Medicinal Chemistry - Volume 12, Issue 3, 2016

Astrocytes exert multiple functions in the brain such as the development of blood–brain barrier characteristics, the promotion of neurovascular coupling, attraction of cells through the release of chemokines, clearance of toxic substances and generation of antioxidant molecules and growth factors. In this aspect, astrocytes secrete several growth factors (BDNF, GDNF, NGF, and others) that are fundamental for cell viability, oxidant protection, genetic expression and modulation of metabolic functions. The platelet derived growth factor (PDGF), which is expressed by many SNC cells, including astrocytes, is an important molecule that has shown neuroprotective potential, improvement of wound healing, regulation of calcium metabolism and mitochondrial function. Here we explore some of these astrocyte-driven functions of growth factors and their possible therapeutic uses in the context of neurodegeneration.

Since ancient time, India is a well known subcontinent for medicinal plants where diversity of plants is known for the treatment of many human disorders. Grewia asiatica is a dicot shrub belonging to the Grewioideae family and well known for its medicinally important fruit commonly called Falsa. G. asiatica, a seasonal summer plant is distributed in the forest of central India, south India, also available in northern plains and western Himalaya up to the height of 3000 ft. Fruits of G. asiatica are traditionally used as a cooling agent, refreshing drink, anti-inflammatory agent and for the treatment of some urological disorders. Recent advancement of Falsa researches concluded its antimicrobial and anti-diabetic activity. Since ancient time medicinal plants are traditionally used for the treatment of different diseases G. asiatica fruit is the edible and tasty part of the plant, now considered as a valuable source of unique natural product for the development of medicines which are used in different disease conditions like anti-diabetic, anti-inflammatory, anti-cancerous and antimicrobial. Now a days, G. asiatica is being used in different Ayurvedic formulation for the cure of different types of diseases. Different pharmacological investigations reveal the presence of phenols, saponnins, flavonoids and tannins compound in the fruits. Present review highlights the phytopharmacological and different traditional use of G. asiatica which is mentioned in ancient Ayurvedic texts. This review stimulates the researchers and scientists for further research on G. asiatica.

Detection of biomarkers for neurodegenerative disorders (NDDs) within brain tissues of Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients has always been hampered by our inability to access and biopsy tissue of key brain regions implicated in disease occurrence and progression. Currently, diagnosis of NDDs is principally based on clinical observations of symptoms that present at later stages of disease progression, followed by neuroimaging and, possibly, CSF evaluation. One way to potentially detect and diagnose NDDs at a far earlier stage is to screen for abnormal levels of specific disease markers within the peripheral circulation of patients with NDDs. Increasing evidence suggests that there is dysregulation of microRNAs (miRNAs) in NDDs. Peripheral blood mononuclear cells, as well as biofluids, such as plasma, serum, urine and cerebrospinal fluid, contain miRNAs that can be identified and quantified. Circulating miRNAs within blood and other biofluids may thus be characterized and used as non-invasive, diagnostic biomarkers that facilitate the early detection of disease and potentially the continual monitoring of disease progression for NDDs such as AD and PD. Plainly, such a screen is only possible with a clear understanding of which miRNAs change with disease, and when these changes occur during the progression of AD and PD. Such information is becoming increasingly available and, in the near future, may not only support disease diagnosis, but provide the opportunity to evaluate therapeutic interventions earlier in the disease process.

The two most common forms of dementia are Alzheimer’s disease (AD) followed by vascular dementia (VaD), together accounting for a whopping 60-80% of total dementia cases worldwide. Even though these diseases are recognized as ‘common’, they still remain underdiagnosed. Recent research suggests that AD and VaD are closely intertwined. The symptoms of AD and VaD can be similar and the two conditions can occur simultaneously. A large number of patients diagnosed with AD have also been reported with VaD-caused brain damage. Moreover, both the diseases have been reported to have similar risk factors. The overlap between these diseases is important because the lifestyle changes and medications prescribed to curb one of these diseases may also help curb the other. In the present review, we present an inclusive outline of parallelism between AD and VaD by exploring the potential commonalities at the mechanistic and therapeutic levels.

