Current Bioactive Compounds - Volume 10, Issue 3, 2014

This issue (Part II) is aimed for anyone who is interested or works with drug design research, with particular interest in Cancer. We attempt to convey something of the fascination of working in the field of heoretical and Computational Medicinal Chemistry, which overlaps knowledge of chemistry, computation, physics, biochemistry, biology and pharmacology, with emphasis on Cancer. Today, different targets are being explored, characterizing the multifactor aspect of the Cancer disease. Structural features as well as a comprehensive insight into the selectivity and activity of novel ligands are of considerable interest. Multidisciplinary, theoretical-computational medicinal chemistry tools can be used to select potential inhibitors. Euglobal G1 is an acypholoroglucinol (ACPL) with anticancer activity. Many ACPLs are of natural origin, can be found in species of Eucaluptus and exhibit a variety of biological activities. Quantum mechanics can be used to aid in the elucidation of structural, electronic properties, QSAR descriptors, conformations and hydrogen bonding abilities of the ACPLs. In this fifth work, high level quantum mechanical calculations (including HF-6-31g(d,p), DFT/b3lyp/6-31g(d,p), and 6-31g(d,p) with PCM) were performed including in vacuo, water and solvents differing by their polarity and hydrogen bonding abilities in order to investigate the molecular origin of the anti-cancer activity of the naturally-occurring ACPLs. Cancer is a serious world wide public health problem with alarming new cases in 2014. Skin cancer corresponds to a significant number of all malignant tumors. Melanoma is an aggressive neoplasm which in the process of metastasis can migrate to other areas of human body. Discovering new drugs is strategic for public health. Compounds which bind to the active site of tyrosinase and ribonucleotide reductase are potentially useful for the treatment of cancer. Tyrosinase is a key enzyme responsible for melanin production and consequently melanogenesis can be treated by blocking the activity of tyrosinase. Thiosemicarbazone and derivatives should bind to the metal in the active sites of enzymes. They are chelating ligands and can make donation of electrons to the metal atoms. In this sixth work, statistical analysis of density functional theory derived electronic parameters was used to predict the IC50 of ketonethiosemicarbazone derivatives and suggest candidates for anti-tumor agents. Heterogeneous ribonucleoprotein K (hnRNP K) is a protein found in mitochondria, nucleus and cytoplasm interacting with molecules involved in gene expression and signal pathways. Over expression of this protein should lead to colorectal, prostate breast and prostate cancer. Binding to nucleotides is the main interaction that triggers biological activity and is mediated by K homology domains. In this seventh work, the design of anti cancer ligands was evaluated in silico by docking with hnRNP K ligands, propositions of synthetic pathways as well as ligand-based biological activity spectrum evaluations. The Phosphoinositide 3-kinase (PI3K) enzyme is involved in control/signaling of important cell functions for RTK (receptor tyrosine kinase). These enzymes are involved in colorectal, breast and hepatocellular cancer. Overexpression of pathways may occur when gene mutation occurs. This results in an overexpression of tyrosine kinase pathways well as inactivation of the phosphate and tensin homolog (PTEN). In this eight work, studies were made of the known inhibitor in order to obtain profiles and pharmacophores. Filtering based on pharmacokinetic, physicochemical properties, activity and toxicity predictions as well as synthetic accessibility are used to investigate anticancer compounds.

Through a statistical analysis of electronic parameters obtained from DFT calculations we were able to predict the IC50 of ketonethiosemicarbazone derivatives. A quantitative study of the structure-activity with multiple linear regression was performed, using the electronic parameters: electron affinity, HOMO-LUMO energy gap, atomic charges of N, dipole moment and the lipophilicity of the compounds studied. The results indicate a good agreement with existing experimental data and allow us to suggest two new compounds as candidates for anti-tumor agents.

Phosphoinositide 3-kinase (PI3K) is an enzyme involved in the signaling and control of essential cell functions with respect to receptor tyrosine kinase (RTK), for which they are activated. PI3K is involved in some types of cancers in humans, as has been observed in breast, hepatocellular, and colorectal, where, in this latter one, it was only the gene whose mutation was showed. When this gene mutation occurs, overstimulation of this pathway may occur, resulting in an overexpression of tyrosine kinase pathway and inactivation of the Phosphatase and tensin homolog (PTEN), which is a tumor suppressor most frequently deregulated in cancer. The present study aimed to investigate the known inhibitors of PI3K-alpha, deposited in databases such as Binding DB and PDB, in order to draw a profile of physicochemical and pharmacokinetic properties of the most active inhibitors for this enzyme. From this, nine proposals of potential new PI3K inhibitors were developed, which were evaluated with respect to pharmacokinetic and physicochemical properties, activity and toxicity predictions, as well as synthetic accessibility. The results suggest that some of the proposals may be promising new PIK3 inhibitors, containing drug properties.

