Letters in Drug Design & Discovery - Volume 7, Issue 7, 2010

Identification of novel and selective anticancer agents remains an important and challenging goal in pharmacological research. In search of new compounds with strong antiproliferative activity and simple molecular structure, we have synthesized three different series of compounds in which different substituents were linked to the 3-amino position of the 2-(3', 4', 5'-trimethoxybenzoyl)-benzo[b]furan or benzo[b]thiophene ring system. These substituents, corresponding to acetyl/haloacetyl, α-bromoacryloyl and nitrooxyacetyl moieties had different electrophilic properties. The benzoheterocycle parent structures were selected because of their reported bioactivities. Compounds bearing a methoxy group at the 6-position of the benzo[b]furan skeleton, were identified as potent antiproliferative agents against the human chronic myelogenous K562 and murine L1210 leukemia cell lines. Comparison of positional isomers indicated that moving the methoxy group from the 6- to the 5- or 7-position yielded inactive compounds. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. The analysis of structure-activity relationships observed in the series of compounds described here may represent a platform for the design of more active molecules.

The synthesis of two new sulfated xanthones and two O-substituted benzophenones was carried out to evaluate for their inhibitory effect on growth of human tumor cell lines. The sulfation of 3,6-(2) and 3,4-dihydroxyxanthone (3) was accomplished using sulfur trioxide-pyridine to give, respectively, xanthone-3,6-O,O-bis(sulfate) (4) and xanthone- 3,4-O,O-bis(sulfate) (5). Treatment of 2,2',4,4'-tetrahydroxybenzophenone (6) with acetic acid and prenyl bromide furnished 2,2',4,4'- tetraacetoxybenzophenone (7) and (5-hydroxy-2,2-dimethylchroman-6-yl)(2'-hydroxy-4'-(tertpentyloxy) phenyl)methanone (8), respectively. Compounds 2-8 were tested for their effect on the in vitro growth of four representative human tumor cell lines: MCF-7 ER(+) (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), SF-268 (glioma), and A375-C5 (melanoma). Compounds 2 and 7-8 showed an inhibitory activity in the μM range.`

The acridinones represented by imidazo- and triazoloacridinones are a group of potential antitumor agents. The most active derivative, the antitumor imidazoacridone C-1311 expected to be used as a topoisomerase II poison, has been recently selected for extended preclinical and clinical trials. In the current study, one of the chemometric techniques, namely factor analysis was performed to model the relationships between several molecular structural descriptors and the ability of the selected acridinone derivatives to the noncovalent binding to DNA. The noncovalent binding to DNA was measured and expressed as DNA-duplexes stabilization. Factor analysis led to extract four main factors with eigenvalues higher than 1 and the total variance explanation was on the level of 84.5% (by the first three principal component). Among the molecular structural descriptors studied, the most significant influence was recognized for lipophilicity parameters, quantum-chemical parameters and electron affinity specifying parameters. Importantly, distribution of individual compounds on the plane determined by two principal components produced patterns in good agreement with their ability to noncovalent binding to DNA as well as with their chemical structures. Finally, the proposed FA-based strategy enabled to classify the tested acridinone derivatives in view of their ability to noncovalent interaction with DNA.

Doxorubicin and galactose were chemically conjugated to dextran by the carboxypropyl spacers and the conjugate was formulated into nanoparticle with free doxorubicin. The content of doxorubicin was as high as 17.2% in the nanoscale drug delivery systems (nano-DDSs) and the nanoparticle size was less than 190 nm. In an in vitro cytotoxicity experiment, the nano-DDSs had higher cytotoxicity than free DOX against the drug resistant HepG2 cells. In a human tumor xenograft nude mouse model, the nano-DDSs generated higher therapeutic effect than free doxorubicin. These promising data show a better anti-tumor efficacy on drug resistant HepG2 cells of nano-DDSs versus free doxorubicin, and warrant further studies in both animals and humans.

β-Secretase (BACE1, β-site APP cleaving enzyme) is one of the most challenging therapeutic targets in the field of Alzheimer's disease (AD) research. This enzyme catalyses the formation of neuronal amyloid β (Aβ) plaques, whose increased production is a key event in the initial pathogenesis of AD. As a consequence, many BACE1 inhibitors have been developed by several research groups. In the present work, after an analysis of tetraline derivatives reported in a Takeda patent, we designed and synthesized some analogues, making appropriate structural modifications, in order to try to improve the bioavailability features and the activities of Takeda compounds. All the new derivatives were tested on BACE1 with the TR-FRET (Time Resolved-Fluorescence Resonance Energy Transfer) technology and one of them showed a promising inhibitory activity value.

