Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 8, Issue 6, 2008

Anti-Cancer Agents in Medicinal Chemistry (ACA-MC) represents an essential review journal to scientists and pharmaceutical industry covering all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of new anti-cancer agents. Since its launch in 2001, Anti-Cancer Agents in Medicinal Chemistry has successfully completed seven years of publication and will be soon qualified for an impact factor ranking. From 2008, the frequency of the journal has been increased to eight issues per year. Apart from general issues, special issues are also published. These “theme issues” contain reviews covering various important aspects of the selected topic and are written by experts in the field. This special Editorial Board Issue has been devoted to review articles written by ACA-MC Editorial Board Members on topics of their choice, mostly very close to their own research themes. Checkpoint kinase 1 (Chk1) plays a major role in the control mechanism at the G2/M checkpoint of the cell cycle. Since many cancer cells depend upon the G2/M checkpoint more than normal cells for the repair of drug-induced DNA damage, combination of a Chk1 inhibitor and a DNA-damaging agent should force selectively cancer cells to enter a premature and lethal mitosis. Several families of Chk1 inhibitors have been developed. Prudhomme et al. highlight the interest of pyrrolocarbazoles as potent Chk1 inhibitors. Colorectal cancer is the third most common cancer worldwide. The chemopreventive role of selenium and selenium derivatives as well as selenium in combination with antineoplastic agents is reviewed by Rudolf et al. Oceans are important sources of biologically active compounds. Rawat et al. report various classes of anti-cancer compounds of marine origin, their clinical status and synthetic advances of some of these compounds. In the course of anti-cancer research, targeting prodrug strategies have been extensively studied. Papot et al. focused their review on self-immolative linkers for tumor-activated prodrug therapy. Balanol is a well-known fungal metabolite exhibiting inhibitory activities toward kinases, in particular toward protein kinase A and protein kinase C. Gago et al. provide an overview of the structure-activity relationships of balanol analogs. Balanol is an ATPcompetitive kinase inhibitor. New methodologic developments in computational studies using the PKA-balanol complex are reported to allow a rational design for selective balanol analogs, to get an insight into the physical basis that could account for its potent and selective molecular recognition and also to account for the role of protein flexibility in molecular docking. Among the relevant anti-cancer compounds are aromatase inhibitors that are known to play a significant role in breast cancer, in particular for the treatment of postmenopausal breast cancer. Kinghorn et al. reviewed natural products, from plant, microbial and marine origin, exhibiting aromatase inhibitory activity. The review of Shtil et al. is focused on chemistry, photochemical and photophysical parameters of derivatives of bacteriochlorophyll a, and their applications in both cancer photodynamic therapy and boron neutron capture therapy. Kinesin spindle protein plays a major role during mitosis and recently several inhibitors have entered clinical trials as anti-cancer agents. The review of Zhang and Xu reports the various kinds of kinesin spindle protein inhibitors. * ≪ Ingenieur ≫ - ENSCC (France), ≪Docteur Ingenieur ≫ (University of Caen), ≪Docteur d'Etat ≫ - University Blaise Pascal (Clermont-Ferrand). Post-doctoral experience (Laboratory of Professor S. HANESSIAN, University of Montreal, Canada). 1963- Assistant professor University of Caen, 1981- Assistant professor then professor University Blaise Pascal Clermont-Ferrand; Research fields: Anti-cancer drugs, kinase inhibitors, topoisomerase I inhibitors, antimicrobial compounds. Author of 100 publications, 5 patents. Editor-in-Chief of Anti-Cancer Agents in Medicinal Chemistry.

The carbazole framework is found in many natural compounds of biological interest. Indolocarbazoles such as rebeccamycin and staurosporine which are either a topoisomerase I inhibitor (rebeccamycin) or a non selective kinase inhibitor (staurosporine) are bacterial metabolites. In the search for new antitumor agents, DNA damage checkpoint kinases, in particular Checkpoint kinase 1, have recently emerged as attractive targets for cancer therapy. This review reports the synthesis and Chk1 inhibitory activities of pyrrolocarbazole compounds bearing four or five fused rings.

Colorectal cancer is among the most common cancers worldwide, in terms of overall mortality. Environmental factors have been identified to play the most important roles in the development of this disease, in particular diet and its specific components. Selenium is an important micronutrient engaged in the protection of colonic cells against a wide range of external and internal stressors. In addition, selenium has been reported to actively inhibit growth of malignant colonic cells as well as to induce their demise. Furthermore, besides its promising chemopreventive role in the various stages of colorectal cancer development, selected chemical forms of selenium have shown interesting interaction patterns with some cytostatic chemicals or inducers of apoptosis. The advantages of selected selenium preparations thus might reach beyond chemoprevention since they may be used in conjunction with established antioneoplastic drugs, thereby establishing new treatment modality for colorectal cancer. In addition to summarizing our current knowledge about the mechanisms whereby selenium imparts its chemopreventive potential in colon carcinogenesis, the possibilities of a combined use of selenium with other cytostatics and chemicals are discussed.

