Current Medicinal Chemistry (v.23, #40)

Meet Our Editorial Board Member by Ramon Eritja (4505-4505).

Multitarget Opioid/Non-opioid Ligands: A Potential Approach in Pain Management by Rita Turnaturi, Giuseppina Arico, Giuseppe Ronsisvalle, Lorella Pasquinucci, Carmela Parenti (4506-4528).
Polypharmacology, or the associations between two or more drugs producing biological effects on two or more different sites of action could represent a possible therapeutic approach for the clinical management of acute and chronic pain. The multitude and complexity of neuronal mechanisms that contribute to pain transmission provide several possible targets for pharmacological intervention. Thus, multitarget ligands possessing opioid-opioid or non-opioid-opioid mechanisms of action are potential drug candidates for pain relief. In this perspective, the past medicinal chemistry paradigm “one-target, one-disease” has been reconsidered and converted into “one-molecule, multiple targets”. Multitarget ligands in comparison with cocktail drugs, besides an improved analgesic effect, display a more predictable pharmacokinetic and pharmacodynamic profile coupled to a less incidence of side-effects. Thus, they ameliorate patient compliance and decrease the risk of drug-drug interactions. In our previous review multitarget ligands with an opioid-opioid mechanism of action were described. Here, we deal with multitarget ligands with opioid-non opioid mechanism of action as potential drug candidates for the management of different pain states.

Mdm2 is a well studied oncogene and has been reported to be closely related to chemoresistance in different manners. In this article, we discuss the current knowledge of mdm2's function in drug resistance, the novel relationship between MDM2 and Akt phosphorylation, the role of Akt signaling pathway in epithelial-mesenchymal transition, and the positive correlation among MDM2, epithelial-mesenchymal transition and drug resistance. We propose a possible pathway by which MDM2 increases drug resistance through inducing epithelial-mesenchymal transition independent of p53. This pathway may play a significant role in the tumorigenesis and chemoresistance. By targeting MDM2, we can re-activate the function of p53, inhibit the epithelial-mesenchymal transition process and thus increase cancer cells sensitivity to chemotherapy. Thus, from p53-dependent and p53-independent aspects, it may present a better strategy for cancer treatment than targeting other genes.

Overview of the Formulations and Analogs in the Taxanes'; Story by Farah Yassine, Elia Salibi, Hala Gali-Muhtasib (4540-4558).
Taxanes are a family of diterpenes produced by the yews (Taxus genus) that are extensively used in chemotherapy. The family encompasses paclitaxel, docetaxel and the recently added cabazitaxel, all of which were proven to be promising anti-cancer drugs. Due to the over harvesting danger threatening the yew trees as well as the many challenges faced by taxane-based chemotherapy, new formulations, analogs and delivery systems are required. Here, we undertook a structured search of the bibliographical database PubMed for peerreviewed research papers relying on key words and date of publication and organized the information based on the method of taxane drug delivery. Papers retrieved were from journals with significant impact and comparable scope. A total of 126 papers were reviewed, 81 of which published work related to the taxane formulations and nanoparticles, and 22 focused on the analogs derived from the three taxanes. Although recent articles investigate the effectiveness of taxane formulations, most of these formulations are still at the pre-clinical level. However, many of the taxane analogs are currently in clinical trials as second line treatment of aggressive cancers or are used in combination with other chemotherapeutic drugs. The findings corroborate the importance of developing new drug delivery strategies and taxane analogs to improve the efficacy of currently used chemotherapeutic drugs. This finding is further supported by the FDA-approved formulation of paclitaxel that eliminates the need for toxic solvents for drug administration, and the docetaxel analog cabazitaxel which has decreased affinity for efflux pumps.

Protective Effects of Terpenes on the Cardiovascular System: Current Advances and Future Perspectives by Jorge M. Alves-Silva, Monica Zuzarte, Carla Marques, Ligia Salgueiro, Henrique Girao (4559-4600).
Background: Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide that seriously affect patient's life quality and are responsible for huge economic and social burdens. It is widely accepted that a plant-based diet may reduce the risk of CVDs by attenuating several risk factors and/or modulating disease's onset and progression. Plants are rich in secondary metabolites, being terpenes the most abundant and structurally diverse group. These compounds have shown broad therapeutic potential as antimicrobial, antiviral, anti-inflammatory and antitumor agents. Despite their popularity, scientific evidence on terpenes cardiovascular effects remains sparse, limiting their potential use as cardioprotective and/or cardiotherapeutic agents.

Objective: Bearing in mind the lack of comprehensive and systematic studies, the present review aims to gather the knowledge and some of the most scientific evidence accumulated over the past years on the effect of terpenes in the cardiovascular field with focus on CVDs namely ischemic heart disease, heart failure, arrhythmias and hypertension.

Method: Several popular search engines including PubMed, Science Direct, Scopus and Google Scholar were consulted. The bibliographic research focused primarily on English written papers published over the last 15 years.

Results: A systematic and comprehensive update on the cardiovascular effects of terpenes is provided. Moreover, whenever known, the possible mechanisms of action underlying the cardiovascular effects are pointed out as well as an attempt to identify the most relevant structure- activity relationships of the different classes of terpenes.

Conclusion: Overall, this review enables a better understanding of the cardiovascular effects of terpenes, thus paving the way towards future research in medicinal chemistry and rational drug design.


Synthetic Lipoproteins as Carriers for Drug Delivery by Gangliang Huang, Yang Liu, Hualiang Huang (4601-4608).
Synthetic lipoprotein is an effective carrier of targeted delivery for drugs. It has the very small size, good biocompatibility, suitable half-life, and specific lipoprotein receptorbinding capacity. Compared with the traditional natural lipoprotein, synthetic lipoprotein not only retains the original biological characteristics and functions, but also exhibits the excellent characteristics in drug delivery. Herein, the advantages, development, applications, and prospect of synthetic lipoproteins as drug carriers were summarized.