Current Medicinal Chemistry (v.23, #6)

Meet Our Section Editor: by Vasso Apostolopoulos (519-519).

In the late 1980s, reports emerged describing experimental antibacterial quinolones having significant potency against eukaryotic Type II topoisomerases (topo II) and showing cytotoxic activity against tumor cell lines. As a result, several pharmaceutical companies initiated quinolone anticancer programs to explore the potential of this class in comparison to conventional human topo II inhibiting antitumor drugs such as doxorubicin and etoposide. In this review, we present a modern re-evaluation of the anticancer potential of the quinolone class in the context of today's predominantly pathway-based (rather than cytotoxicity-based) oncology drug R&D environment. The quinolone eukaryotic SAR is comprehensively discussed, contrasted with the corresponding prokaryotic data, and merged with recent structural biology information which is now beginning to help explain the basis for that SAR. Quinolone topo II inhibitors appear to be much less susceptible to efflux-mediated resistance, a current limitation of therapy with conventional agents. Recent advances in the biological understanding of human topo II isoforms suggest that significant progress might now be made in overcoming two other treatment-limiting disadvantages of conventional topo II inhibitors, namely cardiotoxicity and drug-induced secondary leukemias. We propose that quinolone class topo II inhibitors could have a useful future therapeutic role due to the continued need for effective topo II drugs in many cancer treatment settings, and due to the recent biological and structural advances which can now provide, for the first time, specific guidance for the design of a new class of inhibitors potentially superior to existing agents.

The Relevance of JAK2 in the Regulation of Cellular Transport by Mentor Sopjani, Vjollca Konjufca, Mark Rinnerthaler, Rexhep Rexhepaj, Miribane Dërmaku-Sopjani (578-588).
Janus kinase-2 (JAK2) is a non-receptor tyrosine kinase signaling molecule that mediates the effects of various hormones and cytokines, including interferon, erythropoietin, leptin, and growth hormone. It also fosters tumor growth and modifies the activity of several nutrient transporters. JAK2 contributes to the regulation of the cell volume, protectS cells during energy depletion, proliferation, and aids the survival of tumor cells. Recently, JAK2 was identified as a powerful regulator of transport processes across the plasma membrane. Either directly or indirectly JAK2 may stimulate or inhibit transporter proteins, including ion channels, carriers and Na+/K+ pumps. As a powerful regulator of transport mechanisms across the cell membrane, JAK2 regulates a wide variety of potassium, calcium, sodium and chloride ion channels, multiple Na+-coupled cellular carriers including EAAT1-4, NaPi-IIa, SGLT1, BoaT1, PepT1-2, CreaT1, SMIT1, and BGT1 as well as Na+/K+-ATPase. These cellular transport regulations contribute to various physiological and pathophysiological processes and thus exerting JAK2-sensitive effects. Future investigations will be important to determine whether JAK2 regulates cell-surface expression of other transporters and further elucidate underlying mechanisms governing JAK2 actions.

The Potential Application of Biomaterials in Cardiac Stem Cell Therapy by Raja Ghazanfar Ali Sahito, Poornima Sureshkumar, Isaia Sotiriadou, Sureshkumar Perumal Srinivasan, Davood Sabour, Jürgen Hescheler, Kurt Pfannkuche, Agapios Sachinidis (589-602).
Biomaterials play a vital role in the field of regenerative medicine and tissue engineering. To date, a large number of biomaterials have been used in cardiovascular research and application. Recently, biomaterials have held a lot of promise in cardiac stem cell therapy. They are used in cardiac tissue engineering to form scaffolds for cellular transplantation, promote angiogenesis, enhance transplanted cell engraftment or influence cell migration. The science of biomaterial designing has evolved to an extent where they can be designed to mimic the microenvironment of a cardiac tissue in vivo and contribute in deciding the fate of transplanted stem cells and induce cardiac lineage oriented stem cell differentiation. In this review, we focus on biomaterials used in cardiovascular stem cell research, tissue engineering and regenerative medicine and conclude with an outlook on future impacts of biomaterial in medical sciences.

Cardiovascular-Active Venom Toxins: An Overview by Carolina Campolina Rebello Horta, Maria Chatzaki, Bruno Almeida Rezende, Bárbara de Freitas Magalhães, Clara Guerra Duarte, Liza Figueiredo Felicori, Bárbara Bruna Ribeiro Oliveira-Mendes, Anderson Oliveira do Carmo, Carlos Chávez-Olórtegui, Evanguedes Kalapothakis (603-622).
Animal venoms are a mixture of bioactive compounds produced as weapons and used primarily to immobilize and kill preys. As a result of the high potency and specificity for various physiological targets, many toxins from animal venoms have emerged as possible drugs for the medication of diverse disorders, including cardiovascular diseases. Captopril, which inhibits the angiotensinconverting enzyme (ACE), was the first successful venom-based drug and a notable example of rational drug design. Since captopril was developed, many studies have discovered novel bradykinin-potentiating peptides (BPPs) with actions on the cardiovascular system. Natriuretic peptides (NPs) have also been found in animal venoms and used as template to design new drugs with applications in cardiovascular diseases. Among the anti-arrhythmic peptides, GsMTx-4 was discovered to be a toxin that selectively inhibits the stretch-activated cation channels (SACs), which are involved in atrial fibrillation. The present review describes the main components isolated from animal venoms that act on the cardiovascular system and presents a brief summary of venomous animals and their venom apparatuses.

Inhibitors of 11β;-Hydroxylase (CYP11B1) for Treating Diseases Related to Excess Cortisol by Weixing Zhu, Zhuo Chen, Qianbin Li, Guishan Tan, Gaoyun Hu (623-633).
The overproduction of cortisol is associated with many severe and life-threatening diseases, such as Cushing's syndrome (CS) and chronic wound healing. 11?-Hydroxylase (CYP11B1) is considered as an attractive target for treating these diseases, since it is a key enzyme responsible for the last step in cortisol biosynthesis. Nowadays, medical therapy has become increasingly important for CS patients, especially for those who are in need of surgery or suffer from surgery failure and those in early phases of radiation therapy. In clinic, steroidogenesis blockers including CYP11B1 inhibitors are utilized most frequently. Nevertheless, drugs that inhibit CYP11B1 are inevitable with side effects due to lack of selectivity over other steroidogenesis enzymes. Recent advances in the development of novel CYP11B1 inhibitors might overcome these limitations. In addition, the beneficial effects of down-regulation of cortisol levels to wound closure have been recently disclosed and have stimulated topical application of CYP11B1 inhibitors as a novel therapeutic strategy for curing chronic wounds. Herein, we provide a review of the current CYP11B1 inhibitors in clinic combating CS and the latest development of novel CYP11B1 inhibitors for treating CS and chronic wounds.