Recent Advances in Medicinal Chemistry

Non-steroidal anti-inflammatory drugs and aureolic acid group of anti-cancer drugs belong to the class of generic drugs. Research with some members of these two groups of drugs in different laboratories has unveiled functions other than those for which they were primarily developed as drugs. Here we have reviewed the molecular mechanism behind the multiple functions of these drugs that might lead to employ them for treatment of diseases in addition to those they are presently employed. The distinct advantage of using old drugs for alternate functions lies in their well-studied Absorption Distribution Metabolism Excretion and Toxicity (ADMET) profile.

3-Mercaptopyruvate sulfurtransferase (MST, EC.2.8.1.2) has two thioredoxin-dependent redox-sensing switches for the regulation of the enzymatic activity. One is an intermolecular disulfide bond formed between two subunits: A cysteine residue on the surface of each subunit was oxidized to form an intersubunit disulfide bond so as to decrease MST activity, and thioredoxin-specific conversion of a dimer to a monomer increased MST activity. Another switch is a catalytic site cysteine, which reversibly forms a low redox potential sulfenate so as to inhibit MST, and thioredoxin-dependent reduction of the sulfenate restored the MST activity. Concludingly, MST partly contributes to the maintenance of cellular redox homeostasis via exerting control over cysteine catabolism. This report is an updated version of the previous review [1] with small modifications.

For effective drug actions, concentrations of drugs in the target tissues must be sufficient enough with minimal levels of degradation and dilution. It is desirable that drugs are delivered to the target tissues efficiently. It is also preferable that drugs and therapeutic chemicals do not affect normal tissues. Various methods for drug delivery systems to enhance drug efficacy and reduce adverse drug effects, have been devised by the concomitant development of novel nanomaterials. Nanobiotechnology is one of emerging scientific area that has utilized a variety of inorganic and organic nanomaterials. Each inorganic nanomaterial has its own unique characteristics. In this review, we focus on the usefulness of inorganic nanomaterials, including iron oxide nanoparticles and gold nanoparticles. We also feature fullerenes and carbon nanohorns, both of which are composed entirely of carbons, as therapeutic vehicles, and summarize recent advances in this exciting field of nanoscience and its medical applications.

Tamoxifen, a selective estrogen receptor modulator (SERM), has been used for many decades as the “gold standard” adjuvant treatment for patients with hormonereceptor- positive early breast cancer. This drug, when administered for 5 years, reduces the risk for recurrence, contralateral breast cancer (BC) and death. These benefits have been observed up to 15 years and are independent of the patient’s age, menopausal status, nodal status, hormonal receptor status, and the use of adjuvant chemotherapy. The optimal duration of tamoxifen in the adjuvant setting has not been established yet, but it has been demonstrated that 5 years are better than shorter treatment while it is still unclear if a prolongation of the treatment for more than 5 years is worthwhile. Tamoxifen is usually well-tolerated, but important adverse events such as endometrial cancer, cerebrovascular accidents and thromboembolic events can occur, and the increase in absolute risk of these adverse events appears to be age-correlated.

In the last decade, third generation aromatase inhibitors (AIs), either steroidal (exemestane) or non-steroidal (anastrozole, letrozole), have shown to be an effective alternative to tamoxifen in postmenopausal patients with BC regardless of its stage. These agents act by blocking the aromatase enzyme which converts androgens into estrogens. Trials comparing AIs to tamoxifen in postmenopausal women with metastatic disease have shown a superiority of AIs over tamoxifen and a more favourable safety profile. In the adjuvant setting, AIs have been shown to be more effective than tamoxifen given for 5 years either in the up-front administration or after 2-3 years (early switch). Two randomised trials which have evaluated the two strategies of AIs administration have shown superimposable results in terms of efficacy with AIs given up-front or in sequence to tamoxifen. AIs seem to give benefits in comparison to placebo if given after 5 years (late switch) of tamoxifen. At the moment, therefore, the treatment decision should be based on individual factors such as risk of relapse, absolute benefit, and comorbidities.

The emergence of drug resistant strains of important human pathogens has made urgent the necessity of finding new targets and novel antimicrobial agents. One of the most promising targets is FabH. Here we summarize the progress made in the design of FabH inhibitors and the role played by the 3D-structure of the enzyme as well as by the modeling studies in the design of new FabH inhibitors.

Natural polyphenols are a wide class of secondary plant metabolites and represent an abundant antioxidant component of human diet. An important, but often neglected, group of natural polyphenols are tannins. This review offers a general description of chemistry of hydrolysable and condensed tannins (proanthocyanidins), and phlorotannins, the mechanisms of their antioxidation action, like free radical scavenging activity, chelation of transition metals, inhibition of prooxidative enzymes and lipid peroxidation. The mechanisms of action of inhibition of various enzyme systems, antibacterial, antiviral, antiprotozoal, anticarcinogenic, antidiabetic, hepatoprotective, cardiovascular system preventing, immunomodulation, antiallergic and anti-inflammatory effects as well as the absorption, metabolic fate and positive in vivo effects of tannins are enclosed.

