Current Medicinal Chemistry - Volume 24, Issue 34, 2017

Lectins are a large group of proteins found in animals, plants, fungi, and bacteria that recognize specific carbohydrate targets and play an important role in cell recognition and communication, host-pathogen interactions, embryogenesis, and tissue development. Recently, lectins have emerged as important biomedical tools that have been used in the development of immunomodulatory, antipathogenic, and anticancer agents. Several lectins have been shown to have the ability to discriminate between normal cells and tumor cells as a result of their different glycosylation patterns. Furthermore, the specific binding of lectins to cancer cells has been shown to trigger mechanisms that can promote the death of these abnormal cells. Here, we review the importance of lectins-carbohydrates interactions in cancer therapy and diagnosis. We examine the use of lectins in the modification of nanoparticles (liposomes, solid lipid nanoparticles and other polymers) for anticancer drug delivery. The development of drug delivery systems (liposomes, alginate/chitosan microcapsules, alginate beads) carrying some antitumor lectins is also discussed. In these cases, the processes of cell death induced by these antitumor lectins were also showed (if available). In both cases (lectin-conjugated polymers or encapsulated lectins), these new pharmaceutical preparations showed improved intracellular delivery, bioavailability and targetability leading to enhanced therapeutic index and significantly less side effects.

Background: Natural medicine monomers (NMMs) isolated from plants have been recognized for their roles in treating different human diseases including cancers. Many NMMs exhibit effective anti-cancer activities and can be used as drugs or adjuvant agents to enhance the efficacy of chemotherapy and radiotherapy. Some NMMs, such as paclitaxel and camptothecin, have been extensively studied for decades and are now used as anti-cancer medicines due to their remarkable curative effects, such as inhibiting cancer cell proliferation and metastasis, and inducing cell death and differentiation. Methods: After extensively reviewing papers related to NMM studies in cancers, we grouped NMMs into six categories based on their chemical structures. We summarized the anti-cancer activities of these NMMs and current knowledge of molecular mechanisms for them to exert their functions. Results and Conclusion: Many NMMs from plants can effectively inhibit cancer cells with low or tolerable toxicity to patients. Some NMMs have been well-characterized for their anti-cancer activities and have already been used as clinical drugs or adjuvant agents; however, the mechanisms underlying the cancer suppressive activities of most NMMs remain poorly understood. Many NMMs can be used as initial structural scaffolds to design and develop novel therapeutics against cancers. This review summarizes reports related to signaling pathways mediated by different NMMs and can provide a theoretical basis for clinical application and new drug development of NMMs.

Background: Cancer metabolic reprogramming rekindles enthusiasm for the research of metabolic regulation in cancer drug resistance. A growing number of metabolic modifiers combined with cancer drugs obtain the expected efficacy in in vitro or in vivo studies, also in clinical trial studies, indicating a good potential of enhancing efficacy and reducing resistance. Hence, a comprehensive review on the attenuations of metabolic modifiers in cancer drug resistance is necessary for rational drug design and clinical cancer drug research. Methods: Cancer drug resistance and cancer metabolic reprogramming were used as the key words to collect publications with reference value in bibliographic databases. Specifically, the focused question is the advances of metabolic modifiers on cancer resistance improvement. Figures and tables were applied to analyze the interventions in accordance with the inclusion criteria. Results: This review summarized the advances of metabolic modifiers combined with cancer drugs in in vitro, in vivo and clinical trial studies, especially for cancer resistance improvement. The relationship between metabolic regulation and cancer resistance was elaborated, and the potential metabolic modifiers were embraced. Metabolic targeting activity or exerting synergism.s were also visualized in categorization in 4 figures and expatiated in 4 tables. Three typical metabolic modifiers, namely lonidamine, 2-DG and 3-BrPA, conferring attenuation to cancer resistance were elucidated systematically. Conclusion: Metabolic regulation is an intervention with targeted perturbation in a modest manner and reflects homeostasis balance. When combined with cancer drugs, the metabolic modifiers always show exciting potential with practical significance, enhanc

Background: Immunomodulation is one of the significant therapeutic strategies. It includes both stimulation and suppression of the immune system by a variety of substances called immunomodulators, designed to regulate the immune response of the organism against infections of varying etiology. An example of such a substance is tuftsin (TKPA) 3 (Fig. (1)). In this paper were included tuftsin derivatives, which were described over the years, their together with biological activity and clinical potential. Methods: We reviewed a bibliographic database to gather all the important information about the tuftsin peptide. We have delineated the significant information on the activity of the tetrapeptide itself and its derivatives. Analogs were divided because of their anti-tumor, anti-inflammatory, antimicrobial and anti-viral activity. Results: This paper describes eighty-six documents. Thirty-two of them concern on activity of tuftsin in the human organism. The remaining fifty-four describe peptide analogues and their properties, including eleven papers about the tuftsin-based peptides contained in the vaccines, nine papers representing anticancer activity of the tuftsin derivatives, twenty-six about antiinflammatory compounds, and five papers describing the antitumor activity of the tuftsin analogs. Conclusion: The findings of this review confirm the importance of the tuftsin and their derivatives. Most of these substances showed anti-tumor, anti-inflammatory or antibacterial activities. A large amount of the compounds may find use in vaccines. Tuftsin can also be used to prepare fusion proteins in the treatment of cancer and as carriers of many biologically active substances.

