Current Medicinal Chemistry - Volume 22, Issue 19, 2015

This review presents an in-depth overview of the modification of porphyrins with bioconjugates and their applications in medicine today. Porphyrin bioconjugates ranging from nucleotides to steroids are under active scrutiny. However, carbohydrates have been at the forefront of such research in recent years and offer significant potential. This is attributed to their own selectivity to lectins on the surface of cancer cells and their influence on the amphiphilicity of the porphyrin macrocycle. These characteristics and the tendency of porphyrin photosensitizers to accumulate in tumor tissues make glycoporphyrins promising candidates for use as photosensitizers. Thus, a detailed overview of the synthesis and biological evaluation of glycoporphyrins is given with a particular focus on their applications in photodynamic therapy and their future prospects as drug candidates have been reported.

The eukaryotic cell, with its organelle organization, represents a challenge for protein traffic. Contrary to what occurs in the endoplasmic reticulum, mitochondrial protein import is proposed to occur postranslationaly, as proteins are synthesized in cytoplasmic ribosomes and only then imported to the organelle. Because the diameter of the Tom and Tim pores is too narrow for the passage of a folded protein, it is assumed that polypeptides must be already in an unfolded, import competent, state for organelle entry. However, it has been suggested that mitochondria might be able to actively unfold proteins itself at the outer membrane. Here we discuss the influence of cytoplasmatic protein folding on mitochondrial import. Despite the contribution of active mitochondrial unfolding to protein import is not excluded, this mechanism is inconsistent with a number of experimental evidences. Accordingly, other alternative models for mitochondrial import are here discussed. Understanding the molecular constraints regulating this process is of crucial importance, since its failure can lead to a number of pathological situations.

Estrogen receptor-alpha positive (ER+) breast cancer constitutes 70-75% of the disease incidence. Tamoxifen has been the basis of endocrine therapy for patients with ER+ breast cancer for more than three decades. The treatment reduces the annual mortality rate of breast cancer by 31%, and remains the most effective targeted cancer therapy. However, approximately one-third of patients treated with adjuvant tamoxifen suffer from aggressive recurrent disease. Resistance to tamoxifen, thus, remains a major challenge in providing effective treatments for these patients. In an effort to overcome the resistance, intensive research has been conducted to understand the underlying mechanisms; this has resulted in the identification of complex factors/pathways contributing to tamoxifen resistance, including modulations of the ERsignaling, upregulation of a set of growth factor receptor networks (HER2, EGFR, FGFR, and IGF1R), alterations of the PI3K-PTEN/AKT/mTOR pathway, and an elevation of the NF-ΚB signaling. Despite these advances, our understanding of the acquired resistance remains fragmented and there is a lack of a platform to integrate these diversified molecular factors/ pathways into a cohesive mechanistic model. Nonetheless, at the cellular level, it is becoming increasingly recongnized that cancer stem cells (CSCs) are key in driving cancer metastasis and therapy resistance. Likewise, evidence is emerging for the critical contributions of breast cancer stem cells (BCSCs) to tamoxifen resistance. In this review, we will discuss these recent developments of BCSC-mediated resistance to tamoxifen and the contributions of those demonstrated molecular factors/pathways to BCSC expansion during the emergency of tamoxifen resistance.

Cyathane diterpenoids, occurring exclusively in higher basidiomycete (mushrooms), represent a structurally diverse class of natural products based on a characteristic 5-6-7 tricyclic carbon scaffold, including 105 members reported to date. These compounds show a diverse range of biological activities, such as antimicrobial, anti-MRSA, agonistic toward the kappa-opioid receptor, antiinflammatory, anti-proliferative and nerve growth factor (NGF)-like properties. The present review focuses on the structure diversity, structure elucidation and biological studies of these compounds, including mechanisms of actions and structure-activity relationships (SARs). In addition, new progress in chemical synthesis of cyathane diterpenoids is discussed.

Alzheimer’s disease (AD) is the most common type of dementia that leads to increasing death and mental disability among humans. Current therapy of AD mainly relies on the use of acetylcholinesterase inhibitors (AChEIs) or antagonists of N-methyl-D-aspartate receptors (NMDARs), which only relieve the symptoms of the disease but not halt its progression. Nevertheless, Traditional Chinese medicines (TCM) are highly prized as many bioactive components isolated from TCM are beneficial for treating AD. In this review, we summarize the latest information on TCM and the bioactive components according to their mechanistic role in alleviating AD. They act as modulators of α- and β-secretases, and inhibitors of betaamyloid (Aβ) aggregation. Some of them suppress Aβ-induced neuronal cytotoxicity and inflammation. Hence, this work has demonstrated the feasibility of applying TCM in AD therapy and the possibility of screening of constituents in TCM in the near future.