Mini Reviews in Medicinal Chemistry - Volume 10, Issue 8, 2010

Fullerenes, the third carbon allotrope, have emerged as agents which could revolutionize the treatment of many diseases. Fullerenes possess different biological applications like neuroprotective agents, antioxidants, anti-HIV activity, enzyme inhibition, antiapoptotic activity and the list is ever increasing. Moreover, they are being utilized as drug carrier systems and also for many non-biological applications like superconductors, catalysis and so on. Their size has made them promising agents for nanotechnology. This article aims at outlining the chemistry, properties and non-biological applications of fullerenes and their evolution to biological applications, thereby traversing their evolution from simple carbon allotropes to present day nano-medicinal agents.

Phthalimide analogues have been extensively used in medicinal chemistry owing to their wide range of applications as anti-convulsant, anti-inflammatory, analgesic, hypolipidimic and immunomodulatory activities. Number of anti-inflammatory phthalimide analogues have been synthesized as tumor necrosis factor-α (TNF-α) inhibitors. TNF-α plays a critical role in certain physiological immune systems and its over-production causes severe damage to the host. It promotes the inflammatory response leading to many of the clinical problems associated with auto-immune disorders like rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriasis and refractory asthma. One of the phthalimide derivatives, LASSBio-468, was recently demonstrated to inhibit TNF-α production induced by lipopolysaccharide (LPS), in vivo. Its potential against chronic inflammatory diseases was also witnessed. Another derivative, DIMP, showed good anti-androgenic activity. These analogues have also been employed for the synthesis of several kinds of important therapeutic synthones. However extensive research on the chemistry and biological activities of phthalimide analogues has been carried out and number of reports appeared, a compilation focusing on chemistry and biological activity is still needed. This review, concisely describes the chemical and therapeutic aspects of phthalimide derivatives.

Quantitative structure-activity relationships (QSAR) analyses have been attempted on a new set of 4- oxothiazolidines and 5-arylidines derivatives using linear free energy related (LFER) model of Hansch to explain the structural requirements for lipoxygenase inhibition. The QSAR study showed that successful correlation can be achieved for inhibitory activity of 4-oxothiazolidines and 5-arylidines (R>0.9, Q2>0.7). The result of the QSAR study suggests the bulky substituents in the thiazolidine nucleus will decrease the binding affinity of 4-oxothiazolidines derivatives towards lipoxygenase indicated by negative contribution of molar refractivity and connolly accessible area. The positive contribution of topological parameters (BI, MTI, CC and TVC) illustrates that increase in branching and presence of heteroatom are favorable for lipoxygenase inhibitory activity.

Cyclodextrins are pharmaceutical excipients used to enhance the solubility, stability, safety and bioavailability of drugs. Recent findings have shown them to display adjuvant activity in vaccine therapy and prophylactic and therapeutic activity in the treatment of several host-pathogen infections. This article focuses on their activity and mechanism of action.

Guanine-rich DNA sequences can form planar four-stranded structures via Hoogsteen hydrogen bonds. These sequences in telomeric DNA and some oncogenes have been identified as targets for novel anticancer drugs. Consequently, there is great current interest in developing small molecules that can facilitate the formation of, and stabilize G-quadruplexes as potent antitumor chemotherapeutic agents. Metal complexes with planar geometries and π-delocalised ligands are emerging as a new class of quadruplex DNA ligand with unique features for optimal binding. This review will summarize the different types of metal-based compounds that target G-quadruplexes and provide useful information on the design of small ligands.

In this review we have focused on the utilization of the biocompatible nanomaterials to reverse multidrug resistance (MDR), a major clinical obstacle in cancer therapeutics. Based on the comprehension of the mechanism of MDR and common reversal methods, the strategies and key properties of anti-MDR nanomaterials are explored and described to show how these features could provide the potential therapeutic effects that are not achievable with other modalities. The use of biocompatible nanoparticles with different designs and therapeutic approaches to reverse the MDR of cancer chemotherapeutics offers promising opportunities to benefit patients in the future.

The development of an adequate immune response against pathogens is mediated by molecular interactions between different cell types. Among them, binding of antigenic peptides to the Major Histocompatibility Complex (MHC) molecule expressed on the membrane of antigen presenting cells (APCs), and their subsequent recognition by the T cell receptor have been demonstrated to be crucial for developing an adequate immune response. The present review compiles computational quantum chemistry studies about the electrostatic potential variations induced on the MHC binding region by peptide's amino acids, carried out with the aim of describing MHC-peptide binding interactions. The global idea is that the electrostatic potential can be represented in terms of a series expansion (charge, dipole, quadrupole, hexadecapole, etc.) whose three first terms provide a good local approximation to the molecular electrostatic 'landscape' and to the variations induced on such landscape by targeted modifications on the residues of the antigenic peptide. Studies carried out in four MHC class II human allele molecules, which are the most representative alleles of their corresponding haplotypes, showed that each of these molecules have conserved as well as specific electrostatic characteristics, which can be correlated at a good extent with the peptide binding profiles reported experimentally for these molecules. The information provided by such characteristics would help increase our knowledge about antigen binding and presentation, and could ultimately contribute to developing a logical and rational methodology for designing chemically synthesized, multiantigenic, subunit-based vaccines, through the application of quantum chemistry methods.

Saxagliptin (BMS-477118), a recently FDA approved drug for the management of T2DM, has been developed by Bristol-Myers Squibb and AstraZeneca under the trade name Onglyza™. Saxagliptin is a nitrile-containing selective, potent, reversible and durable DPP IV inhibitor developed as an alternative second-line to Metformin in place of a sulphonylurea. Saxagliptin increases and prolongs the action of incretin hormones by inhibiting the DPP IV enzyme that inactivates incretins usually within minutes. Saxagliptin is well absorbed and has low plasma protein binding and displays slow-binding properties to DPP IV. Saxagliptin is metabolized in vivo to form an active metabolite (BMS-510849), which is twofold less potent than the parent molecule. The X-ray crystallography revealed that Saxagliptin is covalently bound to the DPP IV active site. In drug-naive patients with T2DM and inadequate glycemic control, once-daily Saxagliptin monotherapy for 24 wks demonstrated clinically meaningful with no weight gain and was generally well tolerated.

Despite the beneficial effect of the HAART, adverse reactions and drug interaction have been observed. Abnormalities in lipid and glucose metabolism make HIV-positive patients to high risk for the development of coronary heart disease and diabetes, respectively. Besides adverse reactions, drug interaction with other medication can also be observed. In fact, drug interaction may interfere in the periodontal therapy in HIV-infected individuals. For instance, fluconazole, ketoconazole, itraconazole, metronidazole, ciprofloxacin, midazolam and triazolam can interact with some antiretroviral medications, such as zidovudine, nevirapine and ritonavir. The aim of the current study was to show to periodontists and general dental practitioners the importance of understanding the drug interaction in HIV-infection in order to establish a better control during periodontal treatment.