The chemical, biological and ecological diversity of the marine ecosystem has contributed immensely in the discovery of extremely potent compounds that have shown potent activities in antitumor, analgesia, antiinflammatory, immunomodulation, allergy, anti-viral etc. The compounds of marine origin are diverse in structural class from simple linear peptides to complex macrocyclic polyethers. The recent advances in the sophisticated instruments for the isolation and characterization of marine natural products and development of high-throughput screening, have substantially increased the rate of discovery of various compounds of biomedical application. Didemnin was the first marine peptide that entered in human clinical trials in US for the treatment of cancer and other compounds such as dolastatin-10, soblidotin, didemnin B, ecteinascidin 743, girolline, aplidine, cryptophycins (also arenastatin A), bryostatin 1, ILX 651, kahalalide F, E7389, discodermolide, ES-285 (spisulosine), HTI-286 (hemiasterlin derivative), squalamine, KRN-7000, vitilevuamide, Laulimalide, Curacin A, diazonamide, peloruside A, eleutherobin, sarcodictyin, thiocoraline, salicylihalimides A, ascididemnin, CGX-1160, CGX-1007dictyodendrins, GTS-21 (aka DMBX), manoalide, IPL-576,092 (aka HMR-4011A) have entered in the clinical trials. This article summarize clinical status and synthetic advances of some of these compounds.

The main drawback of most cancer chemotherapy is its relatively low ability to target tumour cells versus normal cells. As a consequence, chemotherapy is usually connected with severe side effects due to the toxicity of traditional cytostatic agents towards normal tissues. A few years ago, the site-specific activation of non-toxic prodrugs in tumours has been proposed in order to enhance the selectivity for the killing of cancer cells. Within this framework, most of the prodrugs that have been designed were three part compounds comprising trigger, linker and effector units. The main function of the linker is to release the effector unit after selective trigger activation via a spontaneous chemical breakdown. However, its structure also affects significantly many prodrug properties such as stability, pharmacokinetic, organ distribution, bioavailability or trigger activation. This review, focussed on the linker unit, is an update of our previous article published in 2002. It deals with recent advances in the design of prodrug linkers including new delivery systems such as elongated linkers or selfimmolative dendrimers.

Balanol, a fungal metabolite, is a potent ATP-competitive inhibitor of Protein Kinase C (PKC) and Protein Kinase A (PKA), important targets in oncology. Since its discovery in 1993, a number of studies have been performed in order to design selective and bioavailable balanol analogs. Several crystal structures of PKA in complex with balanol and a few analogs bound within the catalytic site have also been solved providing insight about the key interactions for binding. The PKA-balanol complex has also served as an interesting model system for structurebased ligand design and validation of a number of computational methodologies aimed at both understanding the physical basis for molecular recognition and addressing the important issue of protein flexibility in ligand binding. We provide an overview of the structure-activity relationships of balanol analogs and summarize the progress made in structural and computational studies involving balanol.

With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purposes (e.g., botanical dietary supplements) may also afford AIs with reduced side effects. A thorough review of the literature regarding natural product extracts and secondary metabolites of plant, microbial, and marine origin that have been shown to exhibit aromatase inhibitory activity is presented herein.

The review summarizes the chemistry of the third generation of photosensitizers, namely, the derivatives of natural bacteriochlorophyll a for photodynamic treatment of cancer. The compounds of this class strongly absorb light at λ=770-850 nm. This unique property opens new therapeutic opportunities due to deeper tissue penetration of light, thereby increasing the photodamage for tumor eradication. Analyzed are the modifications of bacteriochlorophyll a that improve physico-chemical characteristics of compounds and enhance accumulation in tumors. Focusing on the delivery of photosensitizers to the tumor site and to specific intracellular compartments, we describe the conjugates of bacteriochlorophyll a derivatives with carbohydrate and protein carriers. Boronated bacteriochlorins can be used in both photodynamic and boron neutron capture therapy.

The kinesin spindle protein (KSP, also known as Hs Eg5) plays an essential part in the proper separation of spindle poles and the correct formation of bipolar mitotic spindle during mitosis. Inhibition of this protein results in cells apoptosis followed by mitotic arrest and the formation of characteristic monoaster spindles. Compared with the traditional chemotherapeutic agents (taxanes, vinca alkaloids), KSP inhibitors (KSPi) will not lead to the neuropathic side effects, so KSP has become a novel and an attractive anticancer target. Accordingly, more and more interest has been focused on the development of high effective and selective KSPi. This review will focus on some kinds of KSPi on the basis of introducing structure and function of KSP.