Rho GTPases, which control processes such as cell proliferation and cytoskeleton remodeling, are often hyperexpressed in tumors. Several members, such as RhoA/B/C, must be isoprenylated to interact with their effectors. Statins, by inhibiting the synthesis of prenyl groups, may affect RhoA/B/C activity and represent a promising tool in anticancer therapy.

Chemoprevention is presumably one of most effective means to combat prostate cancer (PCa). Patients usually require more than a decade to develop a clinically significant PCa, therefore, an ideal target for chemoprevention. This review will focus on recent findings of a group of naturally occurring chemicals, carotenoids, for potential use in reducing PCa risk.

Various saponins, plant glycosides with favorable anti-tumorigenic properties, have been used to inhibit tumor cell growth by cell cycle arrest and apoptosis with IC⁵⁰ values of up to 0.2 μM. We describe several groups of saponins (dioscins, saikosaponins, julibrosides, soy saponins, ginseng saponins and avicins) currently investigated for their use in tumor therapy. We focus on cellular and systemic mechanisms of tumor cell growth inhibition both in vitro and in vivo, combinational approaches with saponins and conventional tumor treatment strategies, and successful syntheses of saponins. The increasing interest in saponins for tumor therapy is very promising for the future development of sophisticated anti-cancer drugs.

Traumatic spinal cord injury (SCI) is a major problem in clinical medicine. Etiology depends on several factors such as mechanism of injury and level of injury. The result is a very heterogeneous population of SCI patients. The characteristics of this pathology make for high levels of inter-patient variability. The validation of pharmacological neuroprotective therapy in the acute phase of traumatic SCI has been a treacherous road. Today, there are no FDA-approved therapies for medical management of acute SCI. The clinician depends on recommendations from the AANS/CNS suggesting that the use of methylprednisolone or GM-1 ganglioside is permissible but no real benefits have been observed. Several poorly designed prospective randomized controlled trials have obscured the real value of these promising therapies. This review systematically revises the current treatment protocols while also analyzing the validity and feasibility of the most cutting-edge basic and clinical treatment strategies. With this in mind, the objective is to inform healthcare providers of the present state of acute SCI pharmacological neuroprotective treatment and where is it going in the future.

HPLC is discussed as an essential tool for the analysis of tricyclic antidepressants in biological samples, providing clinicians with efficient fast and reliable methods to define individual optimum therapeutic concentrations in treatment of depressions. Additional information on mechanism of action, structure activity relationship and metabolism is provided. Sample preparation issues are discussed.

The estrogens play important role in the homeostatic maintenance of several target tissues including those in the mammary gland, uterus, bone, cardiovascular system, and brain. Most of estrogen’s action is thought to be mediated through its nuclear estrogen receptors, ER and ER, which are members of the nuclear receptor superfamily that act as ligand-induced transcription factors. Acting via its receptors, estrogen also plays an essential role in the development and progression of human breast cancer. The ER and progesterone receptor (PR), which is regulated by estrogen via ER, have been used as prognostic markers in the clinical management of breast cancer patients. However, the prognosis of a patient with ER+/PR+ breast cancer can be highly variable and a significant proportion of hormone receptor positive breast cancers do not respond to endocrine therapy. The identification of estrogen receptor target genes may improve our understanding of the role played by estrogens in breast cancer making it possible to better tailor hormone treatments and improve a patient’s response to hormonal therapy. In this review, we explore the literature for data regarding the identification of estrogen receptor-regulated genes in breast cancer cell lines and breast tumor biopsies using high throughput technologies such as serial analysis of gene expression (SAGE) and cDNA microarrays.

The plasma membrane redox (PMR) system is important for cell metabolism and survival; it is also crucial for blood coagulation and thrombosis. This review will give an update on the PMR system, with a particular regard to platelets, and on the role of antioxidant vitamins belonging to this system.

Most proteins fold into their native structure through defined pathways which involve a limited number of transient intermediates. Intermediates play a relevant role in the folding process; many diseases of genetic nature are in fact coupled with protein misfolding, which favours formation of stable inactive intermediate species of a protein. This review describes a number of diseases originated from protein misfolding and briefly discusses the mechanism(s) responsible, at molecular level, for these pathologies. It is also envisaged the native ⇄ molten globule transition since sometimes the conversion of the native form into a compact intermediate state permits a protein to carry out distinct physiological functions inside the cell. A non-native compact form of cyt c, for example, is involved in the programmed cell death (apoptosis) after that the protein is released from the mitochondrion; in addition, non-native forms of the protein are involved in some of the disorders attributed to amyloid formation.