The use of natural products in drug discovery and development have an important history. Several therapeutic agents have been investigated during the biological screenings of natural compounds. It is well documented that plants are possibly the core of novel substances that led to the discovery of new, novel, and effective therapeutic agents. Therefore, in the last few decades, scientists were thoroughly attempting for the search of benevolent drugs to protect mankind from various diseases and discomforts. The diverse chemical structures of natural products are the key element of their success in modern drug discovery. Cholinesterase enzyme inhibitors (ChEI) are chemicals which inhibit the splitting of cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase). Acetyl cholinesterase (AChE) and butyrylcholinesterase (BChE) are two types of cholinesterase enzymes that have been identified in vertebrates that are responsible for Alzheimer’s disease and related dementia. Withanolides are affective plant secondary metabolites which inhibit acetylcholinesterase and butyrylcholinesterase enzyme and thus possibly will be the future drug for Alzheimer’s disease. By viewing the importance of natural products in drug discovery and development, we present here, the importance of withanolides in the treatment of Alzheimer’s disease. In this article, we also describe the classification and structural characterization of withanolides. This review comprises of 114 compounds.

For decades, adjuvant hormonal therapy has become the standard treatment of patients with estrogen receptor-positive breast cancer. Currently, the drugs available are GnRH agonists, selective estrogen receptor modulators, and aromatase inhibitors. The use of GnRH agonists represents a potentially reversible treatment that can restore ovarian function after chemotherapy. In premenopausal women, systemic therapy based on selective estrogen receptor modulators administration (e.g., tamoxifen) usually represents the standard adjuvant treatment. There are not sufficient data to recommend the routine addition of GnRH agonists to other endocrine therapies. In postmenopausal women, the disease-free survival was significantly prolonged in patients treated with aromatase inhibitor compared with those treated with tamoxifen, but the survival benefit was modest. Better results were obtained when the two drugs were administered sequentially. According to the ASCO guidelines, after 5 years of tamoxifen treatment, either tamoxifen or aromatase inhibitors therapy should be suggested for an additional 5 years. Unfortunately, most adverse events are consistent with estrogen deprivation and are common to all therapies, and the cumulative toxicity causes discontinuation and nonadherence to therapy in up to 50% of patients. Switching tamoxifen to an aromatase inhibitor may reduce adverse event incidence. Molecular-targeted therapy is useful in patients with advanced, relapsed or hormonal therapy-resistant tumors, usually as second- or third-line treatment. These drugs are usually added to aromatase inhibitors; however, currently, they have not yet been used in patients with early breast cancer.

Triple-negative breast cancer represents approximately 10-20% of all breast cancers and is associated with worse prognosis than other subtypes, with a higher risk of recurrence and death than other breast cancer types. This cancer is considered a heterogeneous disease comprising a spectrum of cancers with distinct activated biological pathways, various levels of chemosensitivity and different propensity for metastasis. Currently, chemotherapy represents the mainstay of medical treatment of these patients, because of the absence of well-defined molecular target agent, and we cannot use investigational classifications to determine appropriate systemic therapy outside of clinical trials. The specific adjuvant chemotherapy that may be most effective is still being determined but there is general consensus that regimens containing anthracyclines and taxanes are the standard approach for patient after surgery. Unfortunately, although some patients respond to treatment, other women have a high degree of intrinsic resistance to the same therapy. Moreover, in some studies, the pathological complete response was significantly higher in women treated with platinum-based regimen with respect to those treated with other chemotherapy regimen. The systematic evaluation of the predictive value of genomic alterations is critically important for a better comprehension of this entity and to develop new effective therapeutic strategies. In the future, a personalized therapeutic approach based on biology-oriented characteristics and molecular profiling may be effective for the patients.

The approach to the axilla is an evolving paradigm, and recognition of the complexity of breast cancer (BC) biology is changing treatment options. The sentinel lymph node biopsy (SLNB) technique is based on the excision and histological examination of the axillary lymph nodes(s), which is assumed to be the first one draining from the primary tumor. SLNB can accurately stage the axilla, and several trials have shown that there are no significant differences in local recurrence and overall survival between patients treated with or without axillary node dissection (ALND) after a negative SLNB. Surgical morbidity was significantly reduced in terms of rates of lymphedema and neuropathy, with reduced hospital stay and better quality of life after the SLNB procedure. ALND can safely be omitted in patients with 2 positive nodes who received conservative surgery and radiotherapy, while ALND is still recommended in clinically N1 BCs, in case of 3 positive nodes, and when the number of positive nodes would be crucial for the choice of chemotherapy. Micrometastatic disease can be safely managed with SLNB alone, and additional identification of micrometastases with immunohistochemistry does not affect disease-free survival or overall survival. An appropriate management of the axilla is crucial for the outcome of patients with early BC, and SLNB introduction into the clinical practice dramatically changed the surgical treatment, reducing morbidity without decreasing survival. A tailored approach should be suggested in each patient with BC, considering the biology of the tumor rather than nodal involvement.

