Current Medicinal Chemistry (v.23, #12)

Tribute to Dr. Allen B. Reitz by Allen B. Reitz (i-i).

Meet Our Editorial Board Member by Agapios Sachinidis (1185-1185).

The great progress of knowledge of both M. tuberculosis physiology and how human host and bacilli interact has provided fertile ground for improving diagnosis and cure of TB infection. Once M. tuberculosis has infected humans, it elaborates strategies for evading the risk to killing by the cells of the host immune system and by the anti-tuberculosis (anti-TB) agents employed to cure infection. These strategies give rise to a bacterial multidrug resistance (MDR) status. This stems firstly from genetic mutations targeting a constellation of drug-processing mechanisms that still need full identification, as drug efflux pumps and drug activating/ inactivating enzymes (genetic resistance). Secondly, from the bacterial adaptation to stressful environmental conditions by adopting a temporary dormancy state lasting for decades and characterized by indifference to anti-TB drugs (phenotypic resistance or tolerance). The clarification of the strategies elaborated for surviving by M. tuberculosis has brought to the identification in the last few years of a number of mycobacterial molecular targets worth to exploitation for the development of novel and powerful anti-TB drugs. These targets include drug-efflux pump systems, considered partly responsible for genetic multi-drug resistance, and several enzymes and pump systems, as well, that sustain the metabolic adaptations of M. tuberculosis in the host and give rise to its phenotypic drug resistance.

Immunoproteasome-Selective Inhibitors: A Promising Strategy to Treat Hematologic Malignancies, Autoimmune and Inflammatory Diseases by Roberta Ettari, Santo Previti, Alessandra Bitto, Silvana Grasso, Maria Zappalà (1217-1238).
The immunoproteasome is predominantly expressed in monocytes and lymphocytes and is responsible for the generation of antigenic peptides for cell-mediated immunity. Upon the exposure of inflammatory cytokines IFN-? and TNF-?, constitutive subunits can be replaced by the synthesis of the immuno-core particles ?1i, ?2i and ?5i. Recent studies demonstrated that the immunoproteasome function is not only limited to MHC class I presentation, but it is also implicated in a number of pathological disorders including hematological malignancies, inflammatory and autoimmune diseases. At present the commercially available proteasome inhibitors Bortezomib and Carfilzomib, which have been validated in multiple myeloma and other diseases, appear to target both the constitutive and immunoproteasomes indiscriminately. This lack of specificity may, in part, explain some of the side effects of these agents. In contrast, by selectively targeting the immunoproteasome, it may be possible to keep the antimyeloma and antilymphoma efficacy unchanged and, at the same time, to increase the therapeutic index. The aim of this review article is to discuss the most promising immunoproteasome core particle-selective inhibitors which have been developed in the recent years, with a particular attention to their structural features, mechanism of action and therapeutic application.

New Therapeutic Applications of Phosphodiesterase 5 Inhibitors (PDE5-Is) by Giovanni Ribaudo, Mario Angelo Pagano, Sergio Bova, Giuseppe Zagotto (1239-1249).
Background: Phosphodiesterase 5 inhibitors (PDE5-Is) sildenafil, vardenafil, tadalafil and the recently approved avanafil represent the first-line choice for both on-demand and chronic treatment of erectile dysfunction (ED). In addition to this, sildenafil and tadalafil, have also been approved for the treatment of pulmonary arterial hypertension. Due to its expression and localization in many tissues, PDE5 and its regulation has been reported to be involved in several other diseases. Objective: We aim to provide an updated overview of the emerging therapeutic applications of PDE5-Is besides ED, taking into account the latest ongoing research reports. Methods: We searched online databases (Pubmed, Reaxys, Scopus) to lay the bases for an accurate, quality criteria-based literature update. We focused our attention on most recent research reports, in particular when supported by pre-clinical and clinical data. Results: The regulation of PDE5 may influence pathological conditions such as, among the others, heart failure, cystic fibrosis, cancer, CNS-related diseases, diabetes and dysfunctions affecting male urinary/reproductive system. Conclusion: Sildenafil, vardenafil, tadalafil and the other chemical entities considered PDE5-Is showed overall positive results and significant improvements in the studied disease, thus some discordant results, in particular when comparing pre-clinical and clinical data, have to be pointed out, suggesting that further insights are needed especially to assess the exact molecular pathway underlying.

Anti-Psoriasis Agents from Natural Plant Sources by Marco Bonesi, Monica Rosa Loizzo, Eugenio Provenzano, Francesco Menichini, Rosa Tundis (1250-1267).
Psoriasis is a chronic inflammatory immune-mediated skin disease. It affects most races, does not have any sexual predilections and can manifest at any age of life. Psoriasis is more frequent in certain racial groups and geographical areas. For these reasons, both genetic and environmental factors could be considered. In this review, we discuss promising natural compounds, their molecular targets and mechanisms, which may help the further design of new anti-psoriasis agents. Literature documents the widespread use of herbal remedies worldwide, and the presence of some phytochemicals supports the efficacy of some botanical treatments. The research on natural products has greatly contributed to the progress in the treatment of skin diseases such as psoriasis and many of these compounds are now being used. Understanding the mechanism of these molecules will contribute to the development of more specific preventive strategies for the treatment of psoriasis.

Monofunctional Platinum (PtII) Compounds - Shifting the Paradigm in Designing New Pt-based Anticancer Agents by Shu Xian Chong, Steve Chik Fun Au-Yeung, Kenneth Kin Wah To (1268-1285).
Platinum (Pt)-based anticancer drugs, exemplified by cisplatin, are key components in combination chemotherapy. However, their effective use is hindered by toxicity and emergence of drug resistance. They bind to DNA and mainly form the Pt-GG diadduct, subsequently leading to apoptosis to mediate cell death. On the other hand, the Pt drug -proteins and -metabolites interactions, which involve the reaction between Pt and sulfur sites located in protein side chains and important bionucleophiles (e.g., glutathione), are responsible for the toxicity and drug resistance problem. Therefore, carefully designed coordinating ligands may provide the means of fine tuning the electronic environment around the core Pt atom and allow the resulting Pt compounds to bind with the DNA in a different manner. This may produce alternative cell death mechanisms in cancer cells, thereby circumventing Pt resistance. This article reviewed the recent development in monofunctional Pt complexes and their prospects in becoming a new generation of anticancer drugs.