinogen induced cancers in rodents and inhibit the growth of human tumors in xenotransplant or orthotransplant animal models. Several phase I and phase II clinical trials indicated that curcumin is quite safe and may exhibit therapeutic efficacy. The utility of curcumin is limited by its lack of water solubility and relatively low in vivo bioavailability. Multiple approaches including nanoparticles, liposomes, micelles and phospholipid complexes are being sought to overcome these limitations. This review describes the general properties of curcumin and its potential effect against cancer including evidences of its antitumor action in vitro, in vivo, clinically and the strategies to overcome its low bioavailability.
Tubulin-based Structure-affinity Relationships for Antimitotic Vinca Alkaloids by Claire Coderch (219-225).
The Vinca alkaloids are a group of widely used anticancer drugs, originally extracted from the Madagascar periwinkle, that disrupt microtubule dynamics in mammalian cells by interfering with proper assembly of α,β-tubulin heterodimers. They favor curved tubulin assemblies that destabilize microtubules and induce formation of spiral aggregates. Their binding energy profiles have been characterized by means of sedimentation velocity assays and the binding site of vinblastine at the interface between two tubulin dimers (α1β1
Chemotherapeutic Targeting of Cell Death Pathways by Sylvia Mansilla (226-238).
Cell death plays an important role in cancer growth and progression, as well as in the efficiency of chemotherapy. Although apoptosis is commonly regarded as the principal mechanism of programmed cell death, it has been increasingly reported that several anticancer agents do not only induce apoptosis but other forms of cell death such as necrosis, autophagy and mitotic catastrophe, as well as the state of permanent loss of proliferative capacity known as senescence. A deeper understanding of what we know about chemotherapyinduced death is rather relevant considering the emerging knowledge of non-apoptotic cell death signaling pathways, and the fact that many tumors have the apoptosis pathway seriously compromised. In this review we examine the effects that various anti-cancer agents have on pathways involved in the different cell death outcomes. Novel and specific anti-cancer agents directed toward members of the cell death signaling pathways are being developed and currently being tested in clinical trials. If we precisely activate or inhibit molecules that mediate the diversity of cell death outcomes, we might succeed in more effective and less toxic chemotherapy.
NGR-based Strategies for Targeting Delivery of Chemotherapeutics to Tumor Vasculature by Mingming Zou (239-246).
In the last decades, NGR-containing peptides have been proved useful for ligand-directed targeted delivery of various chemotherapeutic drugs to tumor vasculature. Aminopeptidase N (APN; CD13) has been demonstrated to be a key binding site for NGR peptides on tumor vasculature. For drug targeting, chemical means have been applied to couple NGR-peptides to small molecule drugs, such as cytokines, antiangiogenic compounds, viral particles, contrast agents, DNA complexes and other biologic response modifiers. Some products have shown impressive results in preclinical animal models, such as NGR-TNF which was currently tested in Phase III trials. In this article we will review the process of NGR-to-isoDGR transition and provide suggestions for the design of the diverse NGR peptide-chemotherapeutics conjugates.
Selective Histone Deacetylase Inhibitors by Huili Pan (247-270).
Histone deacetylases (HDACs) are a family of conserved metalloproteases which play a key role in the development of cancer. They can be divided into 18 subtypes according to their structural diversity. Histone deacetylase inhibitors are considered as potential anti-cancer agents and a lot of pan-HDAC inhibitors have entered clinical trials. Selective HDAC inhibitors targeting only one member or one class subtype are less exploited at present and regarded less toxic as well as more tolerable than pan-HDAC inhibitors. Certain structural modifications or new moieties may help to acquire isoform selectivity. In this review, we will focus on each member of HDACs and selective HDAC inhibitors as well as the relationship between structure and selectivity.
Genistein and its Synthetic Analogs as Anticancer Agents by Qing-Shan Li (271-281).
Genistein, one of the predominant isoflavones derived from soybeans, has been shown beneficial effects in cancer prevention and treatment. There is an accumulating body of experimental evidences suggesting that genistein affects cancer progression by increasing apoptosis, inducing cell cycle arrest,modulating intracellular signaling pathways, and inhibiting invasion and metastasis of cancer cells. During last decade, many researchers have conducted extensive studies by synthesizing amounts of structurally-modified derivatives based on the isoflavone skeleton of genistein to enhance its anticancer activity, some analogs of which possess more potent activities of the prevention and/or treatment of various cancers. In this review, we summarized the current knowledge regarding anticancer effects,structure-activity relationships and action mechanisms of genistein and its synthesized analogs, which would be beneficial to the rational design of new genistein derivatives as anticancer drugs.