Current Medicinal Chemistry (v.23, #23)

Meet Our Editorial Board Member by Paola Perego (2395-2396).

Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones by Yulin Ren, Jianhua Yu, A. Douglas Kinghorn (2397-2420).
Sesquiterpene lactones are of considerable interest due to their potent bioactivities, including cancer cell cytotoxicity and antineoplastic efficacy in in vivo studies. Among these compounds, artesunate, dimethylaminoparthenolide, and L12ADT peptide prodrug, a derivative of thapsigargin, are being evaluated in the current cancer clinical or preclinical trials. Based on the structures of several antitumor sesquiterpene lactones, a number of analogues showing greater potency have been either isolated as natural products or partially synthesized, and some potential anticancer agents that have emerged from this group of lead compounds have been investigated extensively. The present review focuses on artemisinin, parthenolide, thapsigargin, and their naturally occurring or synthetic analogues showing potential anticancer activity. This provides an overview of the advances in the development of these types of sesquiterpene lactones as potential anticancer agents, including their structural characterization, synthesis and synthetic modification, and antitumor potential, with the mechanism of action and structure-activity relationships also discussed. It is hoped that this will be helpful in stimulating the further interest in developing sesquiterpene lactones and their derivatives as new anticancer agents.

From Bone Marrow to Cardiac Atrial Appendage Stem Cells for Cardiac Repair: A Review by Marc Hendrikx, Yanick Fanton, Leen Willems, Annick Daniels, Jeroen Declercq, Severina Windmolders, Karen Hensen, Remco Koninckx, Luc Jamaer, Jasperina Dubois, Dagmara Dilling-Boer, Jos Vandekerkhof, Filip Hendrikx, Eric Bijnens, Nick Heuts, Boris Robic, Virginie Bito, Marcel Ameloot, Paul Steels, Jean-Luc Rummens (2421-2438).
Traditionally the heart is considered a terminally differentiated organ. However, at the beginning of this century increased mitotic activity was reported in ischemic and idiopathic dilated cardiomyopathy hearts, compared to healthy controls, underscoring the potential of regeneration after injury. Due to the presence of adult stem cells in bone marrow and their purported ability to differentiate into other cell lineages, this cell population was soon estimated to be the most suited candidate for cardiac regeneration. Clinical trials with autologous bone marrow-derived mononuclear cells, using either an intracoronary or direct intramyocardial injection approach consistently showed only minor improvement in global left ventricular ejection fraction. This was explained by their limited cardiomyogenic differentiation potential. To obtain more convincing improvement in cardiac function, based on true myocardial regeneration, the focus of research has shifted towards resident cardiac progenitor cells. Several isolation procedures have been described: the c-kit surface marker was the first to be used, however experimental research has clearly shown that c-kit+ cells only marginally contribute to regeneration post myocardial infarction. Sphere formation was used to isolate the so-called cardiosphere derived cells (CDC), and also in this cell population cardiomyogenic differentiation is a rare event. Recently a new type of stem cells derived from atrial tissue (cardiac atrial stem cells - CASCs) was identified, based on the presence of the enzyme aldehyde dehydrogenase (ALDH). Those cells significantly improve both regional and global LV ejection fraction, based on substantial engraftment and consistent differentiation into mature cardiomyocytes (98%).

The Use of Stilbene Scaffold in Medicinal Chemistry and Multi- Target Drug Design by Elisa Giacomini, Sebastiano Rupiani, Laura Guidotti, Maurizio Recanatini, Marinella Roberti (2439-2489).
The stilbene scaffold is a basic element for a number of biologically active natural and synthetic compounds, and it is considered as a privileged structure. Stilbenes exemplified by resveratrol, combretastatin A-4 and pterostilbene are of significant interest for drug research and development because of their potential in therapeutic and preventive application. Resveratrol, present in grapes and other food products, plays a role in the prevention of several human pathological processes and has been suggested as an anticancer agent. Moreover, recent evidence has revealed its potential effect on the aging process, diabetes and neurological dysfunction. Combretastatin A-4, from the bark of South African bush willow Combretum caffrum, also shows significant antitumor activity. Pterostilbene is closely related to resveratrol, sharing the same unique therapeutic potential as anti-inflammatory, antineoplastic and antioxidant agent.
Therefore, research and development of stilbene-based medicinal chemistry have become rapidly evolving and increasingly active topics covering almost the whole range of therapeutic fields.
In the present review, we provide an overview of the role of stilbenes in medicinal chemistry. In this context, we highlight the chemical methodologies adopted for the synthesis of stilbene derivatives, and outline the successful design of novel stilbene based hybrids in the field of cancer, Alzheimer's and other relevant diseases. This information may be useful in further design of stilbene-based molecules as new leads for the development of novel agents with clinical potential or as effective chemical probes to dissect biological processes.

Nanomedicine for Intra-Articular Drug Delivery in Rheumatoid Arthritis by Hannah O';Mary, Inmaculada del Rinc|n, Zhengrong Cui (2490-2506).
Rheumatoid arthritis is characterized by chronic inflammation within the joint. Recent developments in the understanding of inflammation have led to an increased interest in the use of nanomedicine in the treatment and diagnosis of rheumatoid arthritis. The ability of nanomedicine, such as nanoparticles, to permeate into and/or retain within the inflamed joint after intravenous and/or intra-articular administration has proven to be beneficial in improving rheumatoid arthritis therapy while reducing systemic exposure of patients to potentially toxic anti-arthritic drugs. This review aims at explaining the major applications of nanomedicine in rheumatoid arthritis treatment and diagnosis.

Current Progresses and Trends in the Development of Progesterone Receptor Modulators by Wenlu Li, Xi Li, Bin Zhang, Chunmei Gao, Yuzong Chen, Yuyang Jiang (2507-2554).
The progesterone receptor (PR) is a ligand-activated steroid receptor in the nuclear receptor (NR) superfamily of transcription factor. Besides gynecological and obstetrical indications, the involvement/mechanism of PR in many other diseases, such as oncology, neurology, immunology, etc. has been revealed and studied in recent decades. Therapeutic agents that selectively activate or inhibit PR have been developed. PR agonists have generally been used in oral contraception and postmenopausal hormone replacement therapy (HRT), typically in combination with estrogens. PR antagonists and selective PR modulators (SPRMs) can be useful therapies for hormone dependent breast and prostate cancers, nonmalignant chronic conditions such as fibroids, and endometriosis. This review provides an overview and detailed discussions about the recent development of chemical structures of the PR ligands, their structural characteristics (particularly those contributing to their activity and selectivity), in vitro/in vivo studies and clinical trial outcomes, and the synthetic methodologies.