Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 7, Issue 2, 2007

Acridine derivatives are interesting chemotherapeutic agents that were first used as antibacterial and antiparasite agents. In this review we wish to concentrate our attention on the anticancer properties of acridines used in clinics since the 1970's. Based on recent results, an outlook on antitumour acridine chemotherapy will be proposed. The biological activity of acridines is mainly attributed to the planarity of these aromatic structures, which can intercalate within the double-stranded DNA structure, thus interfering with the cellular machinery. Recent understanding of the mode of action of acridines leads to continuous and exciting research in this heterocyclic family. Indeed, biological targets such as topoisomerases I and II, telomerase/telomere and protein kinases emerge and allow the design of novel acridine-based patterns. This review further pinpoints the latest progress in the development of anticancer agents based on naturally occurring and synthetic acridines (e.g. acridones, pyridoacridines); for this matter in vitro/in vivo studies and clinical trial results will be discussed. The DNA-affinic property of acridine is also useful to vectorise drugs into cell nuclei and some applications in hypoxia-selective treatment, platinum or N-mustard derived conjugates will be reported. Some other properties including inhibition of multidrug resistance or potential impact on Alzheimer disease will be treated. It is noteworthy that the position and the nature of the substituent on the heterocyclic core are determinants for the biological property and selectivity observed. So, we wish also to disclose a summary of recent synthetic methodologies developed for acridine synthesis.

Protein kinases are among the most exploited targets in modern drug discovery due to key roles these enzymes play in human diseases including cancer. The in silico approach, an important part of rational design of protein kinase inhibitors, is founded on vast information about 3D structures of these enzymes. This review summarizes general structural features of the kinase inhibitors and the studies applied toward a large scale chemical database for virtual screening. Analyzed are the ways of validating the modern docking tools and their combinations with different scoring functions. In particular, we discuss the kinase flexibility as a reason for failures of the docking procedure. Finally, evidence is provided for the main patterns of kinase-inhibitor interactions and creation of the hinge-region-directed 2D filters.

This review highlights structural diversity of antimitotic agents. In particular, we emphasized current antimitotic therapies based on modulation of microtubule dynamics. With several successful anticancer drugs on the market and numerous compounds in clinical developments, tubulin-binding agents remain among the most important categories of anticancer agents. Compounds targeting mitotic kinases and kinesins are also discussed.

This meta-analysis examines a wide range of small molecule anticancer drugs to search for a structure common to all. Although they encompass a very wide range of structures, nearly all reveal the presence of an allylic O, N, or S atom. In some, the allylic oxygen is a carbonyl group, or an alcohol group, which can be substituted (ester, lactone, glycoside, ether) or replaced by an amino or imino nitrogen Some antineoplastic drugs do not exhibit this moiety but are converted in vivo to allylic derivatives. An allylic hydroxyl is also present in most sphingolipids, ubiquitous body components that control proliferative and anti-proliferative cell functions. Ceramide, the precursor of all the allylic sphingolipids, seems to be a general inducer of apoptosis in cancer cells. Further examination of sphingolipids and anticancer drugs shows the frequent occurrence of [i] double bonds conjugated to the allylic bond, (ii) two or more allylic moieties in each molecule, (iii) lipophilic features, especially linear chains, and (iv) attachment of an O, N, or S atom to a carbon atom of the allylic double bond, e.g., -CH2-C(OMe)=CH-CH(OH)-CH2-. Suggested mechanisms of action: (a) allylic ketone drugs undergo a Michael condensation with tumor thiols or other reactive groups; (b) allylic OH drugs undergo oxidation to an allylic ketone, generating reactive oxygen; (c) some interfere with mitochondrial ubiquinone, blocking ATP production; (d) some act as a ceramide mimic (inhibitor or agonist) in ceramide-controlled kinases, phosphatases, and proteases; (e) many antineoplastic drugs stimulate ceramide-forming processes.

Angiogenesis, or formation of new blood capillaries from preexisting vessels, plays both beneficial and damaging roles in the organism. It is a result of a complex balance of positive and negative regulators, and vascular endothelial growth factor (VEGF) is one of the most important pro-angiogenic factors involved in tumor angiogenesis. VEGF increases vascular permeability, which might facilitate tumor dissemination via the circulation causing a greater delivery of oxygen and nutrients; it recruits circulating endothelial precursor cells, and acts as a survival factor for immature tumor blood vessels. The endotheliotropic activities of VEGF are mediated through the VEGF-specific tyrosine-kinase receptors: VEGFR-1, VEGFR-2 and VEGFR-3. VEGF and its receptors play a central role in tumor angiogenesis, and therefore the blockade of this pathway is a promising therapeutic strategy for inhibiting angiogenesis and tumor growth. A number of different strategies to inhibit VEGF signal transduction are in development and they include the development of humanized neutralizing anti-VEGF monoclonal antibodies, receptor antagonists, soluble receptors, antagonistic VEGF mutants, and inhibitors of VEGF receptor function. These agents can be divided in two broad classes, namely agents designed to target the VEGF activity and agents designed to target the surface receptor function. The main purpose of this review is to summarize all the available information regarding the importance of the proangiogenic factor VEGF in cancer therapy. After an overview of the VEGF family and their respective receptors, we shall focus our attention on the different VEGF-inhibitors existent nowadays. Agents based upon anti-VEGF therapy have provided solid proofs about their success, and therefore we believe that a critical review is of the utmost importance to help researchers in their future work.

Natural and synthetic carbazoles, either in a pure substituted or in an annellated substituted form, represent an important and heterogeneous class of anticancer agents, which has grown considerably over the last two decades. Many carbazole derivatives have been tested for cyctotoxic activity, some of them have entered clinical trials, but only very few have been approved for the treatment of cancer so far, since the clinical application of many carbazoles has encountered problems like severe side effects or multidrug resistance. Due to their polycyclic, planar and aromatic structure carbazoles are predestined for intercalation into DNA and therefore DNA remains one of the main targets for cytotoxic carbazoles. For many carbazoles cytotoxicity can be related to DNA-dependent enzyme inhibition such as topoisomerase I/II and telomerase. But also other targets such as cyclin-dependent kinases and estrogen receptors have emerged.