Breast cancer is common in the elderly, as more than 50% of these tumors are diagnosed in patients aged 65 years or older. Elderly women may also delay reporting or underreport to their physician suspicious symptoms and lesions, so that breast cancer is more likely to be diagnosed at a more advanced stage, with putatively inferior outcomes. Adjuvant hormonal therapy has clear benefits for all women with hormone receptor-positive early breast cancer, despite the fact that it is still under-prescribed in elderly women, but the benefits of tamoxifen are more evident than that observed in younger patients. Aromatase inhibitors significantly prolong disease-free survival, reducing the risk of metastases and contralateral cancer compared with tamoxifen, and these benefits are greater in women aged ≥65 years. However, in case of a history of pathological fractures, arthritis or chronic musculoskeletal pain syndromes, tamoxifen still represents the preferred adjuvant option. In patients with a high risk of recurrence with hormonal therapy alone, the cardiac toxicity of nonanthracycline regimens should be taken into account. Trastuzumab-based therapy should be offered to most patients with HER2-overexpressing tumors. Older patients have an increased risk of disease recurrence and cancer-related mortality, because they are usually undertreated due to their age and longevity. Thus, a multidisciplinary geriatric approach is required, but the optimal management of these patients is still not well defined.

The prognosis of breast cancer is strongly influenced by the stage of the disease; therefore, it is essential that breast cancer lesions be diagnosed at the earliest stages. There is an urgent need to identify different biomarkers with a high accuracy for the early detection of this cancer to facilitate clinical management of the disease. A wide number of substances named serum tumor markers can be detected in the serum of patients with breast cancer, including tumor-associated proteins, cytokines, stimulating or inhibiting factors, autoantibodies to antigen tumor-associated substances and miRNAs. Despite ASCO and NACB recommendations, the routine use of breast cancer tumor markers by a significant proportion of oncologists is common, particularly after primary treatment of early tumors. The new promising circulating markers are HER2/neu, Trx 1, CSF1, autoantibodies against these tumor-associated antigens, and miRNAs, which are non-coding RNA molecules that regulate the translation of mRNA and control a number of biological processes, including oncogenic cells proliferation. The expression of single miRNA results in a miRNA signature, and is considered a potential biomarker for early breast cancer. However, additional studies are needed to identify its real usefulness.

Succinate dehydrogenase inhibitors (SDHIs) are fungicides with an amide bond widely used to control plant diseases caused by phytopathogenic fungi. Because of broad spectrum activity of new SDHIs, they have attracted wide attention from the research community. A series of structurally novel SDHIs with a bioactive 1,2,3-triazole moiety were designed and synthesized. Bioactivity screening showed that some of designed N-phenethyl-1,2,3-trizole-4-carboxyl amide analogues exhibited good fungicidal activities toward Sclerotinia sclerotiorum and Botrytis cinerea, while some of Nbenzyl- 1,2,3-trizole-4-carboxyl amide analogues exhibited good fungicidal activities toward Phytophthora capsici and Cercospora arachidicola. EC50 value of compound 5d against Cercospora arachidicola (6.6 μg/mL) was lower than that of chlorothalonil (12.3 μg/mL).

Background: As a virulence factor secreted into host cells, the Mycobacterium tuberculosis protein tyrosine phosphatase (MptpB) mediates the intracellular survival of M. tuberculosis. MptpB has become an attractive target for the development of new anti-tuberculosis drugs. Objective: In the present study, we assessed the inhibitory activity of marine fungus-derived bostrycin and its derivatives against MptpB in vitro. Method: The compounds were tested for their inhibitory effects on MptpB in vitro and the inhibition mode. The binding characteristics of inhibitors and MptpB were determined by microscale thermophoresis (MST). Results: Our data showed that one of the derivatives, compound 25 (IC50 = 64.6 ± 9.1 μM), possessed a greater inhibitory activity compared with bostrycin (IC50 = 327.6 ± 60.4 μM) and behaved as a non-competitive inhibitor. The binding characteristic of MptpB and compound 25 was determined by MST, exhibiting a moderate affinity with a KD constant of 5200 ± 1020 nM. Conclusion: We, for the first time, reported that bostrycin and one of its analogues exhibited inhibitory activity against MptpB, which possessed potential as novel agents against tuberculosis.