Background: 4-Functionalized isoxazolin-5-ones (isoxazolones) have attracted much attentions as precursors of functionalized building blocks because the multiple functionalities. These structural features facilitate the construction of large compound libraries that is important for development of new functional materials. However, the systematic review article dealing with nitroisoxazolone has not been published although they exhibit different reactivity from other functionalized isoxazolones. This review describes the interesting behavior of the nitroisoxazolone motif and its application to the synthesis of polyfunctionalized compounds. Methods: Peer-reviewed research literatures describing the chemistry of nitroisoxazolones were collected, and each paper was appraised using standard criteria. inclusion/exclusion criteria. The papers were analyzed, and divided according to the reaction patterns. Results: This review consists of two parts. In the former part, the chemistry of pyridinium salt of nitroisoxazolone is described, and in the latter part, chemistry of methylnitroisoxazolone is introduced. Sixty-eight papers were included in this review. Twelve papers deal with pyridinium salt or its ring-opened product, cyano-aci-nitroacetate. Nine papers mention the chemistry of methylnitroisoxazolones and derived nitroenamines and nitrile oxide. With regard to each chemistry, reaction mechanism and reactivity are discussed with citing related literatures. Conclusion: The findings of this review confirm the importance of nitroisoxazolones in synthetic chemistry for polyfunctionalized compounds, which are not readily available by alternative methods. This review will provide useful information and synthetic tools for many chemists studying synthetic chemistry and medicinal chemistry.

Background: Dementias and all related neurodegenerative diseases of the Central Nervous System (CNS) are a current issue arousing a great deal of interest in the international scientific community. This is due to the increasing number of patients suffering from these diseases. These pathologies represent a serious problem, not only concerning the quality of life of the patient, but in addition, the enormous economic efforts that society has to do for their treatment. There are currently a few strategies that are available in order to prevent the progression or to mitigate symptoms of the aforementioned diseases. This consideration is particularly true if we consider the specific pathology of Alzheimer's Disease (AD). Methods: We performed a literature search for peer-reviewed articles using different databases, such as PubMed or Scopus, and exploiting different keywords and different logical operators. Results: Ninety-eight papers were included in the review. Four papers give an overview of the background of the dementias all over the world. The remaining papers are focused on new possibilities of treatment with natural and semi-synthetic compounds for AD. Conclusion: The aim of this review is to give an overview of new and promising natural products and semi-synthetic compounds which could represent a source of “lead compounds” for the development of new potential drugs that could be a valid therapeutic strategy for the treatment of this pathology

Background: Design of inhibitors for HIV-1 reverse transcriptase inhibition (HIV-1 RT) is one of the successful chemotherapies for the treatment of HIV infection. Among the inhibitors available for HIV-1 RT, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have shown to be very promising and clinically approved drugs. However, the efficiency of many of these drugs has been reduced by the drug-resistant variants of HIV-1 RT. The aim of the current review is to provide a summary of lead optimization strategies from the 3D-QSARs studies on NNRTI class from the past 21 years (1995 to 2016). Methods: The conformation dependent-alignment based (CoMFA and CoMSIA) methods have been proven very successful ligand based strategy in the drug design. Here, CoMFA and CoMSIA studies reported for structurally distinct NNRTIs including thiazolobenzimidazole, dipyridodiazepinone, 1,1,3-trioxo [1,2,4]-thiadiazine, formimidoester disulfides, thiocarbamate, thiazolidinone derivatives, etc. have been discussed in detail. In addition, we explore the position of the functional groups that drive the protein-ligand interaction. Results: The structure-activity relationship (SAR) revealed from CoMFA and CoMSIA studies of these drug classes is not only in agreement with the structure-based method but also provides an efficient way of lead optimization. In addition to molecular docking experiments, protein-ligand interaction fingerprints were calculated in order to understand the common binding mode of NNRTI compounds. Conclusion: Overall, this review enlightens the protein-ligand interactions with a detailed SAR discussion for chemotypes. Such discussion will help medicinal chemist to gain a better understanding for the design of novel and promising NNRTI candidates.

Background: Thromboembolic events, principally stroke, represent one of the leading causes of morbidity and mortality among subjects with atrial fibrillation. Chronic kidney disease determines a further increase of thromboembolic events, bleeding and mortality and complicates the pharmacological management of patients with atrial fibrillation, mainly due to the side effects of antiarrhythmic and anticoagulant drugs with renal excretion. Apixaban is a new oral anticoagulant characterized by good bioavailability and renal elimination accounting for only 25%, showing a safety profile and effectiveness in patients with renal impairment. Objective: In this manuscript, we reviewed literature data on the use of apixaban in the management of non-valvular atrial fibrillation in patients with renal failure, in order to clarify an often-debated topic in clinical practice. Method: A PubMed search was performed on the terms atrial fibrillation, apixaban and renal failure with the aim of identifying relevant manuscripts, large randomized clinical trials, meta-analyses, and current guidelines. Results: Literature data show that apixaban could represent an interesting alternative to warfarin and other selective antagonists of coagulation factors in patients with impaired renal function. About the risk of major bleeding, apixaban appears to be safer than warfarin in the presence of any degree of renal failure. Conclusion: Apixaban show to be an effective anticoagulant in patients with atrial fibrillation, even superior to warfarin in reducing the risk of stroke and systemic embolism regardless of the presence of renal insufficiency. Moreover, Food and Drug Administration allows the use of apixaban in patients with end stage renal disease on hemodialysis.