Broad-spectrum reactivator is an oxime which is able to reactivate acetylcholinesterase (AChE) inhibited by many kinds of organophosphate inhibitors of AChE, mainly nerve agents. There are many AChE reactivators (oximes) as suitable candidates for the broad-spectrum reactivator. Among them, oxime HI-6 is considered as number one, and due to its properties, it is recommended by many armies to be introduced as universal antidotal mean. In this study, we wanted to summarize that the designation “broad spectrum” is prerogative. For this purpose, in vivo evaluation of therapeutical dose of HI-6 (39.0 mg/kg) was performed. Soman, cyclosarin and tabun were used as the typical members of nerve agent family. According to the obtained results, oxime HI-6 did not sufficiently reactivate tabun-inhibited AChE. Brain AChE was also only partially protected. Based on these results, it seems that HI-6 in therapeutical dose has effect only in peripheral compartment.

A bioassay oriented fractionation of Gloeophyllum odoratum dry extract has led to the isolation of three active fractions. On the basis of spectroscopic data, MS spectroscopy and microanalysis a new tetracyclic triterpene: 3α- hydroxy-12β-acetoxy-lanosta-8,24-dien-29-oic acid, together with two known ones: trametenolic acid and 15α- hydroxytrametenolic acid, have been isolated, identified and proved to selectively inhibit thrombin but not trypsin.

Chagas' disease, infection caused by the protozoan Trypanosoma cruzi, is an important, social and medical ailment in the Latin America. This disease is endemic in 21 countries, mostly Latin America countries, with more than 300,000 new cases every year and about 16-18 million infected people. Current therapy is not effective in the chronic phase of the disease. Thus, new and better drugs are urgently needed. In this sense, the in vitro activity of primaquine (PQ) was reported. Based on this, peptide prodrugs of primaquine containing dipeptides - lysine-arginine (LysArg), phenylalanine-alanine (PheAla) and phenylalanine-arginine (PheArg) -- as carriers, were designed to be selectively cleaved by cruzain, a specific cysteine protease of T. cruzi. The prodrugs have shown to be active against tripomastigote forms according to this order: LysArg-PQ> PheAla-PQ> PheArg-PQ. The molecular mechanism of action considered a probable nucleophilic attack of the catalytic residue of cruzain (Cys25) on the respective prodrug amide carbonyl carbon, releasing PQ. In order to test this hypothesis, molecular modeling studies were performed, physicochemical parameters and stereoelectronic features calculated by using the AM1 semi-empirical method suggest that the amide carbonyl carbon is favorable for cleavage, where the LysArg showed the most electronic reactive and sterically disposable, leading to the prodrug release and action. In addition, the docking study indicates the occurrence of specific interactions between prodrugs and the pockets S1 and S2 of cruzain through the dipeptides carriers, being the distance between cruzain Cys25 and the amide carbonyl group related to the biological activity of the prodrugs.

New organotin (IV) based on 2-(thiophene-2-yl)acetic acid and 1-H-pyrazole-3-carboxylic acid derivatives 1-ae and 2a-e was prepared and characterized by IR, 1H and 13C NMR spectroscopy. These reactions were carried out under refluxing conditions using CHCl3 / EtOH (3:1) as solvents and 2:1 / 1:1 acid / metal oxide rations. The tin products were recuperated with moderate and good yields (55-85%). The Compounds (1b, 1e and 2e) were screened for their antitumor activities against two human tumor cell lines: HeLa, an epithelial cell from a fatal cervical carcinoma and HEK293, an embryonic kidney tumor. All three materials show an activity in vitro against these cell lines.

PEDF is a highly effective endogenous inhibitor of angiogenesis. However, the pathophysiological role of PEDF in therapeutic angiogenesis in the setting of limb ischemia is not fully understood. In this study, we investigated whether inhibition of PEDF could augment vascular endothelial growth factor (VEGF)-induced therapeutic angiogenesis and blood flow recovery in ischemic hindlimbs of precocious-aging klotho mice. Adductor PEDF mRNA levels in nontreated mice were dramatically decreased at day 3 and 7 after ischemic surgery, whereas those in VEGF-treated mice were significantly increased after the surgery. VEGF treatment caused a progressive improvement of limb perfusion after induction of ischemia, which was augmented by the simultaneous treatment with anti-PEDF Ab. Further, PEDF administration was found to significantly impair the recovery of limb perfusion and post-ischemic angiogenesis in VEGF-treated mice. However, anti-PEDF Ab administration did not enhance the VEGF-induced increase in capillary number in ischemic adductor muscles. Our present study suggests that blockade of PEDF is a novel therapeutic strategy for limb ischemia, which could potentiate the beneficial effects of VEGF on therapeutic angiogenesis.