Cancer disease is characterized by genomic abnormalities and gene expression aberrations that leads to misregulated activity of apoptosis, angiogenesis and cell proliferation. Heterogeneous ribonucleoprotein K (hnRNP K) is a constitutive protein found in nucleus, cytoplasm and mitochondria of cells and interacts with molecules involved in gene expression and signal transduction pathways. It is believed that the over expression of hnRNP K leads to prostate, breast and colorectal cancer types. The binding to nucleotides is the main interaction that triggers biological activity and is mediated by its three K homology (KH) domains. Trying to optimize a phenylbenzamide derivative, already reported as an hnRNP K ligand, and design novel ligand candidates with anticancer activity, synthetically viable phenylbenzamide derivatives coupled to pyrimidine nucleosides were evaluated in silico by docking simulations with KH3 domain of hnRNP K. The cytosine nucleoside and phenylbenzamide moieties could be able of simulating the polar interactions performed by natural celular nucleotide ligands with ARG40 and ARG59, the main residues of KH3 domain responsible for nucleotide recognition. Ligand-based in silico biological activity spectrum evaluation also revealed that phenylbenzamide coupled to pyrimidine nucleosides are potential anticancer candidates.

Euglobal G1 (E-G1) is an acylphloroglucinol exhibiting anticancer activity. The phloroglucinol moiety is a derivative of jensenone and forms a chroman skeleton fused to a terpene unit. A computational study of E-G1 was carried out in vacuo at the HF/6-31G(d,p), DFT/B3LYP/6-31+G(d,p) and MP2/HF/6-31G(d,p) levels, and in solution at the DFT/B3LYP/6-31+G(d,p) level, with the PCM model and considering three solvents – chloroform, acetonitrile and water. All the computed molecular properties are reported and analysed in detail. The results in vacuo are compared with those of two other molecular structures, one (E-G2) differing by interchanged positions of the acyl chains with respect to E-G1 and proven non-active against cancer; the other (GX) differing from E-G1 only by the position of the bridge in the terpene unit. It appears reasonable to infer that the nature and positions of the two acyl chains in E-G1 have a role in determining its biological activity.

Herbal medicines are more and more worldwide used. This fact certainly presents serious problems for the potential human health risks. This is due to the fact that the laws in force generally do not provide for strict quality controls of herbal medicines to certify the concentration of compounds and elements that may be hazardous for human health, and sometimes very severe or even lethal. Heavy metals have a decidedly substantial part of the contaminants in herbal medicines. The present review proposes an exhaustive focus on what are the metals of interest, and what is the state of the art about analytical methodologies suitable to detect these toxic metals in herbal medicines. This review would also be a stimulus to solicit International Organizations to fill the gap of the lack of strict and comprehensive laws regulating the maximum allowable concentrations for an increasing number of contaminants in these matrices, especially considering their enormous consumption.

Since the time of Ehrlich (1854-1915) the antimicrobial activity of synthetic, non-chemotherapeutic compounds like phenothiazines and methylene blue, has been known. This article reports synthesis of some new 10Hphenothiazines, their sulfones and nucleosides, which have shown antimicrobial activity to a good extent against some selected strains of fungi, Gram positive and Gram negative bacteria leading us to a possibly potent class of antimicrobial agents. Reported 10H-phenothiazines were prepared using smiles rearrangement. These synthesized 10H-phenothiazines yield sulfones on oxidation with 30% hydrogen peroxide in glacial acetic acid and form nucleosides when treated with β-D-ribofuranose-1-acetate-2,3,5-tribenzoate (sugar). Structural assignment is done by spectral and elemental investigations.

Chemical investigation of the endophytic strain A1021B ascribed to the Fusarium incarnatum-equiseti species complex led to the isolation of a novel pyridine alkaloid related to fusaric acid. The structure was elucidated by 1D and 2D NMR experiments (1H, 13C, COSY, HSQC, CIGAR-HMBC, H2BC). The compound induced cytotoxic effects on six human cancer cell lines (SK-N-BE(2)-C, SH-SY5Y, A549, HepG2, HeLa, and MCF-7).

Callus culture of Cassia occidentalis L. was studied using nodal explants. Maximum callus induction was obtained on basal MS medium supplemented with 2, 4-D (5 mg/l) and Kinetin (0.02 mg/l). Sigmoid pattern of growth was obtained with highest growth index was 6th week and lowest at 2nd week of subculture. Analysis of plant parts revealed maximum content of flavonoids in leaves of C. occidentalis (1.95 mg/gdw) and minimum in stem (1.24 mg/gdw). Callus culture of C. occidentalis showed more total flavonoid content (2.01 mg/gdw) than the plant parts. Plant parts and in vitro cultures were studied for their antioxidant potential using DPPH assay. Among the plant parts the highest activity was found to be of leaves and lowest in seeds. The antioxidant potential of in vitro grown callus (IC50-155 µg/ml) was almost at par with leaves (IC50-150 µg/ml).